The development and characteristics of general notice in Chinese Pharmacopoeia 2025 Edition

Each volume of each edition of Chinese Pharmacopoeia has its own general notice. “General Notice” serves as the basic principles for the proper application of the Chinese Pharmacopoeia, and the unified provision on the monographs, general requirements and common problems related to drug quality inspection and QC testing. Since the founding of the People’s Republic of China, China has promulgated and implemented 11 editions of Chinese Pharmacopoeia. The current edition is the 2020 Edition, and the 2025 Edition will be promulgated and implemented soon.

The current edition of the Chinese Pharmacopoeia is composed of four volumes. The Volume I includes traditional Chinese medicine, the Volume II chemical drugs, the Volume III biological products along with relevant general requirements and guidelines, and the Volume IV general requirements, guidelines and pharmaceutical excipients. Each volume of the Chinese Pharmacopoeia is provided with different contents, including the general notices also with some emphasis and differences. The Chinese Pharmacopoeia has no unified general notices but retains relative uniformity and keeps the characteristics of the content of each volume. The major pharmacopoeias in the world, including the United States Pharmacopoeia (USP), the Japanese Pharmacopoeia (JP), the European Pharmacopoeia (EP) and the British pharmacopoeia (BP), all have their own unified general notices, which are not differentiated depending on the content included.

Compared with the above foreign pharmacopoeias, Chinese Pharmacopoeia provides the most complete categories, including standards for traditional Chinese medicine, chemical drugs, biological products, pharmaceutic excipients, pharmaceutical packaging materials, etc. Depending on the development history, the general notices in each volume of the Chinese Pharmacopoeia present differences in format or content. With the introduction and revision of regulations, changes in the content of pharmacopoeias, and the application of new technologies, methods, and concepts in drug quality control, given the importance and significance of the general notices in Chinese Pharmacopoeia, it is necessary for the industry to coordinate the general notices in each volume of Chinese Pharmacopoeia. Considering the unique characteristics of various drugs in quality control and supervision, the general notices in the Chinese Pharmacopoeia 2025 Edition has been comprehensively revised. It retains relative uniformity and keeps the characteristics of the content of each volume.

Compared with the previous editions, the general notices of the Chinese Pharmacopoeia 2025 Edition have been comprehensively standardized with relevant requirements. While taking into account the characteristics of Volume I, Volume II, Volume III and Volume IV, it achieves the unified standardization of the general notices of each volume in format and the coordination and consistency of common content. This article elaborates the general notices of the Chinese Pharmacopoeia 2025 Edition.

1 Unify the format and chapters of general notices in all volumes of the Chinese Pharmacopoeia

The general notices in all volumes of the Chinese Pharmacopoeia 2020 Edition have different framework structures, common and different content. The general notices of the Chinese Pharmacopoeia 2025 Edition have unified the format and structure of the general notices among the various volumes of the Pharmacopoeia, retained the characteristics of traditional Chinese medicine, chemical drugs, biological products and excipients, revised the general principles governing each volume, and improved the classic format of the Chinese Pharmacopoeia.

1.1 General information for chapters of general notices in Volume I, Volume II, Volume III and Volume IV of Chinese Pharmacopoeia 2020 Edition

The content framework of general notices in Volume I, Volume II and Volume IV of Chinese Pharmacopoeia 2020 Edition is composed of 12 parts respectively, including general principles, general requirements, monographs, titles and arrangements, items and requirements, testing methods and limits, reference standards and chemical reference materials (chemical reference materials, reference drugs, reference extractives and reference standards for Volume I), units of measurement, precision, reagents, test solutions and indicators, animal test, package insert, package and label.

The Chinese Pharmacopoeia 2020 Edition (Volume III) has quite different general notices from the other three volumes in terms of content, items and arrangements. It is divided into 11 parts: general principles, monographs, general chapters, title and arrangements, basic requirements, precision, testing methods and limits, standard materials, reference materials, unit of measurement, packaging, labeling, directions for use, storage and transportation, and abbreviations in English.

The Chinese Pharmacopoeia 2020 Edition (Volume III) does not have the title items of reagents, test solutions and indicators, and animal test, while the corresponding content of reagents, test solutions and indicators are included under precision, which is not appropriate. The content of animal test is expressed as animals used in production and control tests and written under the basic requirements. The Chinese Pharmacopoeia 2020 Edition (Volume III) has abbreviations in English, which are not available in the other volumes.

The 10 common chapters from Volume I to Volume IV of the Chinese Pharmacopoeia 2020 Edition also have slight difference in names, such as items and requirements in Volume I, Volume II and Volume IV, but basic requirements in Volume III; package insert, package and label in Volume I, Volume II and Volume IV, but packaging, labeling, directions for use, storage and transportation in Volume III; the expression of standard substances in the Volume I and Volume III is also different from that of Volume II and Volume IV of the Chinese Pharmacopoeia 2020 Edition.

1.2 Coordination and unification of the format of general notices and the names of chapters in Volume I to Volume IV of the Chinese Pharmacopoeia 2025 Edition

In line with the principle of seeking common ground while reserving differences, the number of total 12 chapters of the general notices in Volume I, Volume II and Volume IV of the Chinese Pharmacopoeia 2020 Edition remain unchanged in the new edition of pharmacopoeia. The chapters of the general notices in the Chinese Pharmacopoeia (Volume III) are adjusted and two chapters of “Reagents, Test Solutions and Indicators” and “Animal Test” are added, so that the number of the chapters of the general notices in Volume III is 12, which is completely consistent with general notices in Volume I to Volume IV of the Chinese Pharmacopoeia 2025 Edition.

The corresponding content of the general notices in the Chinese Pharmacopoeia (Volume III) is revised so that the chapter title “Reagents, Test Solutions and Indicators” and its contents are completely consistent with those of Volume I, Volume II and Volume IV, achieving the unification of the chapter title “Reagents, Test Solutions and Indicators” and its content in the four volumes of the Chinese Pharmacopoeia 2025 Edition.

The content under the “Animal Test” in the general notices of the Chinese Pharmacopoeia 2025 Edition (Volume III) corresponds to paragraphs 1 and 6 in Article 17 “Animals used in production and control tests” of the general notices of the Chinese Pharmacopoeia 2020 Edition (Volume III): Animals used for quality control shall satisfy the relevant requirements of the “Requirements for Animals Used for the Production and Quality Control of Biologics”, and be defined with the days of age and weight.

The contents of articles 2-5 and 7 under “Animals used in production and control tests” of the general notices of the Chinese Pharmacopoeia 2020 Edition (Volume III) remain unchanged, without adjusting the order and position of the original entries, and are listed in article 5 “Animals used in production” under “Items and Requirements” in the general notices of the Chinese Pharmacopoeia 2025 Edition (Volume III).

After overall coordination, there are a total of 12 chapters in the general notices in all volumes of the Chinese Pharmacopoeia 2025 Edition, and the title name of each chapter is basically the same without affecting the implementation of the pharmacopoeia, as follows.

① General Principles; ② General Requirements; ③ Monographs; ④ Titles and Arrangements; ⑤ Items and Requirements; ⑥ Testing Methods and Limits (Volume I, Volume II，Volume III and Volume IV); ⑦ Reference Standard; ⑧ Units of Measurement; ⑨ Precision; ⑩ Reagents, Test Solutions and Indicators; ？Animal Test; ？ Package Insert, Package and Label.

1.3 Retain the characteristics of general notices of each volume in the chapters “Titles and Arrangements” and “Items and Requirements”

In the chapters in the general notices in all volumes of the Chinese Pharmacopoeia 2020 Edition, the “Titles and Arrangements” and “Items and Requirements” have their own characteristics and large differences, which are difficult to coordinate and unify. For example, Chinese Pharmacopoeia (Volume I) includes traditional Chinese medicine, the theoretical characteristics of traditional Chinese medicine are included in the monographs, and the inherent mode of its standard format has a long history in ancient classics, forming a tradition. Although the content (such as usage and dosage, precautions, etc.) set in the specifications for some traditional Chinese medicine is unrelated to quality control, the characteristics of traditional Chinese medicine standards have been reflected in the “Items and Requirements” of the general notices of the Chinese Pharmacopoeia (Volume I), and the format of the Volume I of previous editions of pharmacopoeia has been passed down to the present day, forming the difference between the standard format of the monographs of the Chinese Pharmacopoeia (Volume I) and format of the other volumes.

Since 2005, the Regulations for Biological Products in China has been incorporated into the Chinese Pharmacopoeia as a part of Volume III. For a long time, there are great differences between the Chinese Pharmacopoeia (Volume III) and the other volumes in format. The content included in the Chinese Pharmacopoeia (Volume III) has the characteristics of biological products, such as “basic requirements”, closely related to the monographs, and contains many specific items in GMP. It is recommended in the industry that the style and format of Chinese Pharmacopoeia (Volume III) should be gradually integrated and unified with the other volumes in the near future.

In summary, the “Items and Requirements” is also one of the most important chapters of the general notices, and the characteristics of the traditional Chinese medicine, chemical drugs, biological products and excipients in the “Items and Requirements” are retained in order to ensure the smooth promulgation and implementation of the Chinese Pharmacopoeia 2025 Edition. The common contents, such as storage, solubility and physical constants, are uniformly standardized and revised in the general notices of the Chinese Pharmacopoeia 2025 Edition.

It should also be particularly noted that since the content of the last chapter “Packaging, Labeling, Directions for use, Storage and Transportation” of the general notices in the Chinese Pharmacopoeia 2020 Edition (Volume III) is quite different from the other three volumes, it is retained in the Chinese Pharmacopoeia 2025 Edition without revision and unification.

2 Revisions to specific content in general notices of the Chinese Pharmacopoeia 2025 Edition

2.1 Basic principles of writing the general notices of the Chinese Pharmacopoeia 2025 Edition

The general notices of previous editions of Chinese Pharmacopoeia are representative of the characteristics of each edition, reflecting some common problems of drug standards in the era of each edition of pharmacopoeia. With the rapid development of science and technology, updated scientific concepts and technologies, as well as some new analytical methods and legal provisions are developed inevitably followed by promulgation and implementation of each edition of pharmacopoeia. In order to meet these requirements, make our drug standards better and fully reflect the core status of the Chinese Pharmacopoeia, each edition of the Chinese Pharmacopoeia shall be improved and revised on the basis of the previous edition, and reflects the upgrading and advanced management concepts and technical requirements of the current edition. Many common problems can be explained and embodied through the explicit provisions in the general notices.

These revisions mainly focuse on the unified provisions and requirements of the common problems in the implementation of laws, regulations and standards, and improves the general notices combined with current laws and regulations, additions and revisions.

2.2 Emphasis on the connection with the newly revised laws and regulations

The basis of the Vaccine Administration Law of the People’s Republic of China has been added to Article 1 in the General Principles in the general notices of the Chinese Pharmacopoeia 2025 Edition.

In accordance with the definition of drug standards in Article 47 of the Measures for the Administration of Drug Standards, Article 8 of the monographs has been standardized and the definition of monographs has been revised from “Monographs are technical requirements for quality control of a drug and for justification of whether the quality of a drug complies with the pharmaceutical standards and whether the quality is consistent. Monographs are set forth according to the physicochemical properties and biological characteristics of drugs and based on the approved formulation source, production process as well as the storage and shipping conditions, etc.” to “Monographs are technical requirements for quality control of a drug and for justification of whether the quality of a drug complies with the pharmaceutical standards in the shelf life and whether the quality is consistent. Monographs are set forth according to the physicochemical properties and biological characteristics of drugs and based on the source, formulation, preparation, shipping and storage conditions, etc.”.

2.3 Clearly distinguish between the mandatory requirements of the general requirements included in the Chinese Pharmacopoeia and the guiding status of the guidelines

The Provisions for Drug Registration stipulates that the general requirements included in the Chinese Pharmacopoeia are mandatory requirements. In order to further clarify the guiding status of the guidelines, the guidelines in the general notices of the Chinese Pharmacopoeia 2025 Edition are separated from the general requirements into two parts: general requirements and guidelines. The general requirements and guidelines are defined and distinguished in the general notices of the Chinese Pharmacopoeia 2025 Edition respectively, and it is clearly stipulated that the guidelines included in the Chinese Pharmacopoeia are recommended technical requirements. This distinction is conducive to the implementation of Chinese Pharmacopoeia. Therefore, the General Principles in the general notices of the Chinese Pharmacopoeia 2020 Edition are revised to form Article 2 of the General Principles in the general notices of the Chinese Pharmacopoeia 2025 Edition:

“The Chinese Pharmacopoeia consists of general notices, general requirements and monographs” is revised as “The Chinese Pharmacopoeia consists of general notices, monographs, general requirements and guidelines”.

“The general requirements include the general chapters and guidelines, as well as the general chapters and general monographs of biological products in the Chinese Pharmacopoeia” is revised as “The general requirements include general chapters and relevant general monographs in the Chinese Pharmacopoeia”.

“The guidelines are non-mandatory and recommended technical requirements stipulated for standardizing the implementation of the pharmacopoeia, guiding the development and revision of drug standards, and improving the level of drug quality control” is revised as “The guidelines are recommended technical requirements stipulated for standardizing the implementation of the pharmacopoeia, guiding the development and revision of drug standards, and improving the level of drug quality control”.

Article 3 of the General Principles: “The general notices and the general chapters/general chapters and general monographs of biological products in the current edition of Chinese Pharmacopoeia are also official for other standards of drugs in addition to those included in Chinese Pharmacopoeia” is revised as “The general notices and the general requirements in the current edition of Chinese Pharmacopoeia are also official for other standards of drugs in addition to those included in Chinese Pharmacopoeia”.

2.4 Further clarify the relevant provisions and requirements of Chinese Pharmacopoeia, and clarify the location and reference of general notices of Chinese Pharmacopoeia

It should be clear that “National drug standards consist of general notices, monographs and cited general requirements” and that the national drug standards consist of general notices, monographs and cited general requirements, not just the monographs themselves. Any national standards must be governed by the general notices and general requirements included in the current edition of Chinese Pharmacopoeia. Article 3 of the General Principles “The drug standard is composed of monograph and its cited general notices and general requirements” is revised as “The drug standard is composed of general notices, monographs and its cited general requirements.”

2.5 Improve the description of the requirements of pharmaceutical excipients involved in the drug products included in each volume

The requirements and descriptions of pharmaceutical excipients used for drug products in each volume are not unified. According to the overall requirements for pharmaceutical excipients in the Chinese Pharmacopoeia 2025 Edition (Volume IV), the corresponding content and description have been revised accordingly by taking into account the characteristics of each volume. See Table 1 for details.

Table 1 Description of the requirements for pharmaceutical excipients in general notices in each volume of the Chinese Pharmacopoeia 2025 Edition

3 Characteristics of general notices of the Chinese Pharmacopoeia 2025 Edition

3.1 Revise the requirements for abnormal toxicity in the general notices of Chinese Pharmacopoeia (Volume III)

It is specified in the general notices of the Chinese Pharmacopoeia 2025 Edition (Volume III) that “Where the monographs contain abnormal toxicity item, it is not regarded as a mandatory test item for release of each batch combined with the risk assessment results and quality control strategy, but still needs to be tested irregularly.” In addition, it is also specified in the general notices that “In case of a major pharmaceutical change, sufficient batches must be tested to determine the safety of the changed product; if the component properties of a product are not suitable for Test for Abnormal Toxicity, the test is not required on the basis of sufficient evidence and evaluation”. This revision not only emphasizes the main responsibility of the enterprise to ensure product quality, reduces the workload of the enterprise release inspection to a certain extent, but also provides a basis for the supervision and inspection of the test, and facilitates drug evaluation acting on international harmonization in terms of safety test items.

3.2 Achieve the harmonization and unification with ICH Q3C and Q3D guidelines and international standards by adding elemental impurities and revising residual solvents

According to national conditions, the Chinese Pharmacopoeia 2025 Edition has introduced the core content of assessment and control in ICH Q3C and Q3D guidelines, revised 0861 Residual Solvents and added 0862 Elemental Impurities to realize the harmonized transformation of ICH Q3C residual solvents and Q3D elemental impurities, and strengthen the control of drug safety risks and better protect the medication safety for Chinese people.

Relevant requirements for transformation and implementation of ICH Q3C and Q3D guidelines have been added in Article 17 of the general notices of the Chinese Pharmacopoeia 2025 Edition (Volume II). In the case that the original test items of the monographs have not been changed for the time being, enterprises are encouraged to adopt risk-based management concepts and methods for risk assessment and control of organic volatile compounds, elemental impurities, and genotoxic impurities in drug substances and drug products. If the risk assessment and control meet the requirements, the residual solvents, heavy metals, arsenic salts, etc. specified in the monographs can be waived. Meanwhile, it is specified that any change in methods or limits shall be subject to approval before implementation.

In the harmonization of the Chinese Pharmacopoeia 2025 Edition (Volume II) with ICH-related guidelines, measures such as parallel adoption and gradual transition of the ICH test methods and current test methods for a period of time are taken while taking full account of China’s national conditions, through the introduction of risk management concepts and methods to benchmark against the advanced international standards, actively and steadily promote the transformation and implementation of the ICH-related guidelines in the monographs of chemical drugs, and continuously strengthen the safety control of chemical drugs, reducing the test burden of enterprises. This revision is conducive to better protecting the safe and effective use of drugs in humans.

3.3 Further clarify the relevant provisions and requirements of pharmacopoeia

In response to comments from some clinicians that the requirements of [Usage and Dosage] item in some standards for Chinese medicinal materials and prepared slices of Chinese crude drugs in the current edition of Chinese Pharmacopoeia (Volume I) have restricted the use of drugs by clinicians, the requirements of [Usage and Dosage] item in the standards for Chinese medicinal materials and prepared slices of Chinese crude drugs in the general notices of the Chinese Pharmacopoeia 2025 Edition (Volume I) have been revised accordingly to “as per the guidance for clinical medication, clinical use should follow the doctor’s advice”, avoiding that some clinicians misunderstand the original provision as “restricted use”.

3.4 Clarify the rounding conventions for numerical values

The digital rounding requirement in the general notices of the Volume I, Volume II and Volume IV of the Chinese Pharmacopoeia 2025 Edition is described as “rounding up or down to the specified decimal place by the rounding conventions of significant figures”, without mentioning the reference basis of the rounding conventions. It is specified in the general notices of the Chinese Pharmacopoeia 2025 Edition (Volume III) that the rounding conventions for numerical values are based on the national standard GB/T 8170-2008 (Table 2). According to the convention, the rounding conventions for numerical values should be unified from Volume I to Volume IV of the pharmacopoeia, i.e. “4 rounded down, 6 rounded up and 5 round-to-even”, only that the basis for rounding conventions is clarified in Volume III.

Comparing the European, US and Japanese Pharmacopoeia, the rounding conventions for numerical values have been included in the US and Japanese Pharmacopoeias and the rounding convention in the European, US and Japanese Pharmacopoeia is “4 rounded down, 5 rounded up”.

According to the research, GB/T 8170-2008 Rounding Conventions for Numerical Values & Expression and Judgment of Limiting Values is the basis for the rounding conventions for numerical values adopted in the current edition of Chinese Pharmacopoeia and other national standards. If these conventions are revised, all national standards in the current edition will be affected. In order to ensure the proper implementation of the national standards, the original rounding conventions for numerical values in the general notices of the current edition of Chinese Pharmacopoeia are maintained and it is specified in the general notices of each volume of the Chinese Pharmacopoeia 2025 Edition that the rounding conventions for numerical values are based on GB/T 8170-2008, and see Table 2 for details.

Table 2 Simplified table of national standard GB/T 8170-2008 Rounding Conventions for Numerical Values

With the rapid development of pharmaceutical industry in China, the matched advanced analytical techniques and the research and development of instruments and equipment are also improved vigorously. At present, the Chinese Pharmacopoeia 2025 Edition has been further developed to expand the coverage of the Catalogue of National Essential Medicines and the Catalogue of Medicines for Basic Medical Insurance, adhering to the clinical application orientation. Therefore, the number of monographs included in each edition of Chinese Pharmacopoeia has increased, reflecting the achievements of medical science and technology innovation, and further meets the clinical drug needs in China. Furthermore, it has also led in improving the national standards system that conforms to the characteristics of traditional Chinese medicine, chemical drugs and biological products, and reflecting the scientific, normative, forward-looking and guiding role of the Chinese Pharmacopoeia.

It is hoped that by introducing the overall situation and revised content of the general notices in the Chinese Pharmacopoeia 2025 Edition, more medical workers and relevant persons can deeply understand the Chinese Pharmacopoeia and its essence.

The general notices of current edition of Chinese Pharmacopoeia have been gradually improved and formed after 11 editions. The general notices of the Chinese Pharmacopoeia 2025 Edition have undergone significant changes and improvements in both form and content. The general notices of the Chinese Pharmacopoeia can be representative of the whole core content. To better understand the Chinese Pharmacopoeia, we should first learn the general notices of the Chinese Pharmacopoeia, because the general notices are the basic principles for the proper application of the Chinese Pharmacopoeia, and the principles are fundamental. The general notices are the most direct interpretation and embodiment of the monographs, general requirements and guidelines in the pharmacopoeia, and the unity and coordination of the monographs needs to be reflected in the general notices. The Chinese Pharmacopoeia is developed and upgraded, and its general notices also keep up with the times. Given the importance and significance of the general notices in Chinese Pharmacopoeia, the coordination of the general notices in all volumes of the Chinese Pharmacopoeia 2025 Edition is also a common expectation and development need.

(Chinese Pharmacopoeia Commission)