《中国药典》微生物鉴定相关标准体系建立的回顾及展望

微生物污染在制剂、原辅料以及生产环境中具有分布不均匀、控制难度大等特点,控制不得当会严重影响着产品质量和用药安全。微生物鉴定在微生物的检验和控制工作中尤为重要,只有对微生物进行了适宜的鉴定,才能满足药品质量控制、偏差调查和溯源分析的需要,进而实现对药品的全生命周期质量控制。本综述全面回顾了《中国药典》收载的与微生物鉴定相关标准内容和检验方法,对比国外药典微生物鉴定相关部分标准要求,同时对《中国药典》微生物鉴定相关未来发展方向进行了展望,旨在为药品相关微生物检验工作提供信息,同时也为今后药典增修订相关通则及指导原则提供借鉴和参考。     

《中华人民共和国药典（2015年版）》（四部）中微生物检验相关通则的增、修订情况介绍

目的：介绍《中华人民共和国药典（2015年版）》（四部）中微生物检验相关通则的主要增、修订情况。方法：比较本版和前版药典相关内容的主要差异。结果：本版药典中微生物检验相关通则体现了新的检验理念,在检验技术、检验方法、环境设施、培养体系和质量管理等方面均进行了增、修订。结论：本版药典中微生物检验相关通则更趋完善,已与国际全面接轨。     

《中国药典》水分活度在非无菌产品微生物控制中的应用指导原则标准的增订

《中国药典》2020年版“水分活度在非无菌产品微生物控制中的应用指导原则”标准的增订依托药典委员会2017标准提高课题15展开。本文从指导原则的制定背景、研究思路、主要内容、相关说明和应用展望等5个方面综合介绍标准的制订过程。新增订的“水分活度在非无菌产品微生物控制中的应用指导原则”标准将为药品的微生物过程控制提供有力工具，是对当前药品微生物检测和控制体系的重要补充，对于推动我国药品微生物过程控制，进一步实现药品质量控制的科学化、合理化、国际化具有重要意义。     

国家药品标准修订公示信息

国家药典委员会近期对《中国药典》2015年版微生物通则拟增修订草案和第四批药用辅料等品种的拟增修订标准进行征求意见,拟增修订的品种及通则公示期限见下表,增修订内容详见国家药典委员会网站（http：//www．chp．org．cn）。请相关单位认真复核,若有异议,请尽快向国家药典委员会反馈意见。     

《中国药典》污染微生物鉴定相关标准体系建立的回顾及展望

微生物污染在制剂、原辅料以及生产环境中具有分布不均匀、控制难度大等特点,控制不当会严重影响产品的质量和用药安全。对污染微生物的鉴定在微生物的检验和控制工作中尤为重要,只有对污染微生物进行了适宜的鉴定,才能满足药品质量控制、偏差调查和溯源分析的需要,进而实现对药品的全生命周期质量控制。本综述全面回顾了《中国药典》收载的与微生物鉴定相关的标准和检验方法,对比国外药典与微生物鉴定相关的要求,对《中国药典》未来的微生物鉴定发展方向进行了展望,旨在为药品污染微生物检验工作者提供信息,同时也为今后药典相关通则及指导原则的增修订提供借鉴和参考。     

国家药品标准修订公示信息

国家药典委员会近期对2010年版药典附录“微生物限度检查法”拟修订内容及“胆汁槟榔维B,胶囊”等26个品种的拟修订标准进行征求意见,拟修订的品种及方法公示期限见下表,修订内容详见国家药典委员会网站（http：／／www．chp．org．cn）。请相关单位认真复核,若有异议,请尽快向国家药典委员会反馈意见。     

近年来我国药品微生物限度检查方法验证概况

对药品微生物限度检查进行方法学验证是现行《中国药典》的一大特点。药品生产企业必须对其所有进行微生物限度检查的品种进行微生物限度检查方法学验证，采用经过验证的方法检验，以保障得出可靠的结论。2005年10月国药典发[2005]98号文对各药品检验所进一步规定，药品在进行无菌检查及微生物限度检查时，应首先进行方法学验证，否则不能出具“符合2005版中国药典的规定”的结论。为此，广大药品微生物检验工作者做了大量的方法学验证工作，取得了可喜的成果。笔者根据所查阅的自2005年至2007年的相关文献资料，按消除抑菌作用需使用不同的处理方法，作如下归纳、综述。     

《中国药典》2015年版非无菌产品微生物限度检查：控制菌检查法解读与对策

目的:解读《中国药典》2015年版非无菌产品微生物限度检查控制菌检查法的主要增修订情况。方法:对比《中国药典》2015年版非无菌产品微生物限度检查控制菌检查法与《中国药典》2010版微生物限度检查法相关内容的主要差异。结果:《中国药典》2015年版非无菌产品微生物检查控制菌检查法在检查内容、检查方法、培养体系及质量控制理念等方面都做了较大修订。结论:《中国药典》2015年版将微生物限度检查控制菌检查法完善成为更加科学的与国际接轨的检查方法。     

中国药典2005年版微生物检定法的增修订情况及要点

介绍中国药典2005年版附录的抗生素微生物检定法的增修订情况，并与美国药典、英国药典、欧洲药典和日本药局方收载的抗生素微生物检定法进行比较。对中国药典2005年版微生物检定法新增的浊度法的原理及操作要点进行探讨。     

病毒消口服液微生物限度检查方法验证

目的：根据《中国药典》2005年版要求，对病毒消口服液的微生物限度检查进行方法验证。方法：培养基稀释法和薄膜过滤法。结果：采用薄膜过滤法处理样品符合《中国药典》2005版微生物限度检查的要求。结论：以薄膜过滤法验证试验结果为依据．确定本品微生物限度检查方法。     

痰热清注射液联合头孢哌酮舒巴坦治疗重症肺炎的临床研究

近年来,近红外光谱技术在中药制造领域得到广泛应用,已经成为中药制造过程分析的重要技术手段。通过建立注射用益气复脉（冻干）的质量标志物的近红外光谱分析方法,并结合工艺特点与质量要求确定过程分析技术应用方式,介绍该制剂生产过程近红外光谱分析系统的构建,详细描述该系统建立过程工艺监测点的筛选原则、检测方式的选择依据。同时,结合笔者工作经验,提出了将近红外光谱分析技术运用于中药制造过程质量控制中需注意的问题（包括系统构建的前期准备、近红外光谱分析方法开发与运行管理体系完善等）并进行讨论。     

环境分离菌在药品微生物检验中的应用

目的：讨论环境分离菌在药品微生物检验中的应用。方法：通过对各国药典、法规、指导原则、行业标准和行业指南等文件的梳理和分析,列出了环境分离菌在药品微生物检验中的应用建议和要求,并结合实例,进一步介绍了环境分离菌的应用范围。结果：各国药典和行业指南均要求或建议在消毒剂效能验证、抑菌效力检查、培养基方法适用性（培养基促生长试验）、检验方法的适用性、快速微生物检验方法和微生物检验替代方法验证等检验项目中增加使用环境分离菌（包括生产检验过程中人员、环境以及样品中分离菌）。结论：与标准菌株相比,环境分离菌更能够反映样品或环境实际存在微生物的情况,因此,在药品微生物检验中应用环境分离菌能够使检验结果对产品质量或环境做出更客观和科学的评价。可根据检验项目、药品的生产工艺和产品本身的特点,在风险评估的基础上选择适当的环境分离菌应用于检验过程中。     

荧光染色计数法在制药用水微生物限度检查替代方法可行性探讨

摘要 目的：考察荧光染色法在测定制药用水中微生物的方法适用性，评价荧光染色法在制药用水进行微生物限度检查的可行性。方法：按药品微生物检验替代方法验证指导原则的要求，从准确度、精密度、线性、定量限、范围等方面来进行定量检验的替代方法验证,并取实验室不同取样点纯化水样进行测试比较。结果：荧光染色法的各项验证参数均与药典方法相当，且不同取样点纯化水样的两种方法检测结果无显著差异。结论：本文的试验为荧光染色计数法后续在制药用水微生物检测中实际应用提供了参考。     

生产过程分析技术中所提倡使用的快速微生物检查法的作用

本篇文章讨论了FDA在其倡议的生产过程分析技术(PAT)中,采用快速微生物检查法对中间产品和成品进行质量监控的作用.文章中指出了依靠微生物生长而导致培养时间较长的检查法的缺点.作者在文中简要阐述了几种候选的快速微生物检查法.作为风险评估的手段,作者提出了生产中哪些关键的微生物检验环节可采用快速微生物检查法.     

Study progression in application of process analytical technologies on film coating

Film coating is an important unit operation to produce solid dosage forms, thereby, the monitoring of this process is helpful to find problems in time and improve the quality of coated products. Traditional methods adopted to monitor this process include measurement of coating weight gain, performance of disintegration and dissolution test, etc. However, not only do these methods cause destruction to the samples, but also consume time and energy. There have recently emerged the applications of process analytical technologies (PAT) on film coating, especially some novel spectroscopic and imaging technologies, which have the potential to real-time track the progress in film coating and optimize production efficiency. This article gives an overview on the application of such technologies for film coating, with the goal to provide a reference for the further researches.     

HER-2/neu targeted delivery of a nanoprobe enables dual photoacoustic and fluorescence tomography of ovarian cancer

Development of sensitive and specific imaging approaches for the detection of ovarian cancer holds great promise for improving survival of ovarian cancer patients. Here we describe a dual-modality photoacoustic and fluorescence molecular tomography (PAT/FMT) approach in combination with a targeted imaging probe for three-dimensional imaging of ovarian tumors in mice. We found that the selective accumulation of the HER-2/neu targeted magnetic iron oxide nanoparticles (IONPs) led to about 5-fold contrast enhancements in the tumor for PAT, while near-infrared (NIR) dye labeled nanoparticles emitted strong optical signals for FMT. Both PAT and FMT were demonstrated to be able to detect ovarian tumors located deep in the peritoneal cavity in mice. The targeted nanoprobes allowed mapping tumors in high resolution via PAT, and high sensitivity and specificity via FMT. This study demonstrated the potential of the application of HER-2/neu-targeted PAT/FMT approach for non-invasive or intraoperative imaging of ovarian cancer.From the Clinical EditorThis paper details the development of a dual-modality photoacoustic and fluorescence molecular tomography approach in combination with a targeted imaging probe for three-dimensional imaging of ovarian tumors in a mouse model, demonstrating the application of the HER-2/neu-targeted approach for non-invasive or intraoperative imaging of ovarian cancer.     

Regulatory considerations for development of bioanalytical assays for biotechnology products

Ligand-binding assays are the predominant method used for determination of concentrations of biotechnology products in serum or other matrices, as well as for the determination of antidrug antibodies in nonclinical and clinical studies. The challenges regarding the design and validation of these assays are well understood. The US FDA published a Guidance for Industry on Bioanalytical Method Validation and a Draft Guidance for Industry on Assay Development for Immunogenicity Testing of Therapeutic Proteins. The purpose of this article is to highlight specific elements in these guidance documents that should also apply to new methods, discuss the application of new generation ligand-binding methods and LC-MS for these purposes and provide a scientific and regulatory perspective on the specific challenges assessing the pharmacokinetics and immunogenicity of monoclonal antibodies.     

A Drosophila model to identify polyamine-drug conjugates that target the polyamine transporter in an intact epithelium

Polyamine transport is elevated in many tumor types, suggesting that toxic polyamine-drug conjugates could be targeted to cancer cells via the polyamine transporter (PAT). We have previously reported the use of Chinese hamster ovary (CHO) cells and its PAT-deficient mutant cell line, CHO-MG, to screen anthracene-polyamine conjugates for their PAT-selective targeting ability. We report here a novel Drosophila-based model for screening anthracene-polyamine conjugates in a developing and intact epithelium ( Drosophila imaginal discs), wherein cell-cell adhesion properties are maintained. Data from the Drosophila assay are consistent with previous results in CHO cells, indicating that the Drosophila epithelium has a PAT with vertebrate-like characteristics. This assay will be of use to medicinal chemists interested in screening drugs that use PAT for cellular entry, and it offers the possibility of genetic dissection of the polyamine transport process, including identification of a Drosophila PAT.     

Applications of process analytical technology to crystallization processes

Crystallizations of pharmaceutical active ingredients, particularly those that posses multiple polymorphic forms, are among the most critical and least understood pharmaceutical manufacturing processes. Many process and product failures can be traced to a poor understanding and control of crystallization processes. The Food and Drug Administration's process analytical technology (PAT) initiative is a collaborative effort with industry to introduce new and efficient manufacturing technologies into the pharmaceutical industry. PAT's are systems for design, analysis, and control of manufacturing processes. They aim to assure high quality through timely measurements of critical quality and performance attributes of raw materials, in-process materials, and final products. Implementation of PAT involves scientifically based process design and optimization, appropriate sensor technologies, statistical and information tools (chemometrics), and feedback process control strategies working together to produce quality products. This review introduces the concept of PAT and discusses its application to crystallization processes through review of several case studies. A variety of in situ analytical methods combined with chemometric tools for analysis of multivariate process information provide a basis for future improvements in modeling, simulation, and control of crystallization processes.