药学学报

Name of guideline	Issuing date	Ref.
Guideline for quality control study of TCM crude drugs of new TCMs (trial)	Oct. 2020	[36]
Guideline on processing study of prepared slices/decoction pieces for new TCMs (trial)	Oct. 2020	[36]
Guideline for quality standard study of new TCMs (trial)	Oct. 2020	[36]
Guideline for pharmacognosy, chemistry, manufacturing and controls (PCMC) study in various phases of study on new TCMs (trial)	Nov. 2020	[37]
Guideline for homogenization studies of TCMs (trial)	Nov. 2020	[38]
Guideline for requirements for PCMC documentation for the communication meetings during the development of new TCMs (trial)	Nov. 2020	[39]
Guideline for study on manufacturing process of compound preparations of TCMs (trial)	Nov. 2020	[40]
Guideline for study on bioassay of TCMs (trial)	Dec. 2020	[41]
Guideline for quality study of new TCMs (trial)	Jan. 2021	[42]
Guideline for studies on PCMC changes to marketed TCMs (trial)	Apr. 2021	[43]
Guideline for PCMC study of compound preparations of TCMs managed in accordance with Directory of Ancient Classic Formulas of Traditional Chinese Medicines (trial)	Aug. 2021	[44]
Guideline for study on samples for toxicology studies on new TCMs (trial)	Jan. 2022	[45]
Guideline for study on TCMs with identical name and formula (to marketed TCMs) (trial)	Dec. 2022	[46]
Guideline for study on the preparation of investigational medicinal product of new TCMs (trial)	Jul. 2023	[47]
Guideline for PCMC study on other compound preparations of TCMs originated from ancient classic formulas (trial)	Jul. 2023	[48]
Guideline for PCMC study of new compound preparations of TCMs based on human experience (trial)	Oct. 2023	[49]
Guideline for stability testing of TCM preparations (Trial)	Feb. 2024	[50]
Guideline for characteristic/fingerprint chromatograph for TCMs (trial)	Feb. 2024	[50]
Guideline for application dossiers compilation for PCMC of compound preparations of TCMs managed in accordance with Directory of Ancient Classic Formulas of Traditional Chinese Medicines (trial)	Apr. 2024	[51]
Guideline for the study on improved new TCMs	May. 2024	[52]
Guideline for quality control study in production process for oral TCM preparations (trial)	Jun. 2024	[53]

Name of guideline	Issuing date	Ref.
Guideline for quality control study of TCM crude drugs of new TCMs (trial)	Oct. 2020	[36]
Guideline on processing study of prepared slices/decoction pieces for new TCMs (trial)	Oct. 2020	[36]
Guideline for quality standard study of new TCMs (trial)	Oct. 2020	[36]
Guideline for pharmacognosy, chemistry, manufacturing and controls (PCMC) study in various phases of study on new TCMs (trial)	Nov. 2020	[37]
Guideline for homogenization studies of TCMs (trial)	Nov. 2020	[38]
Guideline for requirements for PCMC documentation for the communication meetings during the development of new TCMs (trial)	Nov. 2020	[39]
Guideline for study on manufacturing process of compound preparations of TCMs (trial)	Nov. 2020	[40]
Guideline for study on bioassay of TCMs (trial)	Dec. 2020	[41]
Guideline for quality study of new TCMs (trial)	Jan. 2021	[42]
Guideline for studies on PCMC changes to marketed TCMs (trial)	Apr. 2021	[43]
Guideline for PCMC study of compound preparations of TCMs managed in accordance with Directory of Ancient Classic Formulas of Traditional Chinese Medicines (trial)	Aug. 2021	[44]
Guideline for study on samples for toxicology studies on new TCMs (trial)	Jan. 2022	[45]
Guideline for study on TCMs with identical name and formula (to marketed TCMs) (trial)	Dec. 2022	[46]
Guideline for study on the preparation of investigational medicinal product of new TCMs (trial)	Jul. 2023	[47]
Guideline for PCMC study on other compound preparations of TCMs originated from ancient classic formulas (trial)	Jul. 2023	[48]
Guideline for PCMC study of new compound preparations of TCMs based on human experience (trial)	Oct. 2023	[49]
Guideline for stability testing of TCM preparations (Trial)	Feb. 2024	[50]
Guideline for characteristic/fingerprint chromatograph for TCMs (trial)	Feb. 2024	[50]
Guideline for application dossiers compilation for PCMC of compound preparations of TCMs managed in accordance with Directory of Ancient Classic Formulas of Traditional Chinese Medicines (trial)	Apr. 2024	[51]
Guideline for the study on improved new TCMs	May. 2024	[52]
Guideline for quality control study in production process for oral TCM preparations (trial)	Jun. 2024	[53]

保障功效稳定的中药制剂质量控制体系

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顾杰 ¹^,² , 周思源 ¹^,²^,^* , 阳长明 ¹^,²^,^* , 申向荣 ¹^,² , 王若瑾 ¹^,²

药学学报 | 综述 2025,60(6): 1682-1691

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药学学报 |综述 2025 , 60 (6) : 1682 -1691

保障功效稳定的中药制剂质量控制体系

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顾杰¹^,², 周思源¹^,²^,^*, 阳长明¹^,²^,^*, 申向荣¹^,², 王若瑾¹^,²

作者信息

¹国家药品监督管理局药品审评中心, 北京 100076

²药品监管科学全国重点实验室, 北京 100076

通讯作者:

周思源, E-mail: zhousiyuan@cde.org.cn

阳长明, E-mail: yangchm@cde.org.cn

作者简介:

作者贡献:

顾杰、阳长明负责文章撰写、修改; 周思源、阳长明负责文章整体构思、布局和修改; 申向荣、王若瑾负责文章翻译和核校。

Quality control system ensuring consistent efficacy for traditional Chinese medicine preparations

Jie GU¹^,², Si-yuan ZHOU¹^,²^,^*, Chang-ming YANG¹^,²^,^*, Xiang-rong SHEN¹^,², Ruo-jin WANG¹^,²

Affiliations

¹Center for Drug Evaluation, National Medical Products Administration, Beijing 100076, China

²State Key Laboratory of Drug Regulatory Science, Beijing 100076, China

出版时间: 2025-06-12 doi: 10.16438/j.0513-4870.2025-0075

文章导航

摘要

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中药制剂兼具中医属性和药品属性, 需要兼顾中医临床长期用药习惯与药品属性的一般要求。保证制剂质量稳定是药品质量属性的基本要求, 也是保障其功效稳定的基础。基于中药天然来源、组成复杂的药物成分、独具特色的理论体系及来源于临床实践的安全性有效性等特点, 以化学成分进行定性和定量的质量控制模式实际难以客观评价和有效控制中药的质量, 如何保证中药制剂质量稳定进而保障其功效稳定是中药监管科学亟待解决的产业技术问题, 也是中药质量研究及评价的关键点和难点。自药品审评审批制度改革以来, 药审中心深入开展中药监管科学研究, 基于中药制剂特点、研发规律和生产实际, 尊重中医药用药经验和用药习惯, 将传统中药质量控制理论和经验应用于中药制剂质量控制, 并践行“质量源于设计”“全过程质量控制”等现代药品质量控制理念, 研究建立符合中药特点的中药技术审评体系, 发布了一系列中药药学研究技术指导原则。本文根据中药制剂特点及其质量控制要求, 梳理分析上述中药药学指导原则, 认为上述系列指导原则兼顾了中医临床长期用药习惯与药品关于安全、有效、质量可控的一般属性要求, 为保障中药制剂药物成分基本稳定、减小批间质量波动提供了指导, 符合中药制剂特点、实际和质量控制要求, 构成了保障中药制剂功效稳定的质量控制体系。

关键词

中药 / 中药制剂 / 中药监管科学 / 质量控制体系 / 保障功效稳定

Abstract

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The essential requirements of traditional Chinese medicine (TCM) and its identity of drug make it necessary to treat TCM preparations with considerations of clinical practice routines and drug attributes. Quality stability is an elementary drug quality attribute and lays the foundation to guarantee a consistent traditional Chinese medicines (TCMs) efficacy. In light of the complex ingredients of natural sources, the unique medical theory and the safety & efficacy proof from clinical practices, it's hardly possible to objectively evaluate and effectively control TCMs quality using qualitative and quantitative methods with chemical components as references. To ensure efficacy consistency, stable TCMs quality is a prerequisite and thus is regarded as an industrial focus in earnest need of regulatory attention and also the key points and challenge of TCM quality study and assessment. Since the initiation of drug evaluation system reform, Center for Drug Evaluation has devoted to TCM regulatory science study and issued a series of guidelines. These guidelines are established based on characteristics of TCM preparations, scientific principles and actual production situations. Meanwhile, traditional thinking and experience in TCM quality control and modern theories such as "Quality by Design" and "Whole-process Quality Control" were also adopted. As the characteristics of TCM preparations and quality control requirements, this paper analyses the above guidelines, and concludes that these documents have combined TCM clinical experience and drug attributes of safety, efficacy and quality control. They provide guidance for ensuring basic stability of TCM ingredients and reducing batch-to-batch variations. A quality control system that meets the above requirements is established to ensure consistent efficacy of TCM preparations.

Key words

traditional Chinese medicines (TCMs) / TCM preparation / TCM regulatory science / quality control system / ensure consistent efficacy

引用本文

顾杰, 周思源, 阳长明, 申向荣, 王若瑾. 保障功效稳定的中药制剂质量控制体系. 药学学报, 2025 , 60 (6) : 1682 -1691 . DOI: 10.16438/j.0513-4870.2025-0075

Jie GU, Si-yuan ZHOU, Chang-ming YANG, Xiang-rong SHEN, Ruo-jin WANG. Quality control system ensuring consistent efficacy for traditional Chinese medicine preparations[J]. Acta Pharmaceutica Sinica, 2025 , 60 (6) : 1682 -1691 . DOI: 10.16438/j.0513-4870.2025-0075

正文

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源于传统中医药理论和临床实践的中药复方及其制剂是传统中药防病治病的基本特色和主要用药方法, 一般按照中医药“理法方药”诊治理论及“君臣佐使”组方原则进行个性化组合用药并应用于临床^[1], 是中医药文化传承创新的重要载体^[2], 也是中药新药研究和申报的主要类别和方向^[3]。在现代医学理论和科学思维的框架下, 中医药思维模式与现代科学思维、中医药文化理念与现代医学理念之间不可避免地存在着碰撞^[4], 中医药的传承创新发展也必然要直面中药个体用药经验与满足群体用药需求(中成药) 之间、中医临证处方用药习惯与药品属性要求之间的矛盾和挑战。中药制剂作为具有中国特色的特殊药品, 因其独具特色的理论体系及来源于临床实践的安全性有效性等特点, 兼具中医属性和药品属性^[5], 因此, 将临床应用安全有效的方剂转化为安全有效的中药制剂, 需要兼顾中医临床长期用药习惯与药品关于安全、有效、质量可控的一般属性要求^{[6, 7]}, 研究解决中药制剂面临的现代药品属性和传统中医属性之间的巨大冲突与挑战。一方面, 中药制剂具有丰富的中医属性^[8], 蕴含着中医药理论对药物、疾病的系统认识, 体现了中医临床长期用药经验和用药习惯, 需要从现代医学角度说明白、讲清楚中药制剂的安全有效; 另一方面, 中药是天然来源, 具有组成复杂的特点, 其所含成分丰富、组成复杂, 活性成分不明确或难以明确, 其药物成分及其含量具有波动性, 质量控制难, 需要从药物质量控制角度说明白、讲清楚中药制剂质量可控的逻辑。

保证制剂质量稳定作为药品质量属性的基本要求, 也是中药制剂功效稳定的基础。中药制剂一般通过多种有效成分、多系统、多途径、多靶点的综合调节, 实现患者临床获益^[3], 其质量控制具有复杂性。参照化学药物基于指标成分或活性成分进行定性、定量的质量控制模式对保证中药的质量可控性起到了重要作用, 但由于中药所固有的天然来源、组成复杂的药物成分、独具特色的理论体系以及来源于临床实践的安全性、有效性等特点, 依据单一或几个成分进行质量控制的模式难以全面反映中药的整体质量特征, 也难以客观评价和有效控制药品的质量^[9]。如何对中药这个复杂未知体系的质量进行合理表征和系统控制, 如何保证中药制剂质量稳定进而保障其功效稳定一直是中药质量控制的重点和难点, 也是中药监管科学研究的重点方向^[5]。特别是自药品审评审批制度改革以来, 药审中心深入开展中药监管科学研究, 分析中药制剂的特点、研发规律和质量控制要求, 认识到中药制剂一般来源于中医临床实践, 具有成分复杂、活性成分难以明确、机制大多不清楚的特点, 加之中药制剂质量受药材、饮片、生产工艺等各环节多因素影响, 质量控制难度大, 需要针对中药制剂的研发路径和特点对其质量控制进行研究。结合修订《药品注册管理办法》^[10]及其配套文件、制定《中药注册管理专门规定》^[11], 药审中心发布了一系列中药药学研究技术指导原则, 不断探索构建并形成了基于中药制剂特点保障功效稳定的中药制剂质量控制体系^{[12, 13]}。

本文通过总结药品审评审批制度改革及中药监管科学的研究成果, 梳理相关指导原则, 认为上述从药材、饮片到制剂生产全链条, 从中药复方制剂工艺到毒理研究用样品制备和临床试验用药品制备, 从药物研发到上市后变更全生命周期管理的中药制剂全过程质量控制的系列中药药学研究技术指导原则体系, 符合中药制剂特点、研发与生产实际和质量控制要求, 兼顾了中医临床长期用药习惯与药品安全、有效、质量可控的一般属性要求, 为保障中药制剂药物成分基本稳定、减小批间质量波动提供了指导, 构成了保障中药制剂功效稳定的质量控制体系。

1　中药制剂特点及其质量控制理念的发展

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中药新药多为复方制剂, 具有传统中医药理论支持和指导, 一般来源于中医临床实践, 在总结个体用药经验的基础上积累长期的临床实践经验, 形成固定处方, 研发制成适合群体用药的中药新药^[14]。不同于化学药物从实验室到临床应用、从未知到已知的探索性研发模式, 中药复方制剂具有独具特色的中医药理论体系, 经临床实践确证其安全性、有效性等特点, 这些特点是决定其临床应用有效的基础, 但长期以来这些特点在研发实践中并未得到足够的重视, 需要加以深入研究与阐释。例如, 关于中医药理论, 其中包含丰富的药学认识和理论, 如药材产地与道地药材、品质评价与鉴定、药材采收加工保养、饮片炮制、药物药性与配伍、剂型选择与制剂技术等, 如何将传统中药理论和经验应用于中药的质量控制? 关于处方剂量, 由于中药新药多来源于临证用药或个体给药长期临床实践经验的总结, 如何设计、选择药物剂量, 以保证中药新药的临床疗效^{[15, 16]}? 关于药材、饮片质量, 中药复方制剂所用药材、饮片来源于自然界的植物、动物、矿物, 存在质量波动, 炮制规格多样, 质量控制难度大, 在中药新药研发实际中, 如何确定药材基原、产地、生长年限等质量控制要求^[17]? 关于制剂工艺, 研究中多采用某一个或几个指标成分进行单因素或正交试验的方法进行生产工艺研究和筛选, 但中药复方成分众多, 活性成分研究欠缺, 药理药效作用机制、作用靶点等基础研究薄弱, 以某一个或几个指标成分优选的工艺生产的制剂, 其物质基础能否代表临床应用有效的汤剂^{[18, 19]}?

由于中药质量受药材、饮片、生产工艺等各环节多因素影响, 质量易波动、成分复杂、活性成分难以明确、作用机制大多不清楚, 加大了质量控制难度。此外, 中药制剂是多种中药共同配伍发挥疗效, 囿于现有化学分离纯化和生物关键分子发现技术水平, 难以完全阐明中药有效成分及多靶点作用间的关系, 中药复方作用的基础基于现有认识还是处于“盲人摸象”的“暗室”状态, 中药复方调控的复杂作用原理尚未被科学描述和阐释^[1]。基于指标成分或活性成分的化学药物质量控制模式, 建立以光谱、色谱为主定性和定量的中药质量标准, 对保证中药的质量可控性起到了重要作用^{[20, 21]}。但由于中药成分的复杂性, 中药制剂的药用物质并非某几个单体成分的简单叠加, 单靠某一个或几个指标成分进行质量控制的模式难以全面反映制剂的整体质量特征。与此同时, 因检测指标与制剂安全性、有效性的关联性低, 缺乏符合中药特点的质量评价方法和指标等问题^{[22, 23]}, 这种化学药物质量控制模式难以全面反映中药的整体质量特征, 难以客观评价和有效控制药品的质量^[24]。

随着“质量源于设计”^{[25, 26]}“源头质量控制”^{[27, 28]}“生产过程控制”^[29-31]等理念的逐步发展成熟, 中药质量控制的理念也随之发生明显转变。业界越来越认识到, 对于中药制剂这一复杂的混合体系的质量控制, 仅关注制剂质量是不够的, 还需要对药材、饮片及制剂生产过程进行质量控制; 中药制剂质量标准难以反映中药制剂整体质量; 以某一药味的某一成分为指标进行中药制剂工艺优选和评价是不合适的, 需要考虑人用经验和用药习惯; 在来源于中医临床实践的中药新药转化研究, 中医药理论、人用经验和临床试验相结合的审评证据体系构建中, 药学相关研究及其质量控制应可评价, 诸如此类, 业界迫切需要一套符合中药特点、适合中药实际的中药药学指导原则体系来研究解决中药制剂研发、生产和上市后变更相关中药制剂质量控制问题。

2　中药新药质量控制指导原则体系的发展

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1992年, 原卫生部发布《关于药品审批管理若干问题的通知》, 针对中药相关部分制定发布了“《新药审批办法》有关中药部分的修订和补充规定”, 对中药的分类、研究内容、资料规范等做出了相关规定, 为推动我国中药新药研究和审评的规范化、科学化发挥了重要作用。1999年, 原国家药品监督管理局修订并颁布实施《新药审批办法》, 在此基础上制定了《中药新药研究的技术要求》。2002年, 原国家药品监督管理局颁布《药品注册管理办法(试行)》, 第一次明确提出药品注册的法规概念, 明确了管理方式、审评方式和审评技术要求的基本规范^[12]。2005、2007年原国家食品药品监督管理局两次对《药品注册管理办法》进行修订、颁布^{[32, 33]}。2008年《中药注册管理补充规定》^[34]发布, 进一步细化和明确关于中药注册管理的要求。在此期间, 一系列配套文件包括中药相关指导原则和技术标准/技术要求相继发布, 涵盖了中药/天然药物原料前处理、提取纯化研究、制剂研究、中试研究、稳定性研究、天然药物新药研究、变更研究及资料规范等, 内容有了较大丰富, 系统性显著提升, 但仍不够全面, 未成体系, 且缺乏基于中药特点的深入研究和探讨, 难以满足中药新药研发的需求、产业高质量发展的需要和审评审批制度改革的要求^[35]。

随着医药产业发展, 药物的可及性得到极大改善, 临床诊疗实践不断更新, 人民群众对于新药、好药需求的不断提高, 亟需建立完善与之相适应的中药审评标准和技术要求。为进一步加快中药新药研发进程和注册上市、促进中药传承创新和高质量发展, 2015年药品审评审批制度改革以来, 药审中心积极开展中药监管科学研究, 深入研究中药特点、研发规律和实际情况, 针对长期以来对中药审评“以西律中”“唯成分论”等质疑^[24], 以问题为导向, 总结中药研发、生产、审评、监管的工作经验和成果, 改革完善中药注册管理, 研究建立符合中药特点的技术审评标准体系。基于中药制剂特点、研发规律和实际, 尊重中医药用药经验和用药习惯, 将传统中药质量控制理论和经验应用于中药制剂质量控制, 并践行“质量源于设计”“全过程质量控制”等现代药品质量控制理念, 于2020年以来发布了一系列中药药学研究技术指导原则(表1)^[36-53], 不断探索构建符合中药特点、保证中药制剂功效稳定的全过程质量控制指导原则体系。

根据中药的特点, 围绕中药质量控制的热点、难点问题, 不断改进优化质量控制方法, 建立了从药材、饮片到制剂生产全链条, 从中药复方制剂工艺到毒理研究用样品制备和临床试验用药品制备, 从药物研发到上市后变更全生命周期管理的基于中药特点保障功效稳定的中药制剂全过程质量控制体系。该体系突出遵循中医药理论指导, 尊重中药特点及药品研发的一般规律, 强调临床实践人用经验的重要性; 重视药材质量、饮片炮制和传统工艺, 强调质量控制的整体性、系统性, 而不是强调化学成分检测; 明确中药变更的评价标准, 修订优化已上市中药变更技术要求; 同时重视毒理研究用样品、临床试验用药品、人用经验所用药物等的质量控制。通过遵循中医药理论, 尊重人用经验和中药研发规律, 构建基于功效稳定的中药制剂质量控制体系, 回应和解决了长期以来对中药审评“以西律中”“唯成分论”的质疑。

3　基于中药制剂特点保障功效稳定的质量控制体系构建

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保证制剂质量稳定是药品质量属性的基本要求, 也是保障其功效稳定的基础。以源于传统中药复方制剂的质量控制为例, 对已发布的系列指导原则并结合作者的认识, 从质量研究设计、源头质量控制、生产过程控制、质量标准研究以及上市后变更研究等方面, 就其保障中药制剂功效稳定的质量控制意义进行阐述和说明。

3.1　以临床为导向, 开展质量控制研究和设计

中药复方制剂一般来源于已有临床实践经验的中药方剂, 具有传统中医药理论的支持和指导, 其研发设计是对临床使用安全有效的方剂进行的成药化设计, 如剂量、工艺等不同可能导致其药物成分的差异, 进而影响其安全有效性, 这可能是中药制剂有别于针对成分明确的化学药物制剂设计的最大不同点^[2]。

中药制剂的设计过程是对中药制剂进行质量设计、质量赋予和质量完善的过程。由于中药质量控制的复杂性特点, 在成药化过程中保证临床方剂的功效得以稳定传递甚至更好发挥, 就需要以临床为导向, 以继承原方安全有效为基础, 根据临床有效的实际使用情况, 基于临床有效的处方、剂量和工艺进行研究^[19]。《中药新药用药材质量控制研究技术指导原则(试行)》《中药新药用饮片炮制研究技术指导原则(试行)》^[36]提出, 药材质量控制研究、饮片炮制研究均应遵循中医药理论, 尊重传统用药经验, 以满足中药新药研究设计需要为目标, 加强药材、饮片的质量控制。《中药复方制剂生产工艺研究技术指导原则(试行)》^[40]、《中药口服制剂生产过程质量控制研究技术指导原则(试行)》^[53]强调, 中药复方制剂研究应基于“质量源于设计”的理念, 制剂工艺研究初期就应以临床价值为导向, 根据产品质量目标要求, 对工艺路线、药物剂型等进行设计, 结合物料性质、工艺条件等, 建立能满足产品质量设计要求且工艺稳健的设计空间, 加强生产过程质量控制研究, 并根据设计空间开展质量风险管理, 确立质量控制策略和药品质量标准体系。《中药新药质量研究技术指导原则(试行)》^[42]也明确中药新药的质量研究应以临床价值和需求为导向, 遵循中医药理论, 坚持传承和创新相结合, 体现质量源于设计、全过程质量控制和风险管理的理念。通过对药材/饮片、中间体、制剂的药用物质及关键质量属性在不同环节之间的量质传递研究, 以及药用物质与辅料、药包材相互影响的研究, 不断提高中药的质量控制水平。

3.2　强化源头质量控制, 明确中药新药用药材、饮片质量控制要求

源头控制是中药全过程质量控制的基础。所谓“药材好, 药才好”, 药材、饮片的质量是保证中药复方制剂安全、有效、质量可控的质量根源^[54]。中药材来源于天然资源, 化学成分复杂, 其生长和内在质量受产地、土壤、气候及栽培技术等影响很大; 中药饮片炮制过程复杂, 质量难以有效控制^[55]。药材种植养殖及生产加工、饮片炮制等不规范而造成的质量问题较为突出, 部分品种农药残留、真菌毒素污染等问题影响了药材的安全性。加之药材、饮片生产链长, 质量影响因素较多, 仅依据标准检验难以满足药材、饮片和制剂的质量控制需要。

为加强对药材、饮片的质量控制, 强化源头质量控制, 《中药新药用药材质量控制研究技术指导原则(试行)》和《中药新药用饮片炮制研究技术指导原则(试行)》^[36]明确了药材基原、产地、种植养殖、采收加工及饮片炮制等方面的质量控制要求。鼓励传承传统经验和技术, 重视传统经验关于药材质量、饮片炮制和生产工艺的要求, 也鼓励探索应用现代科学技术表征传统质量评价经验和指标。鼓励建立多指标、多手段的质控方法, 加强对毒性成分和外源性污染物(农药、重金属及有害元素、真菌毒素等) 等安全性相关指标的研究, 控制安全风险。同时强调, 应以满足制剂质量控制的需要为目标, 基于中药制剂的研究设计, 确定影响药材及制剂质量稳定的关键因素和风险控制点, 制定合理的质量要求。例如, 若药材、饮片质量标准中已有重金属、农药残留等控制项目并符合中国药典相关要求, 制剂中可不必重复要求控制相应的项目, 这也是中药制剂研究设计与全过程质量控制理念的体现^[56]。

此外, 为减少源头质量差异导致的中药制剂批间质量波动, 《中药均一化研究技术指导原则(试行)》^[38]提出, 在不改变投料量的前提下, 可根据中药制剂品种的特点, 对饮片、提取物等合格处方药味开展均一化研究, 确定适当的投料方法, 以期提高制剂的批间质量一致性。

3.3　重视制剂生产过程控制

中药生产过程决定了中药制剂安全有效的物质基础, 是影响中药制剂质量的关键因素。在保证药材、饮片质量的前提下, 制剂生产过程控制是临床应用有效的方剂转变为有效制剂的关键。由于中药复方制剂大多来源于临床有效方剂, 具有基础研究薄弱、有效成分不明确、影响中药制剂质量的因素多等特点, 《中药复方制剂生产工艺研究技术指导原则(试行)》^[40]强调, 中药复方制剂生产工艺的研究既要遵循中医药理论, 尊重传统用药经验, 又要遵循药品研究的一般规律, 利用现代研究成果, 在分析处方组成和各药味之间的关系、各药味所含成分的理化性质和药理作用的基础上, 结合制剂工艺和生产实际, 开展相关研究, 实现中药复方从临床用药经验到中药制剂的有效转化。

针对饮片质量的波动、批量规模的变化、工艺过程较多的影响因素、生产设备的老化更新等实际情况, 中药复方制剂在实际生产中要保持产品质量的均一稳定具有较大难度, 而随着生产数据的积累和对产品质量认识的深入, 持续的工艺研究及优化更有利于持续生产出质量相对稳定均一的产品。为指导生产过程质量控制研究, 提高药品质量可控性, 鼓励符合中药特点的新技术、新方法、新设备在生产中应用, 《中药口服制剂生产过程质量控制指导原则(试行)》^[53]提出, 药品上市许可持有人可根据保障药品质量的需求和生产条件, 通过对产品自身特点和关键质量属性的认知, 进一步对已上市中药开展生产过程质量控制研究, 将先进制造、智能制造等技术引入中药制剂生产中, 以产品质量稳定可控为目标, 对生产工艺、设备进行优化, 以便更好地保证产品质量的批间一致、批内均一。例如, 提取设备的升级改造, 若按原有工艺研究验证发现“涨膏”等情况, 则应基于产品质量设计目标和既往的生产实际, 对相关工艺参数或生产过程参数进行研究考察, 除应考察浸膏得量外, 还应研究相关成分的含量、特征图谱等变化情况, 对相关变更进行验证评估, 以保证变更前后产品质量的一致^[57]。

3.4　强调整体质量控制, 多维度、多角度、多指标质量评价

中药复方制剂的成分组成复杂, 现有研究结果显示, 中药对人体的作用是多靶标、多机制、多途径的综合作用效果, 采用单一检测手段通常无法全面反映其质量信息^[58], 以单一或部分指标成分对中药复方制剂进行质量控制, 往往难以充分表征中药复方制剂的真实质量^[59]。中药制剂质量标准中采用化学成分检测作为常规质量控制方法, 其作用往往被过分强调和局限^[60], 而囿于通常意义的浸出物、大类成分含量测定等整体质量控制指标专属性较弱, 在中药质量研究和标准制定中未得到足够的重视。专属性固然是质量控制方法研究的重要考量, 但针对具有成分复杂、作用不明确等特点的中药制剂, 上述指标可一定程度反映中药的整体质量特征, 同样具有质量控制意义^[61]。加强基础研究整体质量控制研究并行, 建立反映中药整体质量特征的质量控制指标, 多维度、多角度、多指标进行质量评价是说明中药制剂质量可控性的可行方法和策略。

基于中药复杂性、整体性的特点, 《中药新药质量研究技术指导原则》^[42]明确, 中药新药质量研究应以坚持传承和创新相结合, 运用物理、化学或生物学等新技术、新方法从多角度分析药品的质量特征, 有针对性地开展质量研究, 反映中药整体质量。《中药新药质量标准研究技术指导原则(试行)》^[36]强调, 应研究建立符合中药特点的整体质量控制方法, 采用多种方法、多个指标进行质量控制, 并与药品安全性、有效性相关联, 以提高质量标准的可控性, 更好地控制产品质量^[62]。质量标准应以实现中药质量的稳定可控为目标, 根据产品特点建立反映中药整体质量的控制指标, 指标应更能反映中药的整体质量特征, 如浸出物、指纹图谱/特征图谱^[50]、大类成分含量测定等整体质量评价指标和方法, 并尽可能反映产品的质量波动状况^[63]。《中药复方制剂生产工艺研究技术指导原则(试行)》《中药制剂稳定性研究技术指导原则(试行)》^[50]也强调, 生产工艺研究、稳定性研究过程中质量控制指标的选择也应注重体现整体质量特性, 多角度、多维度选择多个指标进行研究和评价, 关注考察指标与药品安全性、有效性、质量可控性的关联, 以更全面、客观地反映药品整体质量变化情况。

同时, 鼓励采用新技术、新方法、新工具, 研究建立反映产品有效性安全性的质量控制指标。例如, 当以理化检测方法等质量控制手段难以充分反映中药质量时, 可参考《中药生物效应检测研究技术指导原则(试行)》^[41]探索生物效应检测方法等, 以弥补现行质量控制方法的不足, 提高中药质量可控性。

3.5　充分认识质量控制的复杂性、渐进性

由于中药具有成分复杂、质量控制难度大等特点, 中药质量控制研究具有复杂性和渐进性, 难以一蹴而就。为提高新药的研发质量和效率, 《中药新药研究各阶段药学研究技术指导原则(试行)》^[37]、《中药新药研究过程中沟通交流会的药学资料要求(试行)》^[39]提出, 应充分认识中药的复杂性、新药研发的渐进性, 可根据中药特点、新药研发的一般规律及不同研究阶段的主要目的, 分阶段开展针对性研究, 随着对产品认识的逐步深入和科学技术的不断进步, 不断推进质量控制研究, 促进产品质量持续提升。

中药制剂一般来源于长期临床应用经验总结, 具有良好的有效性、安全性基础, 对于申请临床试验的中药新药, 重点审查临床试验方案的科学性和对安全性风险的控制, 将质量标准提高等要求留在临床试验通知书中, 促进中药新药及早进入临床研究。对于申请上市许可的中药新药, 建立基本完善的质量控制方法, 保证上市后药品与确证性临床试验用样品质量一致, 在基本满足质量控制要求的前提下, 质量标准提高的工作留在批件中, 促进中药新药尽快上市。同时, 中药质量控制研究应体现全生命周期管理, 探索建立和完善符合中药特点的全过程质量控制体系, 重视上市后的研究完善, 随着对产品认知的提高和科学技术的不断进步, 持续改进质量控制方法和手段, 促进药品质量不断提升^[64]。

3.6　重视毒理研究用样品、临床试验用药品的质量控制

中药制剂研究涵盖药学、药理毒理学、药物临床试验等相关研究工作, 研究过程中涉及的毒理研究用样品、临床试验用药品等是关键研究节点的关键研究用样品, 其质量控制是保证中药制剂质量稳定, 进而保证其安全性、有效性的前提和基础, 在以往研发过程中往往未得到足够的重视。中药新药毒理研究用样品的制备和质量控制是客观、准确地评价药物非临床安全性, 为药物进入临床试验和上市提供可靠的非临床安全性信息的重要保障^[45]。中药新药临床试验用药品的制备和质量控制等研究是开展中药新药临床试验和评价的基础, 关系到临床试验的质量, 影响试验药物安全性、有效性评价的客观性与准确性, 对于满足临床试验需求具有重要意义^[47]。一般而言, 毒理研究用样品、临床试验用药品以及大生产样品的质量应基本一致, 这样才能使临床前研究结果为临床试验提供可靠的参考, 使临床试验准确反映上市后产品的有效性及基本的安全性信息^[65]。

因此, 为保证上市产品的安全性、有效性, 加强研发过程中毒理研究用样品、临床试验用药品的质量控制, 《中药新药毒理研究用样品研究技术指导原则(试行)》《中药新药临床试验用药品的制备研究技术指导原则(试行)》对用于注册申报的中药新药毒理研究用样品和中药新药临床试验用药品的制备、质量控制等研究和管理提出了指导和规范, 明确毒理研究用样品应充分代表临床试验用药品和申请上市样品的质量属性和安全性^[66], 关注毒理研究用样品与临床试验用药品的一致性、上市后样品质量与临床试验用药品质量的一致性, 以使上市产品有准确的研究数据作为支撑, 为制定中药新药质量标准提供依据。

同时, 为更好地构建“中医药理论、人用经验、临床试验”相结合的注册审评证据体系, 《基于人用经验的中药复方制剂新药药学研究技术指导原则(试行)》^[49]明确了作为注册审评证据的人用经验所用药物的药学研究基本要求。

3.7　优化变更研究与评价模式

药品变更管理贯穿于产品的全生命周期, 是优化生产工艺、提高生产效率、完善产品质量信息、保证产品质量等的重要管理方式。由于中药质量控制具有复杂性、渐进性的特点, 随着产品研究和认知的深入进行合理的变更也是提升质量可控性重要手段。以往侧重于从生产工艺或工艺参数等方面比较变更前后变化的评价方式, 导致中药制剂变更难以研究和评价, 部分变更需要进一步开展药理毒理和/或临床试验研究, 业界存在“工艺一变就要做临床”的质疑。

为解决长期困扰企业的工艺变更而不敢申报、监管部门不能准确掌握企业生产工艺变更情况的难点、痛点问题, 2021年4月发布了《已上市中药药学变更研究技术指导原则(试行)》^[43], 改变了唯工艺/制法的评价模式, 建立了中药变更研究评价方法和标准, 研究明确了生产工艺变更可通过药学研究进行质量比较评估的情形, 引导持有人注重对药用物质的质量控制要求。该指导原则强调, 基于中医药理论和传统工艺制备(如: 水煎煮工艺等) 的中药, 在工艺方法不变的情况下, 工艺参数的变更一般可通过药学研究评估变更对药品质量的影响, 通常不再要求进行临床试验。中药成分复杂、影响质量的因素很多, 要想清晰阐释变更对其质量影响的程度不易, 而质量对比研究是评价产品变更前后质量一致性的重要依据^[67], 重视工艺的变化是否引起药品质量的实质变化, 采用浸膏/干膏得率、浸出物、特征/指纹图谱、多指标成分含量等多种评价指标开展变更前后物质基础的质量对比研究, 以指导调控生产过程参数(设备参数、工艺参数等), 避免再出现如“涨膏”等情况, 保障产品质量稳定, 使既往安全性、有效性数据能够支持设备变更后产品的安全性、有效性。

4　总结

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药审中心基于中药的特点、研发规律和实际, 尊重中医药用药经验和用药习惯, 将传统中药质量控制理论和经验应用于中药制剂质量控制, 并践行“质量源于设计”“全过程质量控制”等现代药品质量控制理念, 自2020年以来发布了一系列中药药学研究技术指导原则, 涵盖从药材、饮片到制剂的生产全过程控制, 从中药复方制剂工艺研究设计到毒理研究用样品、临床试验用药品制备的研发全过程控制, 从药物研发到上市后变更的全链条管理。上述指导原则重视以临床为导向开展质量控制研究和设计, 以及研发过程控制; 强调源头质量控制、制剂生产过程控制、整体质量控制和质量评价; 关注毒理研究用样品与临床试验用药品的一致性、上市后样品质量与临床试验用药品质量的一致性; 重视上市后质量控制的研究完善, 不断提高产品的质量可控性, 形成了符合中药制剂特点、实际和质量控制要求的指导原则体系, 兼顾了中医临床长期用药习惯与药品关于安全、有效、质量可控的一般属性要求, 构成了保障中药制剂功效稳定的质量控制体系。

中药制剂是由众多成分组成的复杂体系, 其质量控制体系的构建完善仍然面临很多挑战。随着药品上市许可持有人主体责任的发挥, 科学技术的发展和中药监管科学研究的持续深入, 以及中药监管科学研究相关新工具、新方法、新标准成果的应用, 中药质量控制方法和评价模式的不断创新, 符合中药特点、反映中药整体质量并与有效性及安全性紧密结合的中药制剂质量控制体系将不断完善, 中药制剂质量必将不断提高, 更好地保障中药制剂的安全有效。

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2025年第60卷第6期

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doi: 10.16438/j.0513-4870.2025-0075

接收时间：2025-01-22
首发时间：2026-09-20
出版时间：2025-06-12

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收稿日期：2025-01-22
修回日期：2025-02-26

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¹国家药品监督管理局药品审评中心, 北京 100076

²药品监管科学全国重点实验室, 北京 100076

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周思源, E-mail: zhousiyuan@cde.org.cn

阳长明, E-mail: yangchm@cde.org.cn

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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Name of guideline	Issuing date	Ref.
Guideline for quality control study of TCM crude drugs of new TCMs (trial)	Oct. 2020	[36]
Guideline on processing study of prepared slices/decoction pieces for new TCMs (trial)	Oct. 2020	[36]
Guideline for quality standard study of new TCMs (trial)	Oct. 2020	[36]
Guideline for pharmacognosy, chemistry, manufacturing and controls (PCMC) study in various phases of study on new TCMs (trial)	Nov. 2020	[37]
Guideline for homogenization studies of TCMs (trial)	Nov. 2020	[38]
Guideline for requirements for PCMC documentation for the communication meetings during the development of new TCMs (trial)	Nov. 2020	[39]
Guideline for study on manufacturing process of compound preparations of TCMs (trial)	Nov. 2020	[40]
Guideline for study on bioassay of TCMs (trial)	Dec. 2020	[41]
Guideline for quality study of new TCMs (trial)	Jan. 2021	[42]
Guideline for studies on PCMC changes to marketed TCMs (trial)	Apr. 2021	[43]
Guideline for PCMC study of compound preparations of TCMs managed in accordance with Directory of Ancient Classic Formulas of Traditional Chinese Medicines (trial)	Aug. 2021	[44]
Guideline for study on samples for toxicology studies on new TCMs (trial)	Jan. 2022	[45]
Guideline for study on TCMs with identical name and formula (to marketed TCMs) (trial)	Dec. 2022	[46]
Guideline for study on the preparation of investigational medicinal product of new TCMs (trial)	Jul. 2023	[47]
Guideline for PCMC study on other compound preparations of TCMs originated from ancient classic formulas (trial)	Jul. 2023	[48]
Guideline for PCMC study of new compound preparations of TCMs based on human experience (trial)	Oct. 2023	[49]
Guideline for stability testing of TCM preparations (Trial)	Feb. 2024	[50]
Guideline for characteristic/fingerprint chromatograph for TCMs (trial)	Feb. 2024	[50]
Guideline for application dossiers compilation for PCMC of compound preparations of TCMs managed in accordance with Directory of Ancient Classic Formulas of Traditional Chinese Medicines (trial)	Apr. 2024	[51]
Guideline for the study on improved new TCMs	May. 2024	[52]
Guideline for quality control study in production process for oral TCM preparations (trial)	Jun. 2024	[53]

Name of guideline

Issuing date

Ref.

Guideline for quality control study of TCM crude drugs of new TCMs (trial)

Oct. 2020

[36]

Guideline on processing study of prepared slices/decoction pieces for new TCMs (trial)

Oct. 2020

[36]

Guideline for quality standard study of new TCMs (trial)

Oct. 2020

[36]

Guideline for pharmacognosy, chemistry, manufacturing and controls (PCMC) study in various phases of study on new
TCMs (trial)

Nov. 2020

[37]

Guideline for homogenization studies of TCMs (trial)

Nov. 2020

[38]

Guideline for requirements for PCMC documentation for the communication meetings during the development of new
TCMs (trial)

Nov. 2020

[39]

Guideline for study on manufacturing process of compound preparations of TCMs (trial)

Nov. 2020

[40]

Guideline for study on bioassay of TCMs (trial)

Dec. 2020

[41]

Guideline for quality study of new TCMs (trial)

Jan. 2021

[42]

Guideline for studies on PCMC changes to marketed TCMs (trial)

Apr. 2021

[43]

Guideline for PCMC study of compound preparations of TCMs managed in accordance with Directory of Ancient
Classic Formulas of Traditional Chinese Medicines (trial)

Aug. 2021

[44]

Guideline for study on samples for toxicology studies on new TCMs (trial)

Jan. 2022

[45]

Guideline for study on TCMs with identical name and formula (to marketed TCMs) (trial)

Dec. 2022

[46]

Guideline for study on the preparation of investigational medicinal product of new TCMs (trial)

Jul. 2023

[47]

Guideline for PCMC study on other compound preparations of TCMs originated from ancient classic formulas (trial)

Jul. 2023

[48]

Guideline for PCMC study of new compound preparations of TCMs based on human experience (trial)

Oct. 2023

[49]

Guideline for stability testing of TCM preparations (Trial)

Feb. 2024

[50]

Guideline for characteristic/fingerprint chromatograph for TCMs (trial)

Feb. 2024

[50]

Guideline for application dossiers compilation for PCMC of compound preparations of TCMs managed in accordance
with Directory of Ancient Classic Formulas of Traditional Chinese Medicines (trial)

Apr. 2024

[51]

Guideline for the study on improved new TCMs

May. 2024

[52]

Guideline for quality control study in production process for oral TCM preparations (trial)

Jun. 2024

[53]