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Review paper
Development of the general chapters of the Chinese Pharmacopoeia
2020 edition: A review
Xinyi Xu, Huayu Xu, Yue Shang, Ran Zhu, Xiaoxu Hong, Zonghua Song, Zhaopeng Yang
*
Chinese Pharmacopoeia Commission, Beijing, 100061, China
article info
Article history:
Received 27 December 2020
Received in revised form
5 May 2021
Accepted 9 May 2021
Available online 20 May 2021
Keywords:
Chinese pharmacopoeia
2020 edition
General chapter
Development
Review
abstract
The Chinese Pharmacopoeia 2020 edition was reviewed and approved by the National Medical Products
Administration and the National Health Commission of the People's Republic of China in July 2020. The
current edition was officially implemented on December 30, 2020. The general chapters of the Chinese
Pharmacopoeia discuss the general testing methods and guidelines, which are the common re-
quirements and basis for the implementation of drug standards in the Chinese Pharmacopoeia. Owing to
adherence to the principles of scientificity, versatility, operability, and sustainable development, there is
an improvement in the general chapters of the 2020 edition over those of the previous editions. Further,
the application of advanced and mature analytical techniques has expanded, the development of testing
methods for exogenous pollutants in traditional Chinese medicines has been strengthened, and technical
requirements are now better harmonized with international standards. The updated edition provides
technical and methodological support to ensure safety, effectiveness, and control of pharmaceuticals in
China and will play an important and active role in encouraging the application of advanced technolo-
gies, improving the quality control of medicines, and strengthening the means of drug regulation in
China. This review provides a comprehensive introduction of the main features of and changes to the
general chapters in the Chinese Pharmacopoeia 2020 edition and aims to provide reference for its correct
understanding and accurate implementation.
©2021 Xi'an Jiaotong University. Production and hosting by Elsevier B.V. This is an open access article
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction
The Chinese Pharmacopoeia 2020 edition was reviewed and
approved by the National Medical Products Administration (NMPA)
and the National Health Commission of the People's Republic of
China in July 2020. This edition was officially implemented on
December 30, 2020. The Chinese Pharmacopoeia is a statutory
technical specification that must be implemented for drug devel-
opment, production, use, and regulation in China. The general
chapters in the Chinese Pharmacopoeia are the basis for the accu-
rate implementation of the Chinese Pharmacopoeia. The 2020
edition contains 360 general chapters, including 23 new and 83
revised chapters. This updated edition reflects not only the current
level of technology used in the pharmaceutical industry in China
but also the technologies used for international drug quality
control.
2. Application of advanced and mature analytical techniques
has been expanded
Method 0451, “X-ray fluorescence spectroscopy”, was added to
guide the application of X-ray fluorescence spectroscopy in the
qualitative and quantitative analyses of elemental impurities [1e9].
Oscillating transducer density meter application and instrumen-
tation were added in method 0601, “Determination of Relative
Density”[10,11]. In method 0713, “Tests of Fat and Fatty Oil”, the
melting range, saponification value, and iodine value were revised,
and information concerning unsaponifiable matter, fatty acid
composition, alkaline impurities, anisidine value, sterols, and trans
fatty acids was added [12e16]. Methods 1001, “Polymerase Chain
Reactions”;1021,“Identification of Bacterial DNA Sequences”; and
9108, “DNA Sequencing”, were added. These methods are used to
ensure the accurate identification and clinical safety of drugs
[17e22]. In vitro methods, which involve the use of an instrument
to determine endpoints, have replaced in vivo biological methods,
which is in line with the goal of reducing, replacing, and refining
laboratory animal use. The anti-factor IIa and anti-factor Xa assays
Peer review under responsibility of Xi'an Jiaotong University.
*Corresponding author.
E-mail address: yangzhaopeng@chp.org.cn (Z. Yang).
Contents lists available at ScienceDirect
Journal of Pharmaceutical Analysis
journal homepage: www.elsevier.com/locate/jpa
https://doi.org/10.1016/j.jpha.2021.05.001
2095-1779/©2021 Xi'an Jiaotong University. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.
org/licenses/by-nc-nd/4.0/).
Journal of Pharmaceutical Analysis 11 (2021) 398e404
were added to method 1208, “Biological Assay of Heparin”[23e27].
The heparin-binding capacity assay was added to method 1213,
“Biological Assay of Protamine Sulfate”[28e32]. New sterilization
methods (vapor-phase sterilization and liquid-phase sterilization)
were added to method 1421, “Methods of Sterilization”, to guide the
sterilization/filtration-based production of drugs to ensure that the
sterility level meets the requirements [33e36]. The monocyte
activation test was added in guideline 9301, “Application of Safety
Tests for Injection”[37e42]. Based on research detailing the tech-
nical requirements for the verification and transfer of analytical
methods from the United States Pharmacopoeia (USP) and the
American Association of Analytical Chemists [43e49] to the Chi-
nese Pharmacopoeia, guidelines 9099, “Verification of Compendial
Procedures”, and 9100, “Transfer of Analytical Procedures”,were
added.
The applicability requirements of the analytical methods were
enhanced. In method 1105, “Microbiological Examination of Non-
sterile Products: Microbial Enumeration Tests”, an improved
method for the preparation of aerosol test samples was included,
and information regarding the quantities of small-dose, low-con-
tent, and small-batch samples to be tested was added. In method
1107, “Microbiological Acceptance Criteria of Nonsterile Pharma-
ceutical Products”, the microbiological acceptance criteria for
semisolid preparations were modified to ensure strict control, as is
required for liquid preparations. The definition and scope of anti-
microbial preservatives in method 1121, “Antimicrobial Effective-
ness Testing”, have been revised to enhance accuracy. The recovery
rates of the suitability test for the medium and test microorganisms
used in the operational suitability test were revised to ensure
consistency with method 1105 [50]. Other newly added and revised
general testing methods are detailed in Table 1.
3. Development of testing methods for exogenous pollutants
in traditional Chinese medicines (TCMs) has been
strengthened
Methods for determining exogenous pollutants in TCMs have
been improved in the Chinese Pharmacopoeia 2020 edition.
Qualitative screening and quantitative analytical methods,
including gas chromatography-tandem mass spectrometry (GC-
MS/MS) and high-performance liquid chromatography-tandem
mass spectrometry (HPLC-MS/MS), were added to method 2341,
“Determination of Pesticide Residues”. Qualitative screening
methods are used for the rapid qualitative testing, risk monitoring,
and early warning testing of pesticides. Pesticides with limited
requirements can be directly determined using a quantitative
analytical method. In the 2020 edition, the number of pesticides
tested has increased to 592. Eighty-eight pesticides were identified
using GC-MS/MS and 523 pesticides were determined using HPLC-
MS/MS. For pesticides that can be determined with GC-MS/MS and
HPLC-MS/MS, the preferred method is provided, and the maximum
possible number of characteristic ions is recommended [51e56].
Accurate and low-detection-limit methods, including HPLC-MS/
MS analysis of aflatoxin and patulin; HPLC and HPLC-MS/MS ana-
lyses of ochratoxin A, zearalenone, and vomitoxin; and HPLC-MS/
MS analysis of multiple mycotoxins, were added to method 2351,
“Determination of Mycotoxins”. Considering that the above-
mentioned methods require complex sample pretreatment, spe-
cific instruments, and specialized personnel training, they will be
subject to limitations for being used in quality control of TCMs. A
fast, sensitive, simple, and low-cost aflatoxin ELISA method was
added as a new technique for the quality control of TCM in China
(Table 2)[57e63].
As the development of acceptable microbiological criteria for
TCM decoction pieces was a breakthrough, strategies and methods
for specific microbial contamination control in TCMs with different
uses were introduced. Compared with the medicines produced
according to good manufacturing practices, TCM decoction pieces
contain microorganisms in high abundance, with a wider variety of
species and a more uneven distribution. Further, the microbial
analysis requirements are unique to each type of medicinal mate-
rial. Therefore, method 1108, “Microbiological Examination of
Traditional Chinese Medicine Decoction Pieces”, was added. The
enumerated microbial parameters include total aerobic microbial
counts, total combined yeast/mold counts, and the number of heat-
resistant bacteria; the parameters for specified microorganisms
Table 1
Additions and revisions in the Chinese Pharmacopoeia 2020 edition general testing methods.
General chapter Additions and revisions
0421, Raman Spectroscopy Transmittance, tip-enhanced Raman spectroscopy, and imaging techniques were introduced, and their applications in
the fields of physics, chemistry, process control, and other analyses was expanded.
0512, High-Performance Liquid Chromatography The latest HPLC developments and application progress were fully detailed. Information about multidimensional HPLC,
charged aerosol detection, adjusted chromatographic conditions, and common qualitative analysis methods was added.
0661, Thermal Analysis A thermogravimetry-mass spectrometry method was added to realize the qualitative and quantitative analyses of
crystallization solvents (aqueous) or other volatile components in a test sample
0981, Crystallinity Differential scanning calorimetry was added for crystallinity tests of the sharp endothermic peak of crystalline
materials or the dispersion (or no endothermic peak) characteristics of amorphous materials. This method can also be
used to identify the crystalline form when there is a difference in the endothermic peak position of the solid state of
different crystal forms of the same compound.
0991, Determination of Specific Surface Area;
0992, Determination of the Density of Solids
The basic definitions and terminology of specific surface area and solid density are given. Information about
instruments and measuring methods is provided.
1143, Test for Bacterial Endotoxins;
9251, Guideline for the Application of the
Bacterial Endotoxin test
Traceability with international standards and a description of false-positive results and processing methods were added
to avoid misinterpretation due to
b
-glucans. The gel-clot method was revised, and the requirement to initially fill the
amoebocyte lysate, followed by the addition of endotoxin, was removed. To standardize the design, procedure, and
limit setting of interference experiments, to ensure even quality, and to address a lack of amoebocyte lysate,
information about the contents of the bacterial endotoxin for limit setting, choice of methods, and pretreatment
methods for test samples were added. The recombinant factor C assay, which is suitable for testing samples containing
b
-glucans, factor B, and prothrombin, was introduced to address the shortage of amoebocyte lysate resources.
1146, Test for Histamines;
9301, Guideline for the Application of Safety Tests
for Injections
The preparation method for the test histamine solution, the method suitability test, and the determination of the
minimum valid concentration test were added.
9015, Guideline for Studies and Quality Control of
Drug Polymorphisms
Solid nuclear magnetic resonance spectroscopy method was added. The differences in the chemical environment of the
same atomic nucleus of different crystal forms of a test sample causes differences in chemical shifts, coupling constants,
and relative intensities during identification of the crystalline states.
X. Xu, H. Xu, Y. Shang et al. Journal of Pharmaceutical Analysis 11 (2021) 398e404
399
include the number of bile-tolerant gram-negative bacteria,
Escherichia coli, and Salmonella. The quantity of the product to be
tested, the preparation method for the test solution, and the suit-
ability test of the counting method are specified; and the uncer-
tainty in the interpretation of the results can be greater for TCMs
than that for other products.
In method 2322, “Determination of Mercury and Arsenic
Speciation and Valence States”, the method of test solution prep-
aration was improved to address the difficulties in determining the
valence states of arsenic and mercury in marine- and animal-
derived TCMs. Notably, information regarding the preparation of
the test solution, determination of the sample amount, and prin-
ciple of the method application, was added.
4. Technical requirements are better harmonized with the
International Council for Harmonization (ICH) of technical
requirements for pharmaceuticals for human use guidelines
In 2017, the NMPA joined the ICH. In the process of compiling
the Chinese Pharmacopoeia 2020 edition, the implementation of
international standards was further strengthened (Table 3)
[64e67]. Considering the current status of drug production and
Table 2
Comparison of immunological and chemical methods for the determination of aflatoxins.
Item Pretreatment Sensitivity Type Percent recovery (%) Equipment Speed Cost
(RMB/
test)
Personnel Refs.
Hordei Fructus
Germinatus
Ziziphi
Spinosae
Semen
Persicae
Semen
Coicis
Semen
ELISA Direct dilution or
extraction, 20e60 min
ng/mL AFB
1
82.8e95.9 74.7e88.5 94.1e101.9 84.0e89.1 Fluorophotometer
(10,000e30,000 RMB)
60
min/
test
30e50 Ordinary personnel
can operate
[58]
AFTs 98.4e110.4 87.0e98.6 104.0e112.0 86.8e103.3
HPLC Immunoaffinity
column, 4e8h
ng/mL AFB
1
61.3e70.9 57.0e61.8 68.1e78.5 63.9e69.7 HPLC (<100,000 RMB) 3 h/
test
200
e300
Requires trained
personnel to operate
[58]
AFTs 62.5e78.5 58.1e67.8 69.2e84.0 65.1e74.5
AFB1: aflatoxin B1; AFTs: total aflatoxin.
Table 3
Implementation status of the ICH Q4B in the Chinese Pharmacopoeia 2020 edition.
ICH No./Chinese
Pharmacopoeia
No.
Testing method Implementation
status
Main differences Refs.
Annex 1/0841 Residue on ignition/sulfated ash In the process of
implementation
Sulfuric acid addition amount, ignition temperature, and
conditions for the end of the experiment
[64e66]
Annex 2/0102,
0942
Test for extractable volume of parenteral preparations In the process of
implementation
Sampling method, method details, and result interpretation [64e66]
Annex 3/0903 Test for particulate contamination: subvisible particles In the process of
implementation
Instrument calibration for the light obscuration particle count
test, requirements for testing environmental water samples,
sampling method, and the evaluation of injections with a labeled
volume of 100 mL
[64e66]
Annex 4A/1105 Microbiological examination of nonsterile products:
microbial enumeration tests
In the process of
implementation
Strains, medium, and method details [64,66]
Annex 4B/1106 Microbiological examination of nonsterile products:
test for specified microorganisms
In the process of
implementation
Strains, medium, method details, and result interpretation [64,66]
Annex 4C/1107 Microbiological examination of nonsterile products:
acceptance criteria for pharmaceutical preparations
and substances for pharmaceutical use
In the process of
implementation
Scope, Salmonella tests, and microbial acceptance criteria for
small and microdose preparations such as patches, and standards
for traditional Chinese medicines (vegetable medicines)
[64,66]
Annex 5/0921 Disintegration test In the process of
implementation
Apparatus, result interpretation [64e66]
Annex 6/0941 Uniformity of dosage units In the process of
implementation
Methods, result interpretation [64e66]
Annex 7/0931 Dissolution test In the process of
implementation
Methods, result interpretation [64e66]
Annex 8/1101 Sterility test In the process of
implementation
Strains, number of products to be tested, filter times, and quantity
of the rinsing fluid
[64,66]
Annex 9/0923 Tablet friability In the process of
implementation
Apparatus, notes [64e67]
Annex 10/0541 Polyacrylamide gel electrophoresis In the process of
implementation
Method details [64e66]
Annex 11/0542 Capillary electrophoresis In the process of
implementation
Method details [64e66]
Annex 12/0982 Analytical sieving In the process of
implementation
Chinese Pharmacopoeia includes the manual sieving method; the
ICH guideline includes the sonic-sifter sieving method
[64e66]
Annex 13/0993 Bulk density and tapped density of powders In the process of
implementation
No changes [64e66]
Annex 14/1145 Bacterial endotoxins test In the process of
implementation
Method description [64,66]
X. Xu, H. Xu, Y. Shang et al. Journal of Pharmaceutical Analysis 11 (2021) 398e404
400
quality control and the current applicability of products already on
the market in China, the newly added general technical re-
quirements are consistent with the ICH guidelines, and the revised
general technical requirements are better harmonized with the ICH
guidelines as much as possible.
Stability is one of the critical factors influencing competivity in
the drug market and is an important field of technological inno-
vation. Guideline 9001, “Stability Testing of Drug Substances and
Preparations”, was revised according to the ICH Q1A [68]. The
definition of “significant changes”in preparation quality was pro-
posed to guide manufacturers to focus on critical quality attributes.
Additionally, the requirements for the transportation of
temperature-sensitive drugs have been clarified. For special prep-
arations, such as sustained- and controlled-release preparations
and inhalations, the important parameters affecting their stability
test are listed. Guideline 9101, “Validation of Analytical Methods”,
was revised to be consistent with the ICH Q2 [69]; the contents
regarding the correction factor were deleted and the methods for
accuracy and precision were revised. The reporting, identification,
and qualification thresholds for drug impurities and the decision
tree of the ICH Q3A and Q3B [70,71] were introduced in guideline
9102, “Analysis of Impurities in Drugs”. To ensure consistency with
the ICH Q3C [72], cumene and methyl isobutyl ketone were revised
from class 3 solvents to class 2 solvents, and triethylamine, a class 3
solvent, was added to method 0861, “Determination of Residual
Solvents”. The flow-through cell and reciprocating cylinder
methods were added to method 0931, “Dissolution and Drug
Release Test”. The instruments, methods, and interpretations
related to the ICH Q4B Annex 7 [73e82] and the research results on
specific preparations, such as compound ketoconazole cream and
lithium carbonate sustained-release tablets, were introduced.
Method 1101, “Sterility Tests”, was improved, based on the ICH Q4B
Annex 8, to be more instructive and practical [83]. The scope of
environmental monitoring, the storage and use of culture media
and strains, the culture time of the medium sensitivity test, the
number and quantity of products to be tested, and the re-
quirements of incubation and observation were revised. The bulk
density and tapped density are important functionality-related
characteristics of pharmaceutical excipients in powder form.
These densities are commonly used to calculate the Hausner ratio
and compressibility index of the powders. Referring to the ICH Q4B
Annex 13 [84e86], method 0993, “Bulk Density and Tapped Density
of Powders”, was added. Referring to the ICH M7 [87], guideline
9306, “Genotoxic Impurities Control”, was added, and the general
principles, assessment methods, and calculation methods of
acceptable intakes and limits were introduced.
However, some general testing methods in the Chinese Phar-
macopoeia 2020 edition still differ from those in the ICH Q4B
(Table 3). The general testing methods in the Chinese Pharmaco-
poeia were originally drafted according to the British Pharmaco-
poeia and the World Health Organization, and these general
chapter methods have a long history of use and a wide variety of
applications in China. However, the current mainstream drug
standard harmonization is based on the Pharmacopoeia Discussion
Group and the ICH. Moreover, due to limited information and the
complexity of regulatory adjustments, the information in interna-
tional standards referenced by the Chinese Pharmacopoeia is not
comprehensive, and the revisions are not timely. Despite these
challenges, harmonization with international standards is still
vigorously promoted by the Chinese Pharmacopoeia Commission
(ChPC). In October 2018, the ICH Q4 symposium was held in Beijing.
More than 20 experts from the ICH Expert Working Group and
ChPC discussed strategies for implementing ICH Q4 in China. In
2020, the ICH Q4B implementation status of the Chinese Pharma-
copoeia was added to the official ICH website for the first time [64].
5. Summary and prospects
The general chapters of the Chinese Pharmacopoeia 2020 edi-
tion are based on science, risk, and applicability, and refer to the
ICH guidelines. New technologies and requirements developed in
recent years were introduced to provide technical and methodo-
logical support to ensure the safety, effectiveness, and controlla-
bility of pharmaceuticals in China. The current edition will play an
active role in encouraging the application of advanced technolo-
gies, improving quality control of drugs, and strengthening the
means of drug regulation in China.
As observed from the history of other pharmacopoeias, the
development of drug standards is a process of gradual and
continuous improvement owing to the limitations of scientific
cognition. The concept of quality by design and life cycle manage-
ment will be further implemented in the general chapters of the
2025 Chinese Pharmacopoeia [88e96]. For example, analytical
procedure lifecycle guidelines and process analysis technologies
will be introduced, and the roles of statistical methods in data
evaluation, interpretation, and processing for the development,
validation, transfer, and verification of analytical methods will be
strengthened. The system for microbiological control based on risk
assessment will also be improved.
Widely used analytical technologies, such as HPLC, GC, and
atomic spectroscopy, will be revised. Moreover, additional scienti-
fic, objective, and convenient techniques will be introduced in a
timely manner. The development of personalized microbial testing
methods for specific preparations and research detailing rapid
microbiological methods will be further elaborated [97e101]. The
testing methods for active and toxic ingredients, exogenous pol-
lutants in crude TCMs, and the microbiological examination re-
quirements for TCM decoction pieces will continue to be improved.
In 2020, the revision of the Q4B guidelines was initiated by the
ICH. The ChPC will continue to expand its participation in the
harmonization of drug standards and actively promote harmoni-
zation/interchangeability with ICH Q4 based on validation. Other
ICH guidelines, such as the ICH Q3D, will also be harmonized.
Further, the general chapter of “Elemental Impurities Limits and
Procedures”in the Chinese Pharmacopoeia will be developed to
better assess and control elemental impurities in drugs in China.
Declaration of competing interest
The authors declare that there are no conflicts of interest.
Acknowledgments
The authors acknowledge the financial support from the Chi-
nese Pharmacopoeia Commission Drug Standard Promoting Funds
and Comprehensive Reform of the Chinese Drug and Medical De-
vice Review and Approval System Funds (2015e2020).
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