Anhui and Liaoning: clarify the requirements for formulating standards for traditional Chinese medicine formula granules

Medical Network, April 19, April 15, Anhui Provincial Food and Drug Administration publicly solicited "Technical Requirements for Quality Control and Standard-setting of Anhui Province Traditional Chinese Medicine Formula Granules (Trial)", "Anhui Province Traditional Chinese Medicine Formula Granule Standard Establishment Work Procedures and Application Information Requirement (Trial)" (Draft for Solicitation of Comments) comments
.
On the same day, the Liaoning Provincial Drug Administration issued a notice on the development of the "Liaoning Province Traditional Chinese Medicine Formula Granule Standard (Trial)"
.
The notice clearly stated that the Liaoning Provincial Food and Drug Administration intends to develop the Liaoning Province Traditional Chinese Medicine Formula Granule Standards
.
Relevant drug manufacturers and R&D units are required to comply with the "Notice of the State Food and Drug Administration on Issuing Technical Requirements for Quality Control and Standard Establishment of Chinese Medicine Formula Granules" (No.
16 of 2021) and the National Pharmacopoeia Commission "Relevant Chinese Medicine Formula Granule Drug Standard Establishment" According to the provisions of the "Notice", we will study and draft the standards for formula granules of Chinese medicines of relevant varieties, and submit relevant information to the Drug Registration Office of the Provincial Food and Drug Administration
.
Starting from November 1, 2021, Chinese medicine formula granules that do not have national drug standards or standards established by provincial drug regulatory authorities shall not be marketed
.

The original text is as follows: In
order to standardize the quality standard research of traditional Chinese medicine formula granules in Anhui Province, and clarify the working procedures and requirements for the declaration of quality standard for traditional Chinese medicine formula granules in Anhui Province, our bureau organized the drafting of "Technical requirements for quality control and standard formulation of traditional Chinese medicine formula granules in Anhui Province (for trial implementation)" "And "Anhui Province Traditional Chinese Medicine Formula Granule Standard Formulation Working Procedures and Application Document Requirements (Trial)" for soliciting comments, now open for comments
.
If you have any amendments and suggestions, please give feedback in writing or via email before April 22, 2021
.
Tel: 0551-62999283; Postal Code: 230051; Address: Room 214, District C, Provincial Government Building, No.
509, Ma'anshan Road, Hefei City; E-mail: 1326631745@qq.
com
　　Annex:
1.
Technical requirements for quality control and standard formulation of traditional Chinese medicine granules in Anhui Province (for trial implementation) (draft for comments).
doc 2.
Working procedures for the formulation of standards for traditional Chinese medicine formula granules in Anhui Province and requirements for application materials (for trial implementation) (draft for comments).
doc Anhui Provincial Drug Administration April 15, 2021
　　Annex 1
　　Quality Control and Standardization of Traditional Chinese Medicine Formula Granules in Anhui Province
　　Technical Requirements (Trial)
　　(Draft
for Comment) To meet the clinical use requirements of traditional Chinese medicine prescription granules in Anhui Province, standardize the Anhui Province TCM formula The standard study of granules reflects the characteristics of the quality control of traditional Chinese medicine formula granules
.
This specification is formulated with reference to the "Technical Requirements for Quality Control and Standard Formulation of Traditional Chinese Medicine Formula Granules" of the State Food and Drug Administration, combined with the actual situation of the traditional Chinese medicine formula granule industry in Anhui Province .

　　1.
Basic requirements
Traditional Chinese medicine formula granules are granules that are extracted, separated, concentrated, dried, and granulated from single-flavored Chinese herbal medicine pieces by heating with water.
Under the guidance of the theory of Chinese medicine, they are formulated in accordance with the clinical prescription of Chinese medicine, and then they can be used by patients
.

　　(1)
The preparation of traditional Chinese medicine formula particles with the basic properties of decoction should be basically the same as the traditional decoction except for the molding process, that is, use water as a solvent to heat and extract, and use physical methods for solid-liquid separation, concentration, drying, and Process production such as pellet molding
.

　　(2) Compliance with the relevant requirements of the General Rules of Granules
Unless otherwise specified, the granules of Chinese medicine formula shall comply with the relevant provisions of the current edition of the Chinese Pharmacopoeia for Granules in the General Rules of Preparations
.
According to the nature of each species, the necessary auxiliary materials for particle forming can be used, and the amount of auxiliary materials shall be minimized
.
Unless otherwise specified, the ratio of auxiliary materials and intermediates (extract or dry powder, calculated as dry products) is generally not more than 1:1
.

　　(3) Comply with the principle of variety applicability.
In principle
, some varieties with natural properties that are not suitable to be made into traditional Chinese medicine formula granules should not be prepared into traditional Chinese medicine formula granules
.

　　2.
Requirements for research samples and reference materials
　　(1) Samples for
research The samples for research should be representative, and the origin of the Chinese medicinal materials used should cover the local or main production area where the Chinese medicinal materials are to be used.
Each origin of Chinese medicinal materials There are no less than 3 batches of samples, and a reasonable evaluation of the representativeness of the number of sample batches from the environmental conditions of the place of production, quality level, etc.
, should be collected at least 15 batches of Chinese medicinal materials samples, and after the qualifications of relevant professional and technical personnel, the preparation Formed Chinese herbal medicine pieces and "standard decoction"
.
Among them, at least 3 batches should be of commercial scale to meet the requirements of samples for filing
.
The storage of samples shall comply with the storage requirements under each category
.
All samples should be kept as required
.

　　(2)
Reference substances (including reference substances, reference extracts and reference medicinal materials) approved by the national statutory department shall be used for the establishment of reference substance standards
.
If the reference substance used is self-developed, the corresponding reference substance research data and physical samples of the reference substance should be submitted to Anhui Food and Drug Inspection Institute in accordance with relevant requirements
.

　　3.
Requirements for raw materials and excipients
　　(1) Chinese medicinal materials
for the production of decoction pieces shall comply with the relevant regulations in the current version of the Chinese Pharmacopoeia, other national standards or the "Anhui Provincial Standards for Chinese Medicinal Materials" and other provincial Chinese medicinal materials standards
.
The basis, harvest time, production area, processing method, medicinal site, etc.
should be fixed and the basis for selection should be explained
.
Among them, the Chinese medicinal materials standards of Anhui Province and the Chinese medicinal materials standards of other provinces are included at the same time, and the varieties with the same origin shall be given priority to implement the Chinese medicinal materials standards of Anhui Province
.

　　(2) Decoction pieces of traditional Chinese medicine
1.
Decoction pieces used for the production of granules of traditional Chinese medicine should meet the relevant requirements and general rules of decoction pieces in the current version of the Chinese Pharmacopoeia, other national standards, or the “Anhui Province Traditional Chinese Medicine Decoction Pieces Processing Regulations” and other provincial standards for the processing of decoction pieces.
It is stipulated that the Anhui Province TCM Decoction Pieces Processing Regulations and other provinces TCM decoction pieces have the same name varieties, and the requirements of the Anhui Province TCM Decoction Pieces Processing Regulations should be implemented first
.
Enterprises should formulate internal control standards and key control indicators based on the actual quality of traditional Chinese medicine decoction pieces and the level of process control, and provide three batches of inspection reports
.
2.
The processing methods and conditions of Chinese medicine decoction pieces should be clarified, the key production equipment, scale, yield and auxiliary materials, packaging materials, packaging, storage conditions, etc.
should be clarified, and the corresponding production process quality control methods should be explained
.

　　(3)
Solvent for extraction Chinese medicine formula granules are extracted as pharmaceutical water, and acid-base or organic solvents must not be used
.

　　(4) Medicinal excipients The excipients
used in the production of traditional Chinese medicine formula granules shall meet the requirements for medicinal use, and provide relevant supporting documents, sources, quality standards, inspection reports and selection basis
.

　　(5) Packaging materials and containers in
direct contact with medicines.
Packaging materials or containers in direct contact with medicines shall meet the requirements for medicinal use, and provide relevant supporting documents, sources, quality standards, inspection reports and selection basis.
Capacitive research
.

　　4.
Standard decoction requirements
Chinese herbal medicine is an important medicinal substance for the clinical efficacy of Chinese medicine.
Its safety and effectiveness have been widely recognized, and its customary method is mainly decoction.

.
Single-flavored Chinese medicine formula granules are water extracts of single-flavored Chinese herbal medicines.
In order to ensure that the traditional Chinese medicine formula granules can bear the safety and effectiveness of traditional Chinese herbal medicines, they need to be bridged by standard decoctions, which are used to measure single-flavored Chinese medicine formula granules.
Whether the corresponding clinical decoction of single-flavored pieces of traditional Chinese medicine is basically the same as the material standard
.
The "standard" in the standard decoction mainly covers the authenticity of the prepared pieces of traditional Chinese medicine, the uniformity of the extraction process and the rigor of quality control
.
Characterization standard decoction, required by not less than 15 representative batches of raw material, followed Chinese medicine theory, respectively, according to the clinical side decoction boiling regulation range of the boiling liquid separation, or suitably prepared by suitably concentrating After the method is dried and prepared, determine its paste rate, effective (or index) component content and transfer rate, etc.
, calculate the relevant average value, and specify the acceptable range of its variation
.
All pharmacological studies of traditional Chinese medicine formula granules must be compared with standard decoctions
.

　　(1) Raw materials
for the research and characterization of standard decoctions.
The raw materials for the research and characterization of standard decoctions include Chinese medicinal materials and Chinese medicinal pieces.
In addition to meeting the requirements of the "Research Samples" and the "Requirements for Raw and Excipients", the specifications of the medicinal pieces shall be Consistent with "Chinese Pharmacopoeia"
.

　　(2) Study and characterize the preparation of standard decoction decoctions.
The decoctions are prepared
from single-flavored pieces of traditional Chinese medicine, including decoction, solid-liquid separation, concentration and drying.
The method, equipment, process parameters and operating procedures should be fixed
.

　　1.
Decoction
is based on the full study of ancient and modern documents, taking into account factors such as the properties of traditional Chinese medicine, medicinal parts, texture, etc.
, and referring to the former Ministry of Health and the State Administration of Traditional Chinese Medicine "Management Standards for Traditional Chinese Medicine Decoction Rooms in Medical Institutions" (Chinese Traditional Medicine Issue [2009] No.
3), fix the pre-treatment method, the number of decoctions, the amount of water added, the decoction time and other relevant parameters for decoction
.
There is no uniform regulation for decoction equipment (but continuous reflux extraction equipment shall not be used), and the name and model of the equipment should be indicated in the experiment report and application materials
.
It is recommended that the amount of Chinese herbal medicine pieces used for each decoction is generally not less than 100 grams, and the Chinese herbal medicine pieces such as flowers and leaves can be reduced
.
(1) Pre-treatment: The decoction pieces of Chinese medicine should meet the relevant requirements of the current version of the "Chinese Pharmacopoeia", and the necessary treatment of the pieces of Chinese medicine should also be made with reference to traditional experience
.
For example, depending on the texture of traditional Chinese medicine decoction pieces, mashing or breaking the shell should be carried out according to the requirements of the Chinese medicine adjustment "every shell must be pounded, every seed must be broken", among which the cracking rate should not be less than 90%
.
(2) Soaking: The decoction pieces of Chinese medicine should be soaked first, and the soaking time should be determined according to the texture of the pieces of Chinese medicine, generally not less than 30 minutes
.
(3) Decoction times: each dose of medicine is generally decocted twice
.
(4) The amount of water added: As the texture and water absorption of Chinese herbal medicine pieces are quite different, the amount of water added should be determined according to different Chinese herbal medicine pieces
.
The amount of water to be added is generally 2 cm to 5 cm after the medicinal surface is soaked, and the amount of water can be added to the flower and grass Chinese medicine pieces or the Chinese medicine pieces with a long decoction time
.
(5) Decoction time: The decoction time should be determined according to the medicinal properties and functions
.
It is generally boiled and then decocted for 30 minutes; anti-surface, heat-clearing, and aromatic drugs should not be decocted for a long time.
It is advisable to decoct for 20 minutes after boiling; the decoction time can be appropriately extended for the hard-textured Chinese medicine pieces; nourishing Chinese medicine pieces After boiling with martial fire, switch to slow frying for about 60 minutes
.
The second frying time can be appropriately shortened
.
The properties, efficacy, texture, and water absorption of decoction pieces of traditional Chinese medicine are quite different.
When the above parameters cannot meet the requirements of the "Management Regulations for Traditional Chinese Medicine Decoction Rooms in Medical Institutions", they should be added or subtracted as appropriate, and data parameters should be provided
.

　　2.
Solid-liquid separation
(1) Separation: the solid-liquid separation should be carried out while it is hot, the mesh number of the filter material should be more than 100 meshes, and the method, equipment, consumables and conditions should be fixed
.
(2) Mixing: Mix the two decoction liquids and set aside
.

　　3.
Concentration and drying of the
above-mentioned decoction mixture.
Generally, it is concentrated into a prescribed amount of extract or dried into a dried product by a suitable drying method
.
Concentration can be concentrated under reduced pressure at low temperature, and the temperature generally does not exceed 65°C
.
Drying adopts freeze-drying or suitable drying method to ensure the stability of its quality, easy dissolution and no need to add auxiliary materials
.

　　(3) Characterization and application of
standard decoctions The characterization of standard decoctions requires at least the following three parameters
.
1.
Extraction rate: Calculate the extraction rate and standard deviation (SD) with dry powder
.
The average value plus or minus 3 times SD (or 70%—130% of the average value) is the allowable range of the paste rate
.
2.
Effective (or index) component content and content transfer rate: formulate effective (or index) component content determination method, measure the effective (or index) content of each batch of standard decoction, calculate the transfer rate and standard Deviation
.
The acceptable range of the transfer rate is the mean plus or minus 3 times the SD (or 70%-130% of the mean).
Determine the content limit and range based on the content of the effective (or index) component obtained by the content determination
.
For Chinese herbal medicines that contain volatile oil content measurement items in the standard of traditional Chinese medicine and clinical prescriptions of traditional Chinese medicine that contain volatile oil components, the decoction liquid should be determined by a suitable method for measuring the content of volatile oil in the decoction liquid
.
3.
Characteristic map or fingerprint map: It is recommended to use liquid phase or gas chromatography to compare the number of chromatographic peaks of the main components and specify their relative retention time, etc.
(the calculation method shall be specified separately)
.
Use similarity evaluation software to generate a standard decoction control feature map, and mark its sample concentration (how many grams of decoction pieces per milliliter are equivalent)
.
When the relative retention time of the control feature map is difficult to meet the requirements, the control medicinal material, control extract or multiple reference substances can be used as the accompanying control, and the retention time of the accompanying control should be consistent with the provisions
.
In principle, all pharmaceutical researches of traditional Chinese medicine formula granules, including process parameter determination, quality control method and index selection, limit setting, etc.
, should be compared and studied based on the above three parameters of the standard decoction in principle
.
Encourage the use of fingerprints to characterize standard decoctions
.

　　V.
Production process requirements
　　(1) Production process research
　　1.
Reasonable evaluation index of the
process.
The research on the production process of traditional Chinese medicine formula granules should be based on the standard decoction, with the consistency of the ointment rate, the transfer rate of the main component content, the fingerprint or the characteristic map properties, the raw material, the quality of preparation of intermediates and finished products in the process of transfer and mass balance as index comprehensive study to determine the process parameters
.

　　2.
The extraction
reference standard decoction preparation process is scaled up to commercial scale
.
The main process parameters that affect quality should be studied and evaluated
.
Clarify the main parameters such as cutting (crushing) specifications, extraction methods, extraction temperature, water addition, and extraction times of traditional Chinese medicine pieces for extraction
.
For the traditional Chinese medicine decoction pieces that contain volatile oil and the traditional decoction requires later, the volatile oil can be extracted first in commercial scale production, and then the volatile oil content transfer rate range in the "standard decoction" is calculated according to the volatile oil content, and then added in proportion
.

　　3.
Solid-liquid separation
Investigate the selected solid-liquid separation method and equipment parameters to determine the technical parameters
.

　　4.
Concentrate
Investigate the selected concentration method, temperature, vacuum degree, etc.
, clarify the impact on the inspection index, and determine the technical parameters
.

　　5.
Drying
Investigate the selected drying methods, equipment and process parameters, clarify the impact on the inspection indicators, and determine the technical parameters
.
If auxiliary materials are needed in the drying process, the types and amounts of auxiliary materials should be investigated to determine the types and minimum amounts of auxiliary materials
.

　　6.
The molding
should be carried out research and prescription molding formulation, including the kind and amount of excipients, granulation process, drying method, equipment and technical parameters, product yield, and other packaging materials, specifically materials of the type, amount, and the process Parameters and packaging materials in direct contact with drugs
.
Excipients can be appropriately added to the formulation to ensure that a unified and fixed conversion relationship between granules and traditional Chinese medicine pieces is established, which is convenient for clinical adjustment, and the use of excipients is considered to be minimized.
Unless otherwise specified, the ratio of excipients to intermediates is generally not more than 1 : 1
.

　　7.
Establishment of production process
According to the research results of extraction, solid-liquid separation, concentration, drying and molding process, establish the production process of traditional Chinese medicine formula granules, clarify various process parameters, and formulate scale-up production plans
.

　　(2) Production test and process control
According to the scale-up production plan, conduct more than 3 batches of traditional Chinese medicine formula granules production test.
According to commercial scale test or verification batch data, combined with the comprehensive evaluation of R&D test batch data, various production process parameters are determined and clearly defined The quality control points and control methods of the production process, and the establishment of production process regulations
.

　　(3) Intermediate requirements
In the process of preparing traditional Chinese medicine formula granules, after the Chinese medicinal materials that meet the requirements are made into Chinese medicine decoction pieces, according to the production process requirements of Chinese medicine formula granules, a feeding plan should be established in the process regulations
.
Processing methods such as mixed batch blending can be formulated to solve the problem of raw material quality fluctuations; then, intermediates are obtained after extraction, separation, and concentration according to the prescribed process, and appropriate production process regulations are formulated
.
Intermediate standards should be developed and compared with standard decoctions
.
The parameters characterizing the standard decoction are used as the theoretical values ​​of various indicators of commercial-scale intermediates.
After the production is scaled up, the actual production process parameters are determined, and the intermediate paste rate, the upper and lower limits of the content, the characteristic spectrum or the fingerprint spectrum are established
.

　　(4) Quantity and quality transfer requirements.

Through research on the quality of Chinese medicinal materials, the preparation of Chinese herbal medicines, standard decoctions, and preparation techniques, the key quality attributes are clarified
.
Characterize the extraction rate, content and content transfer rate, characteristic map or fingerprint map, extract, etc.
, specify the quantity and quality transfer of the whole production process, set the acceptable range of variation and reason, from raw material to intermediate The quality and quantity transfer in the whole process of finished product production should be relevant, feasible and reasonable
.

　　(5) The cleaning process
should be cleaned strictly in accordance with the requirements of the "Good Manufacturing Practice for Pharmaceuticals" (GMP)
.

　　6.
Requirements
for standard formulation In order to effectively control the quality of each link in the production of TCM formula granules , standards for TCM materials, TCM decoction pieces, intermediates (extracts or dry powder) and finished products should be established separately to achieve quality control throughout the process
.
Standard research should comply with the relevant technical requirements for the research and formulation of quality standards for traditional Chinese medicine
.
According to the characteristics of traditional Chinese medicine formula granules, strengthen specific identification and multi-component, overall quality control
.
The content determination items of the active ingredients or index ingredients related to the drug efficacy should be established, and the fingerprint or characteristic maps should be used to evaluate the overall quality.
If necessary, a biological activity evaluation method can be established
.
In standard research, a comparative study of raw materials, intermediates, finished products and "standard decoctions" should be conducted to clarify the key quality attributes, and explain the rationality of the quality and quality transfer in the whole production process and the setting of various indicators
.
The standards for Chinese medicinal materials and Chinese medicinal pieces should be formulated with reference to the relevant technical requirements in the "National Pharmaceutical Standards Work Manual", in which items such as thin-layer chromatography identification, content determination, fingerprint or characteristic maps should be related to the quality standards of traditional Chinese medicine formula granules
.
For raw materials with complex sources, DNA molecular identification technology is used to identify the authenticity of the species when necessary
.
Intermediate standards are formulated with reference to the standards of traditional Chinese medicine formula granules
.
For the quality standards of Chinese medicinal materials and Chinese herbal medicines used in the production, when the original standard issuing agency updates the quality standards, the production unit of the formula granules should promptly conduct research in accordance with the updated standards
.
In addition to the above circumstances, if the quality standards of Chinese medicinal materials and Chinese medicinal pieces for production are changed, the research shall be carried out again according to the new Chinese medicinal formula granule varieties
.
The standard contents of traditional Chinese medicine formula granules mainly include: name, source, quality standards for production of decoction pieces, preparation method, properties, identification, inspection, extract, fingerprint or characteristic map, content determination, specifications, storage, etc
.
.
.
????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? Corresponding standards and drafting instructions for traditional Chinese medicine formula granules should be provided
.
The text of the standard should be prepared in accordance with the Chinese Pharmacopoeia, Standards for Chinese Medicinal Materials in Anhui Province, and the Processing Standards for Chinese Herbal Medicines in Anhui Province, etc.
; the standard drafting instructions should be in accordance with the National Drug Quality Standards and the Anhui Province Chinese Medicine Quality Standards Drafting Instructions Compile related requirements
.

　　(1) The name
includes Chinese name and Pinyin
.
The name is composed of "the name of decoction pieces + formula granules", and the names of decoction pieces are named according to legal standards, such as "fried yam formula granules with bran"
.
For varieties with different bases or varieties that need to be distinguished from specific origins in clinical practice, add parentheses in the name of the XXX formula granules to indicate the Chinese name of their plants, such as "Astragalus (Mongolian astragalus) formula granules" or "Astragalus (astragalus membranaceus) formula "Particles"; "Dangshen (Lu Codonopsis) formula granules"
.
, It is not necessary to mark the names of the source plants and medicinal materials that are the same
.

　　(2) Source:
This product is a formula granule prepared by XXX and processed according to the main quality indicators of the standard decoction
.
For example, "This product is a formula granule made from the dried roots of Scutellariabaicalensis Georgi, a plant of the Lamiaceae family, which is processed and processed according to the main quality indicators of the standard decoction
.
" If the source is a multi-base original Chinese medicinal material, one base shall be fixed, and Chinese medicinal materials of different bases shall not be mixed with each other
.

　　(3) The quality standard of
decoction pieces for production accurately express the name of the quality standard of decoction pieces for production
.
Such as ""Anhui Province Traditional Chinese Medicine Preparation Regulations" (2019 Edition) Forsythia Heart"
.

　　(Iv) Preparation
be prepared according to the process described in the "production process" item briefly described, comprises a feeding amount of the preparation process, the main parameters of the paste frequency range, the range of materials and amounts thereof, made amount
.

　　(5) Traits
include color, shape, smell and other characteristics
.

　　(6) Identification
According to the properties of the various varieties of traditional Chinese medicine prescription granules and their raw materials, physical and chemical identification, chromatographic identification and other methods can be used.
The established method should meet the verification requirements of reproducibility, specificity and durability
.
The physical and chemical identification should be based on the chemical properties of the contained ingredients to select the appropriate specificity method
.
Chromatographic identification, including thin-layer chromatography, high-performance liquid chromatography, and gas chromatography, has the characteristics of intuitiveness, large amount of information, and strong specificity.
It can be used as the main method for the identification of traditional Chinese medicine prescription particles
.

　　(7) Check that the
granules of traditional Chinese medicine formulations should comply with the relevant regulations under the current version of the "Chinese Pharmacopoeia" General Preparations for Granules, and should also be based on the possible toxic and harmful substances in the raw materials, possible pollution during the production process, dosage form requirements, and storage conditions.
Wait for the establishment of inspection items
.
The inspection items should be able to truly reflect the quality of traditional Chinese medicine formula granules and ensure safety and effectiveness
.
All Chinese medicine formula granules should be inspected and studied for toxic and harmful substances
.
For traditional Chinese medicine formula granules produced with cultivated Chinese medicinal materials as raw materials, pesticide residue inspection can be studied according to the types of pesticides that may be used; Chinese medicine formula granules produced from Chinese medicinal materials that are prone to mildew (such as seeds, fruit Chinese medicinal materials, etc.
) as raw materials , The inspection and research of mycotoxins should be carried out
.
Establish reasonable limits based on the research results and include them in the standard text
.

　　(8) The extract
should be determined according to the main component categories contained in the variety, and appropriate solvents should be selected for determination, and reasonable limits should be established based on the results of the determination
.
Since the particles of traditional Chinese medicine formulations are all extracted with water as the solvent, and the auxiliary materials are mostly water-soluble auxiliary materials, the solvent used for the extract inspection is generally ethanol or a suitable solvent, and the influence of the auxiliary materials is investigated
.

　　(9) Feature map or fingerprint map
Since the traditional Chinese medicine formula particles no longer have the characteristics of decoction pieces, it is necessary to establish a feature map and fingerprint map with reference medicinal materials, control extracts or multiple reference substances as accompanying controls
.
The characteristic map can be evaluated from the correspondence between the test product and the accompanying control medicinal material, control extract or multiple reference substance chromatographic peaks
.
The fingerprint spectrum can be analyzed by using the Chinese medicine fingerprint similarity evaluation system to analyze the overall information of the test product spectrum (including the peak number, peak position and peak height or peak area ratio of its chromatographic peak), and obtain the similarity value for result evaluation
.
The main components should be identified as far as possible in the characteristics or fingerprints
.
Should focus on the changes of the map in the main process
.
Based on the investigation of the origin, collection period, and origin of Chinese medicinal materials, a characteristic map or fingerprint map of Chinese medicinal materials as initial raw materials is established
.
The characteristic patterns or fingerprint patterns of Chinese medicinal materials, Chinese medicinal pieces, intermediates, and Chinese medicinal formula particles should be relevant and have a clear law of quantity and quality transfer
.
Chromatography is generally used for the determination of the characteristic map or fingerprint of Chinese medicine formula particles, such as high performance liquid chromatography.
According to the characteristics of multiple batches of Chinese medicine formula particles and large inspection volume, ultra-high performance liquid chromatography may also be considered
.

　　(10) Assay determination
should select specific components related to function, indication and activity as assay indicators, and establish as many component assay methods as possible
.
Prototype components in the sample should be selected as the measurement indicators, and products such as hydrolysis, degradation, or non-specific indicator components and trace components should be avoided as indicators
.
For the measured content is less than 0.
01% by component, can increase the content of effective component was measured as total flavonoids, total alkaloids, the total saponin
.
Specific methods should be selected for the determination of particle content in traditional Chinese medicine formulations, otherwise other methods should be used to supplement to achieve overall specificity
.
The selected analytical method must be verified in accordance with the requirements of the "Guidelines for Validation of Analytical Methods" of the current edition of the Chinese Pharmacopoeia
.
The limit range should be established according to the experimental data.
Generally, the upper and lower limits are stipulated, which is expressed as "This product contains XXX per 1g should be XXXmg—XXXmg"
.
Due to the large variety of Chinese medicine formula granules, many batches, and large amount of test data, ultra-high performance liquid chromatography can be considered when selecting the determination method.

.
Necessary methodological verification should be carried out for the conversion of high performance liquid chromatography method and ultra high performance liquid chromatography method
.
Including resolution, peak purity and reproducibility
.
If the sequence and number of chromatographic peaks of the components to be tested are inconsistent before and after the conversion, the test results are obviously inconsistent, or the unqualified situation is involved, the method conversion should be abandoned
.
When selecting the ultra-high performance liquid chromatography method, the specifications of the chromatographic column can be specified under the standard text, but the brand and manufacturer of the chromatographic column generally do not specify it
.

　　(11) Specifications The specifications
are calculated based on the amount of feed and production under the manufacturing method, and are expressed as "each 1g of formula particles is equivalent to XXg of decoction pieces"
.
If the specification is not an integer, generally keep no more than two decimal places
.

　　7.
Stability test requirements The stability test of
traditional Chinese medicine formula granules should be studied in accordance with the "Technical Guidelines for the Stability Research of Traditional Chinese Medicine and Natural Medicines" issued by the Drug Evaluation Center of the State Drug Administration
.
Among them, the long-term stability test generally investigates 12 months to 24 months, and the shelf life of traditional Chinese medicine formula granules is determined according to the results of the investigation (not included in the standard)
.
6 months of room temperature stability test data can be provided when applying for national standards
.

　　8.
Technical requirements
for standard review In order to ensure the scientificity, reproducibility and feasibility of the testing methods in the standard of traditional Chinese medicine prescription granules, and to standardize the test work of standard review, these technical requirements are formulated
.
The standard review of traditional Chinese medicine formula granules is a confirmatory inspection review.
The specific requirements are as follows:
　　(1) Requirements for laboratory conditions
1.
Laboratories engaged in the standard review and inspection of traditional Chinese medicine formula granules should pass the qualification accreditation of relevant provincial departments or national laboratory accreditation.
Provincial-level drug inspection institutions (including sub-provincial level)
.
2.
Have a complete inspection of Chinese medicineThe equipment and necessary facilities meet the quality assurance system and technical requirements of drug inspection
.
3.
Have undertaken related work such as review of drug standards
.

　　(2) Requirements
for standard reviewers 1.
The inspection agency responsible for standard review should appoint a person in charge of standard review to be responsible for the review work, supervise the review experiment process, deal with and solve problems in the experiment in a timely manner, and review and review the results of the experiment.
Responsible
.
The person in charge of the standard review should have a senior technical title (or corresponding technical level), have rich experience in drug standard research and drafting, and be able to guide the personnel responsible for the standard review to conduct an experimental review
.
2.
The personnel responsible for standard review should have intermediate or above technical titles (or possess the corresponding technical level), and have certain experience in drafting and reviewing drug standards
.

　　(3) Requirements for review materials, samples, and reference materials
1.
The person in charge of the experimental review and the personnel in charge should first review the technical data provided by the drafting unit (please review the official documents, the draft standard of traditional Chinese medicine formula granules, drafting instructions, inspection reports for review samples, Samples for review, reference materials for review, etc.
), after confirming that the above-mentioned information is complete and basically meets the drafting technical requirements, arrange the experimental review work
.
Otherwise, the drafting unit should submit supplementary materials or return requests
.
2.
The samples for review should be 3 batch samples produced on a commercial scale, and the sample size should be 3 times the amount used for one inspection
.
3.
The reference material for review shall be provided by the drafting unit to the review unit.
If it is a newly-added reference material, the corresponding technical data of the newly-added reference material shall be provided
.

　　(4) Recheck test technical requirements
.
The laboratory undertaking the review task shall conduct recheck test on the samples and materials sent by the drafting unit in accordance with the following requirements.
When the recheck result cannot be reproduced, the laboratory shall assign another experienced tester Retest
.

　　1.

Whether the traits described in the draft of the trait inspection standard are consistent with the sample
.
Does the color description in the trait specify a certain range
? Whether the gas and taste regulations are appropriate
.

　　2.
Identification and
inspection whether the identification items established are specificity and good reproducibility
.
In TLC identification, it is necessary to examine whether the sample size and preparation method of the test product are reasonable, whether the solvent and concentration of the reference substance are appropriate; whether the amount of control medicinal materials and preparation method are reasonable; the stationary phase, developing agent, spotting amount, color development conditions and Check whether the method is appropriate; whether the chromatographic separation is good, whether the spots are clear, whether the chromatographic characteristics of the test product and the reference substance are consistent, whether the method is specific (if necessary, use a negative control for verification)
.

　　3.
The characteristic/ fingerprint pattern
should examine whether the chromatographic conditions are appropriate, whether the chromatographic peak separation is good, whether the relative retention time is stable (or whether it matches well with the accompanying control), whether the reproducibility is good, and whether the method is feasible
.

　　4.
Check that
there are special limit regulations and inspection items outside the general rules to conduct tests according to the draft standard method to examine the feasibility and rationality of the limits
.
The rest shall be experimentally reviewed according to the methods stipulated in the four general rules of the current Chinese Pharmacopoeia, and the results of the review shall be within the limits
.

　　5.
Determination of extract to
investigate whether the sample amount, solvent and usage amount of the test sample are appropriate; whether the limit value is reasonable
.
The relative average deviation of the two results should not be greater than 2% (the absolute value of the measured value minus the average value divided by the average value multiplied by 100% or the absolute value of the difference between the two numbers divided by the sum of the two numbers multiplied by 100%)
.
The relative average deviation from the data of the drafting unit shall not be greater than 10%
.

　　6.
Assay
shall be verified and reviewed for the specificity, reproducibility and feasibility of the assay method
.
The relative average deviation of the two parallel results of the recheck determination shall not be greater than 3% (the method with relatively large error such as thin-layer chromatography scanning method can be appropriately relaxed to 5%)
.
The relative average deviation from the data of the drafting unit shall not be greater than 10%
.
When the content determination method is different from the method included in the national standards for raw materials, the specificity, accuracy, and repeatability of the method should be verified during the review process
.

　　(1 ) High performance liquid chromatography
investigates whether the sampling volume, extraction and purification methods of the test sample are appropriate; whether the amount, concentration, solvent, etc.
of the reference substance are appropriate; column type, mobile phase (composition and ratio), elution gradient, Whether the detection wavelength (or other detector parameters) is reasonable; whether the chromatographic separation effect is good; whether the prescribed values ​​such as the number of theoretical plates and resolution are feasible; whether the peak of the measured component is interfered; whether the measured amount of the measured component in the test product Within the linear range; whether the content limit is reasonable
.

　　(2 ) Gas chromatography to
investigate whether the sampling volume, extraction and purification methods of the test sample are appropriate; whether the amount, concentration, solvent, etc.
of the reference substance are appropriate; the type of stationary liquid, the temperature program gradient, the temperature of the detector, the temperature of the detector, and the inlet Whether the setting of temperature and other parameters is reasonable; whether the chromatographic separation effect is good; whether the prescribed values ​​such as the number of theoretical plates and resolution are feasible; whether the peak of the measured component is interfered; whether the measured amount of the measured component in the test product is within the linear range; Whether the content limit is reasonable
.

　　(3) When the UV- Visible spectrophotometry
adopts the comparison method of reference substance, it should be checked whether the sampling amount, extraction and purification method, and dilution factor of the test substance are appropriate; determination of solvent, reference substance concentration, measurement wavelength, absorbance value (should be within 0.
3- 0.
7), etc.
whether it is reasonable; whether the content limit is reasonable
.
When using the colorimetric method to determine whether the sample size of the test product, extraction and purification method, dilution factor, and the amount of developer are appropriate; whether the color development conditions such as temperature and time are reasonable; the tested components in the test product solution Whether the measured amount is within the measurement range of the standard curve; whether the reproducibility is good; whether the content limit is reasonable
.

　　(4 ) TLC scanning method to
investigate whether the sample amount, extraction and purification method, spotting amount, etc.
of the test product are appropriate; whether the amount of reference substance, concentration, solvent, spotting amount, etc.
are appropriate; stationary phase, developing agent, color developing agent And check whether the method is appropriate; whether the scanning method and measurement wavelength are reasonable; whether the chromatographic separation and scanning effect is good; whether the amount of the measured component in the test product is within the linear range; whether the measurement result reproduces well; whether the content limit is reasonable
.

　　(5) Requirements for review materials
　　1.
The review unit shall provide the following materials:
　　(1 ) Review results (opinions) reply documents
　　(2 ) Three batches of review inspection reports
　　(3 ) Review summary report The
review summary report shall summarize the review process and results
.
The content includes the review of the technical data provided by the drafting unit, the experimental review process (including data, color photos, maps, etc.
) and the results (including the results of data comparison with the drafting unit, etc.
), and based on the review results, the standard draft Various contents put forward review opinions and review conclusions, etc.

.
In particular, the revisions made to the drafting standards based on the review results should be explained in detail in the summary report
.
2.
The drafting unit shall make corresponding explanations based on the review opinions
.

　　Attachment 2 The
　　working procedures and requirements of application materials for formulating TCM granules standards in Anhui Province (for trial implementation)
　　(Draft
for Solicitation of Comments) is to standardize the formulation of quality standards for TCM formula granules in Anhui Province, and to clarify the work process of declaration and review of the quality standards for TCM formula granules in our province.
Develop this working procedure
.

　　First, the scope
of this program is mainly applied in Anhui Province engaged in the production or sale of Chinese medicine granules production company SFDA "Chinese medicine formulations particles quality control and research standard technical requirements" and "Anhui Chinese medicine formulations particles in accordance with the standard of quality control "Research Technical Requirements", completed the drafting and passed the quality standards reviewed by the corresponding drug inspection agencies, and applied for the technical review of the quality standards for traditional Chinese medicine formula granules in Anhui Province
.

　　2.
Working Procedures
　　(1) The
drafting unit of the selection criteria for varieties shall determine the varieties for which quality standards need to be drafted based on the needs of clinical use
.
The selected varieties must meet the following requirements: 1.
The national quality standard of traditional Chinese medicine formula granules is not included; 2.
The corresponding Chinese medicine decoction pieces have national or provincial TCM decoction pieces standards; 3.
The proposed production process meets the basic quality control of traditional Chinese medicine formula granules Request
.

　　(2) Standard formulation research The
formulation of quality standards for traditional Chinese medicine formula granules in Anhui Province shall be carried out in accordance with the relevant technical guidance documents of the State Food and Drug Administration and the "Quality Control and Standard Research Technical Requirements for Traditional Chinese Medicine Formula Granules in Anhui Province".
Application materials require the submission of corresponding research materials
.
After the study, it is considered that the inspection items that may not be included in the standard text should explain the reasons in the standard drafting instructions
.

　　(3) Application and acceptance After the
quality standard application unit has completed the drafting and review of the standard in accordance with the relevant technical requirements, it shall submit the corresponding technical materials (five copies) to the Anhui Food and Drug Inspection Institute according to the requirements of the application materials, and submit an application for review
.
The Anhui Food and Drug Inspection Institute will complete the formal review of the completeness of the information within 5 working days.
If the information is complete and standardized, it will be accepted and a notice of acceptance will be issued
.

　　(4) Review and release
Anhui Provincial Food and Drug Inspection Institute will organize an expert group to review the application materials within 20 working days after acceptance
.
After the review, the Anhui Provincial Drug Administration will publish its quality standards and drafting instructions on the provincial bureau website for 30 working days.
If there is no objection to the expiration of the publicity period, the Provincial Drug Administration will publish it in accordance with the procedures and report to the National Pharmacopoeia Commission for the record as required
.

　　3.
Requirements for declaration materials
　　(1) The
declaration unit of the letter of commitment shall promise the authenticity and non-infringement of the declaration materials
.
If the application materials are completed by multiple entities, the name of the entity that completed the application shall be listed one by one
.

　　(2) List of
application materials.
The application materials shall include a list of document names and indicate the corresponding page number range
.
The application materials should contain the following content:
　　Data 1.
Basic situation data 2.
Raw material research data 3.
Excipient research data 4.
Standard decoction research data 5.
Production process research data 6.
Other research data related to quality 7.
Quality standard research data 8.
Stability research data 9.
Sample inspection report data 10.
Pharmaceutical packaging material research data 11.
Review inspection report and review opinion data 12.
Reference material information and research data application data should be provided in accordance with the project label, corresponding to the project If there is no relevant information or research materials, the project number and name should also be retained, and "no relevant research materials" or "not applicable" may be indicated under the item
.

　　(3) Application materials requirements
Application materials 1～10 shall be written in accordance with the National Pharmacopoeia Commission’s "Notice on the Formulation of Drug Standards for Chinese Medicine Formula Granules ", and the application materials 11-12 shall be written in accordance with the following requirements
.

　　11.
Review inspection report and review opinions
Provide the review inspection report and review opinions of the same batch of the three batches of large-scale production of Chinese medicine formula granules samples self-inspected
.
Regarding the relevant issues raised by the review opinions, the circumstances and reasons for the adoption or rejection should be elaborated in the quality standard drafting instructions
.

　　12.
The reference material research materials
list the name, production unit, instruction manual, batch number and other information of the reference material used in the above-mentioned research
.
For standard materials used in the quality standards of Chinese medicine formula granules, if non-national drug standard materials are used, when applying for standard review (or review), the technical requirements for the development of national drug standard materials should also be referred to, and information on the development and calibration of new standard materials should be provided.
And physical samples
.

　　Contact:
Xu Jing, Provincial Drug Administration Tel: 0551-62999283; Email: 1326631745@qq.
com; Address: Room 214, District C, Provincial Government Affairs Building, No.
509, Ma'anshan Road, Hefei City
.
Pu Jingzhe, Provincial Food and Drug Inspection Institute Tel: 15155938552; Email: pujingzhe@163.
com; Mailing address: Anhui Food and Drug Inspection Research Institute, Chinese Medicine Room, No.
15, Urumqi Road, Baohe District, Hefei City
.

　　Relevant drug manufacturers and R&D units:
In accordance with the requirements of the " Announcement of the National Medical Products Administration, the National Administration of Traditional Chinese Medicine , the National Health Commission, and the National Medical Insurance Bureau on Ending the Pilot Work of TCM Formula Granules" (No.
22 of 2021), after research, the Provincial Drug Administration The bureau intends to develop the standard formulation of traditional Chinese medicine granules in Liaoning Province
.
Relevant drug manufacturers and R&D units are requested to follow the "Announcement of the State Food and Drug Administration on Issuing Technical Requirements for Quality Control and Standard Establishment of Chinese Medicine Formula Granules" (No.
16 of 2021) and the National Pharmacopoeia Commission "Relevant Chinese Medicine Formula Granule Drug Standard Establishment" According to the provisions of the "Notice", we will study and draft the standards for formula granules of Chinese medicines of relevant varieties, and submit relevant information to the Drug Registration Office of the Provincial Food and Drug Administration
.
Starting from November 1, 2021, Chinese medicine formula granules that do not have national drug standards or standards established by provincial drug regulatory authorities shall not be marketed
.
Contact: Wang Mingdong Tel: 024-31607903 Liaoning Provincial Drug Administration April 15, 2021