An Elemental Impurities Excipient Database: A Viable Tool for ICH Q3D Drug Product Risk Assessment

To support the practical implementation of the International Council for Harmonisation (ICH) Q3D guideline, which describes a risk-based approach to the control of elemental impurities in drug products, a consortium of pharmaceutical companies has established a database to collate the results of analytical studies of the levels of elemental impurities within pharmaceutical excipients. This database currently includes the results of 26,723 elemental determinations for 201 excipients and represents the largest known, and still rapidly expanding, collection of data of this type. Analysis of the database indicates good coverage of excipients relevant to real-world drug product formulations and tested element profiles consistent with ICH Q3D recommendations. The database includes the results from multiple analytical studies for an excipient and thus incorporates within it an indication of both excipient supplier and batch-to-batch variability as well as any variability associated with the different testing organizations and methods employed. The data confirm the findings of earlier smaller studies that elemental impurity concentrations in excipients are generally low and when used in typical proportions in formulated drug products are unlikely to pose a significant patient safety risk. The database is now in active use as one line of evidence in ICH Q3D risk assessments.     

Inhibition of N-Nitrosamine Formation in Drug Products: A Model Study

Nitrosamines, in the absence of toxicological data, are regarded as potential mutagens and need to be controlled at nanogram levels in drug products. Recent high profile product withdrawals have increased regulatory scrutiny of nitrosamine formation assessments for marketed products and for new drug applications. Formation of nitrosamine in drug product is possible when nitrite and vulnerable amines are present. Nitrite is often present as an impurity in excipients at ppm levels, whereas vulnerable amines, if present, stem mainly from the drug substance or its major impurities. In the event a drug product were to contain a major source of vulnerable amines (such as a moiety in the drug substance), it would be desirable to have an inhibitor which could be added to the formulation to minimize nitrosamine formation.  This work demonstrates, for the first time, that the inhibition of nitrosamine formation in oral solid dosage forms is indeed feasible with suitable inhibitors. Five inhibitors investigated (ascorbic acid, sodium ascorbate, α-tocopherol, caffeic acid, and ferulic acid) showed >80% inhibition when spiked at ∼1 wt% level. This work has also shown the potential use of amino acids (glycine, lysine, histidine) as inhibitors of nitrosamine formation in solution.     

N-Nitrosamine Formation in Pharmaceutical Solid Drug Products: Experimental Observations

The potential presence of N-nitrosamines in medicinal products has become a matter of concern for health authorities and pharmaceutical companies. However, very little information is available in published literature on N-nitrosamine formation within pharmaceutical drug products. In response, experiments were undertaken to test if secondary and tertiary amines present in solid drug products could undergo nitrosation due to the presence of nitrite in the excipients used in the manufacture of the drug product. This work focused on solid dosage forms exploring several model amines of varying chemical structure, solubility and pKa which were formulated using common excipients with and without added nitrite. Monitoring the formation of the N-nitrosamines after processing and upon stressed stability conditions showed that N-nitrosamine formation can occur in solid drug product formulations. The results show that the rate and extent of N-nitrosamine formation depend upon the solubility of the amine, level of nitrite, expected local acidity in water layers within the drug product and mode of processing. Our findings agree with the rank order of dosage form risk from the published EFPIA workflows for quality risk management of N-nitrosamine risks in medicines (EFPIA, 2022): amorphous > wet granulation > direct compression > dry blends. In all cases the level of N-nitrosamine formation in solid dosage forms plateaued at a level that was significantly lower than the maximum theoretical yield based on the level of nitrite present. Trace secondary amine impurities were shown to be a significantly lower risk relative to cases containing a secondary amine present at drug substance levels. A comparison of secondary and simple tertiary alkylamine reactivity showed the tertiary amine to be significantly less reactive with nitrite.     

Acrylonitrile: A Reevaluation of the Database to Support an Inhalation Cancer Risk Assessment

Acrylonitrile (ACN) is a monomer used extensively in the production of plastics, synthetic fibers, and rubber. In previous assessments conducted by IARC and the EPA, ACN was classified as a probable human carcinogen based on limited evidence in humans and sufficient evidence in laboratory animals. Specifically, EPA had determined that there was an association between ACN exposure and lung cancer based on a study by O'Berg (1980,J. Occup. Med.22, 245–252). However, a follow-up of this cohort (O'Berget al.,1985,J. Occup. Med.27, 835–840) shows no statistically significant excess of lung cancer mortality or incidence. Our evaluation of the more recent human database taken as a whole shows that there is not a clear association between ACN exposure and human cancer, yet the studies have insufficient power to be able to rule out a small increase. In laboratory rats, however, ACN has been shown to be clearly carcinogenic by the oral and inhalation routes. Applying the methodology of EPA's proposed 1996 cancer risk assessment guidelines to the rat tumor data, the estimated upper bound on the excess lifetime risk at continuous exposure to 1 μg/m³ACN is calculated to be in the range of 8.2 × 10⁻⁶to 1.1 × 10⁻⁵.     

Saporin-S6: A Useful Tool in Cancer Therapy

Thirty years ago, the type 1 ribosome-inactivating protein (RIP) saporin-S6 (also known as saporin) was isolated from Saponaria officinalis L. seeds. Since then, the properties and mechanisms of action of saporin-S6 have been well characterized, and it has been widely employed in the construction of conjugates and immunotoxins for different purposes. These immunotoxins have shown many interesting results when used in cancer therapy, particularly in hematological tumors. The high enzymatic activity, stability and resistance to conjugation procedures and blood proteases make saporin-S6 a very useful tool in cancer therapy. High efficacy has been reported in clinical trials with saporin-S6-containing immunotoxins, at dosages that induced only mild and transient side effects, which were mainly fever, myalgias, hepatotoxicity, thrombocytopenia and vascular leak syndrome. Moreover, saporin-S6 triggers multiple cell death pathways, rendering impossible the selection of RIP-resistant mutants. In this review, some aspects of saporin-S6, such as the chemico-physical characteristics, the structural properties, its endocytosis, its intracellular routing and the pathogenetic mechanisms of the cell damage, are reported. In addition, the recent progress and developments of saporin-S6-containing immunotoxins in cancer immunotherapy are summarized, including in vitro and in vivo pre-clinical studies and clinical trials.     

A Computer Program for Conducting Incinerator Risk Assessments

ABSTRACT

“This research was supported in part by an appointment to the Postgraduate Internship Program at the U.S. Army Center for Health Promotion and Preventive Medicine administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and USACHPPM.”

In 1994, the United States Environmental Protection Agency (USEPA) developed a screening methodology for conducting indirect exposure risk assessments for combustion facilities. The United States Army Center for Health Promotion and Preventive Medicine currently utilizes this methodology in conjunction with other USEPA guidance documents to perform human health risk assessments (HHRAs). The HHRAs require the development of complex human health models using spreadsheet software packages which estimate various media concentrations of contaminants in the environment. Since the quality assurance/quality control procedures associated with verifying the model's results are extremely time consuming, a computer program was developed using Microsoft Excef to minimize the amount of time needed. This discussion describes the 6 steps taken in developing this computer program, which are: (1) understanding the problem; (2) establishing the structure of each table in the spreadsheets; (3) developing an algorithm to solve the problem; (4) writing code; (5) running the program; and (6) testing the results. The automated process of having the computer predict health risk and hazards for each potentially exposed individual saves a tremendous amount of time because each calculated value is placed in the correct spreadsheet cell location. In addition to the time needed to develop human health spreadsheets, this program also minimizes the potential for reducing human error.     

Chitosan-Polycarbophil Interpolyelectrolyte Complex as an Excipient for Bioadhesive Matrix Systems to Control Macromolecular Drug Delivery

The in vitro performance of monolithic matrix systems containing the interpolyelectrolyte complex between chitosan and polycarbophil as excipient was evaluated in terms of their swelling, bioadhesive, and drug release properties. The different matrix systems showed excellent swelling properties without erosion, except for the formulation containing the highest quantity chitosan-polycarbophil complex that exhibited surface erosion in addition to swelling. All the different matrix systems exhibited significantly higher bioadhesive properties than the control group. Furthermore, they showed controlled insulin release without an initial burst release effect. However, only the matrix system that exhibited surface erosion in combination with swelling approached zero-order release.     

医院结构化药学决策知识库建设实践与应用成效分析

目的介绍上海交通大学附属第六人民医院构建结构化药学决策知识库的方法及实践。方法首先进行药学信息结构化梳理,然后构建结构化药学决策知识库,并进行设置测试和运行,最后建立药学决策知识规则库的5步循环更新机制,用于实现用药决策支持功能。在此基础上,比较2016-2018年上半年不合理医嘱比例和构成。结果按用法用量、禁忌症、适应证、相互作用、配伍、特殊人群用药等特征,对药品应用信息进行结构化梳理,并进行设置测试和试运行,经过药事管理与药物治疗学委员会讨论备案后上线,笔者所在医院结构化药学决策知识库共计包含用药规则10 000余条,涉及药品1500余种。该系统自2017年初上线,将不合理医嘱比例从6.02%下降到2.07%,同时显著改变不合理医嘱构成,促进药学服务质量提升。结论笔者所在医院结构化药学决策知识库不仅能提高医疗服务效率和质量,而且能提升医院用药安全的管理水平。     

Back to the Future: Inhaled Drug Products

Inhaled therapeutic aerosols continue to be an important treatment for asthma and pulmonary diseases. A variety of dosage forms are employed for different indications and demographics including pressurized or propellant-driven metered dose inhalers, dry powder inhalers, and nebulizers/nebules. Research and development in this field has shown remarkable innovation in the past decade. Important new drug products for the treatment of asthma, chronic obstructive pulmonary disease, cystic fibrosis, diabetes, and a range of neurological disorders have been developed. New devices in each of the dosage form categories also have been developed, and new formulation technologies have been adopted. Unlike many other dosage forms, as new inhaled products appeared few of the existing products were converted to generic form. This may be explained by the formulation and device complexity, the implications for degree of difficulty in obtaining regulatory approval, and the prevalence of intellectual property in the field. After the setback of the initial approval and subsequent withdrawal of the Exubera® -inhaled insulin, there appeared to be reluctance to consider the pulmonary route of administration for systemically acting agents, particularly peptides and proteins. However, recent product development activities and approvals suggest that attitudes may be changing in favor of systemic delivery following inhaled aerosol administration. The new inhaled drug technologies seem to be driving reconsideration of therapeutic categories for indications that were of interest at the inception of modern inhaled drug therapy in the past century. We should embrace the opportunity to use new drugs and technologies to go back to the future!.     

Lipophilic Conjugates of Drugs: A Tool to Improve Drug Pharmacokinetic and Therapeutic Profiles

Pharmaceutical Research - Lipophilic conjugates (LCs) of small molecule drugs have been used widely in clinical and pre-clinical studies to achieve a number of pharmacokinetic and therapeutic...     

Implications of In-Use Photostability: Proposed Guidance for Photostability Testing and Labeling to Support the Administration of Photosensitive Pharmaceutical Products,Part 1: Drug Products Administered by Injection

Basic guidance on the photostability testing of pharmaceuticals, designed to cover manufacturing and storage over shelf life, has long been established within ICH Q1(ICH,B¹⁰, but the guideline does not cover the photostability of drugs during or after administration (i.e., under conditions of use). To date, there has been a paucity of guidance covering the additional testing that would be of value during the clinical preparation and use of products. This commentary suggests a systematic approach, based on realistic “worst case” photoexposure scenarios and the existing ICH Option 1 and 2 light sources, to provide valuable data to pharmaceutical manufacturers and compounding pharmacists for the safe and effective use of photosensitive injection products. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:3888-3899, 2013     

美国FDA《植物药指导原则》要点和植物处方新药审批概况

第一个植物新处方药NDA申请的批准，标志着植物药有了新的起点。相信这个美国植物新处方药零的突破会更加激发人们从植物中开发新药的积极性。     

Arginine as an Excipient for Protein Freeze-Drying: A Mini Review

Successful development of marketable freeze-dried protein formulations requires adequate stabilization of the active biopharmaceutical ingredient. The choice of a stabilizer must therefore be based on sound knowledge of the physical and chemical properties of the excipients and specific needs of the protein component. Amino acids, such as arginine, have exhibit cryo- and lyoprotective effects similar to those of sugars and polymers and may therefore be considered to be an alternative approach to these established formulation strategies. The chemical structure and physicochemical characteristics of arginine are unique among amino acids and can provide additional benefits to freeze-dried protein formulations with regard to liquid and solid-state stability. This mini review provides a brief summary of research focused on the application of arginine in freeze-dried protein pharmaceuticals, including a discussion of its basic physical and chemical attributes as well as thermal behavior in the frozen and solid states. Mechanisms contributing to solid-state stabilization by arginine are discussed in the context of available stability studies on arginine-containing protein formulations. This mini review seeks to deepen the understanding of the opportunities and challenges associated with arginine-based preparations for freeze-dried protein pharmaceuticals.     

CDER Risk Assessment Exercise to Evaluate Potential Risks from the Use of Nanomaterials in Drug Products

The Nanotechnology Risk Assessment Working Group in the Center for Drug Evaluation and Research (CDER) within the United States Food and Drug Administration was established to assess the possible impact of nanotechnology on drug products. The group is in the process of performing risk assessment and management exercises. The task of the working group is to identify areas where CDER may need to optimize its review practices and to develop standards to ensure review consistency for drug applications that may involve the application of nanotechnology. The working group already performed risk management exercises evaluating the potential risks from administering nanomaterial active pharmaceutical ingredients (API) or nanomaterial excipients by various routes of administration. This publication outlines the risk assessment and management process used by the working group, using nanomaterial API by the oral route of administration as an example.     

Recommendations for the Bioanalytical Method Validation of Ligand-Binding Assays to Support Pharmacokinetic Assessments of Macromolecules

PURPOSE: With this publication a subcommittee of the AAPS Ligand Binding Assay Bioanalytical Focus Group (LBABFG) makes recommendations for the development, validation, and implementation of ligand binding assays (LBAs) that are intended to support pharmacokinetic and toxicokinetic assessments of macromolecules. METHODS: This subcommittee was comprised of 10 members representing Pharmaceutical, Biotechnology, and the contract research organization industries from the United States, Canada, and Europe. Each section of this consensus document addresses a specific analytical performance characteristic or aspect for validation of a LBA. Within each section the topics are organized by an assay's life cycle, the development phase, pre-study validation, and in-study validation. Because unique issues often accompany bioanalytical assays for macromolecules, this document should be viewed as a guide for designing and conducting the validation of ligand binding assays. RESULTS: Values of +/- 20% (25% at the lower limit of quantification [LLOQ]) are recommended as default acceptance criteria for accuracy (% relative error [RE], mean bias) and interbatch precision (%coefficient of variation [CV]). In addition, we propose as secondary criteria for method acceptance that the sum of the interbatch precision (%CV) and the absolute value of the mean bias (%RE) be less than or equal to 30%. This added criterion is recommended to help ensure that in-study runs of test samples will meet the proposed run acceptance criteria of 4-6-30. Exceptions to the proposed process and acceptance criteria are appropriate when accompanied by a sound scientific rationale. CONCLUSIONS: In this consensus document, we attempt to make recommendations that are based on bioanalytical best practices and statistical thinking for development and validation of LBAs.     

A New Model for Toxic Risk Assessments: Construction of Homozygous Rapid and Slow Acetylator Congenic Syrian Hamster Lines

Abstract

Summary: Humans and other mammals exhibit a polymorphic expression for acetylation capacity that can confer genetic predisposition to drug and chemical toxicities. Inbred Syrian hamsters are a particularly suitable animal model for the human trait, in part because of a clearly defined codominant expression of two alleles (r, rapid acetylator; s, slow acetylator) at a single gene (Pat) locus. Homozygous rapid (Pat^r/Pat^r), heterozygous intermediate (Pat^r/Pat^s), and homozygous slow (Pat^s/Pat^s) acetylator congenic Syrian hamster lines were constructed by a selective backcross method. The construction of these congenic inbred lines will enhance efforts to investigate the unique role of the acetylator gene locus in toxic risk assessments of arylamine xenobiotics.