"Other Technical Guidelines for Pharmaceutical Research on Traditional Chinese Medicine Compound Preparations Derived from Ancient Classic Recipes"

(Source: CDE official website)

The relevant information of "Ancient Classic Prescription Chinese Medicine Compound Preparations" that is not managed according to the Catalogue of Ancient Classic Recipes should be consistent with the key information of Ancient Classics, and the quality of the declared preparations should be basically the same as the quality of the
benchmark samples.

"Traditional Chinese medicine compound preparations based on ancient classic recipes plus or minus" should strengthen the collection and collation
of relevant information about the preparations used in clinical practice.
Relevant information includes, but is not limited to, the name, prescription composition, medicinal material base, medicinal site, preparation, dosage, daily tablet quantity, preparation process, dosage form, route of administration, dosage, dosage, etc
.
of the preparation used in clinical practice.
Emphasis should be placed on the consistency
of the declared formulation with the formulation used in clinical practice.

(3) Strengthen the quality control of the whole process to ensure the stability and uniformity of the preparation quality

Traditional preparation and traditional routes
of administration should be used.
It is necessary to strengthen the quality control research of medicinal materials and drinking tablets, improve the quality control of the processing of drinking tablets and the production process of preparations, clarify the key quality attributes and key process parameters, establish intermediate quality standards, study and improve the quality standards of preparations, form a quality control system for the whole process, and ensure that the quality of preparations is stable and uniform
.

Third, the main content

(1) Prescription

The study of key information such as the name, source, prescription composition, medicinal material base, medicinal part, preparation, dosage, dosage form, dosage and dosage of ancient classics should be carried out
.
Clarify the taste of prescription drugs and their dosage, and clarify the origin of medicinal materials, the place of origin, the preparation of drinking tablets, and the quality control methods of
medicinal materials/drinking tablets.
Ensure traceable
quality of medicinal herbs.

"Traditional Chinese medicine compound preparations based on ancient classic recipes plus or minus" should also provide the name of the preparation used in clinical practice, the taste of the prescription (including the base source, medicinal parts, processing, etc.
) and the dosage, etc.
, and compare the consistency
with the preparation used in clinical practice.

(2) Production process

The declared preparation should adopt traditional technology and traditional dosage form
.
The process route, route of administration and dosage form should be consistent with the preparation used in ancient texts and/or clinical practice, in which granules can be made in the form of decoction
.

"Ancient classic prescription Chinese medicine compound preparations that are not managed according to the ancient classic prescription catalogue" should be studied
with reference to the "Guidelines for Pharmaceutical Research Technology of Chinese Medicine Compound Preparations Managed According to the Ancient Classic Recipe Catalogue (Trial)".

The process route of "Chinese medicine compound preparations based on ancient classic recipes plus or minus cuts" should be consistent with the preparations used in clinical practice, including single frying/combined frying, first frying, later down, bag frying, etc
.
In the principle of not increasing safety risks and/or reducing clinical efficacy, the process parameters can be determined
after study according to the actual production and equipment characteristics.
Attention should be paid to the scientificity and rationality of dosage forms and excipient selection, as well as the consistency
with the preparations used in clinical practice.
If there is a large difference between the equipment, production scale, etc.
of the preparation used in clinical practice and the declared preparation, the necessary bridging study
should be carried out.

(3) Quality research and quality standards

The whole process of quality control system should be studied and established, including but not limited to quality control requirements such as medicinal materials/tablets, intermediates, excipients, preparations and packaging materials, to ensure that the quality controllability of the preparation is not lower than that of the benchmark sample and/or the preparation
used in clinical practice.

If the prescription contains toxic medicinal taste or the medicinal taste found to have obvious toxicity in modern studies, the relevant toxic ingredients should be studied for quality control, and the detection method should be established in the preparation according to the research results to determine a reasonable limit or scope
.

The preparation quality standard should be combined with process research to establish exclusive identification, inspection, feature/fingerprint, content determination and other items, and formulate a reasonable content range (upper and lower limits)
for the content determination index.

(4) Stability research

The stability test results should support the proposed expiration date, storage conditions, packaging materials
.
The packaging materials and their quality control requirements for
direct contact with pharmaceuticals should be clarified.

When applying for listing, all completed stability studies should be provided, generally including data from accelerated trials for 6 months and 18 months for long-term trials
.
After the listing, the stability investigation should continue in accordance with the submitted stability research plan, do a good job in the prevention and control of relevant risks, and ensure the stability
of drug quality.

In addition, if the declared preparation is consistent with the prescription of the preparation used in clinical practice, production process, main process parameters, type and dosage of excipients, dosage form, specification, packaging material in direct contact with the drug, etc.
, the stability research data of the preparation used in clinical practice can be used as supporting data
for the proposed validity period of the declared preparation.

(5) Relevance research

For "ancient classic prescription Chinese medicine compound preparations that are not managed according to the ancient classic prescription catalog", the correlation study should be carried out with reference to the content of the "Guiding Principles for the Pharmaceutical Research of Chinese Medicine Compound Preparations Managed According to the Ancient Classic Formula Catalogue (Trial)" and "(6) Correlation Research" to explain the quantitative and qualitative transmission of the whole process
.

For "traditional Chinese medicine compound preparations based on the addition and subtraction of ancient classics", the correlation between the declared preparation and the prescription taste of the preparation used in clinical practice (including the base source, medicinal parts, processing, etc.
), the proportion of dosage, the process route, the amount of daily drinking tablets, and the route of administration should be used to conduct a comparative analysis of the declared preparation and the prescription taste of the preparation used in clinical practice, and the correlation between the declared preparation and the preparation used in clinical practice should be used for comparative analysis
.

Drafting instructions for the drafting of the "Technical Guidelines for the Medicinal Research of Other Traditional Chinese Medicine Compound Preparations Sourced from Ancient Classics (Draft for Solicitation of Comments)"

1.
Purpose of drafting

The Law of the People's Republic of China on Traditional Chinese Medicine clarifies that ancient classical recipes refer to "prescriptions recorded in ancient Chinese medicine classics that are still widely used, have accurate curative effects, and have obvious characteristics and advantages"
.
In order to promote the inheritance and development of traditional Chinese medicine and strengthen the sorting and excavation of the essence of classical medical books, the registration classification of "ancient classic Chinese medicine compound preparations" is refined in the "Requirements for Registration and Declaration of Chinese Medicines", which enriches the scope of ancient classic Chinese medicine compound preparations, and clarifies the registration and declaration paths of Chinese medicine compound preparations and other Chinese medicine compound preparations derived from ancient classic recipes
managed according to the ancient classic recipe catalog 。 Among them, other Chinese medicine compound preparations derived from ancient classic recipes belong to category 3.
2 of the Chinese medicine registration classification, including ancient classic Chinese medicine compound preparations that are not managed according to the ancient classic recipe catalogue and Chinese medicine compound preparations based on the addition and subtraction of ancient classic recipes
.
In order to promote the inheritance of the essence of traditional Chinese medicine, keep the integrity and innovation, and promote the high-quality development of the traditional Chinese medicine industry, guide the applicant to carry out research on other traditional Chinese medicine compound preparations derived from ancient classic recipes, and formulate these guiding principles
according to the opinions and suggestions of the industry.

2.
Drafting process

In July 2021, the Drug Review Center of the State Drug Administration established a drafting group
for the "Technical Guidelines for the Pharmaceutical Research of Other Traditional Chinese Medicine Compound Preparations Derived from Ancient Classic Recipes".
After many discussions and solicitation of opinions by the drafting team, the Technical Committee of the Department of Traditional Chinese Medicine and Ethnic Pharmacy reviewed and formed the "Technical Guidelines for the Medicinal Research of Other Traditional Chinese Medicine Compound Preparations Derived from Ancient Classics (First Draft)" on February 17, 2022
.

On February 22, 2022, an expert seminar on the guiding principles was held, and experts from scientific research institutes, Chinese medicine colleges, traditional Chinese medicine hospitals, and Chinese medicine regulatory scientific research institutions were invited to discuss
the first draft.
After the meeting, the first draft of the Guiding Principles was revised
in the light of expert comments.

On March 25, 2022, a revision meeting of the guiding principles was held with the participation of experts from scientific research institutes, Chinese medicine colleges, traditional Chinese medicine hospitals, Chinese medicine regulatory scientific research institutions and representatives of 10 enterprises, and the guiding principles were further discussed and revised
.

According to the expert opinions and suggestions, the guiding principles were further revised, and further solicited opinions within the Drug Review Center of the State Drug Administration, and reviewed by the Technical Committee of the Department of Traditional Chinese Medicine and Pharmacy, the "Technical Guidelines for the Pharmaceutical Research of Other Compound Preparations of Chinese Medicines from Ancient Classics (Draft for Solicitation of Comments)"
was formed.

Third, the drafting of ideas

According to the characteristics of other compound preparations of Chinese medicines derived from ancient classic recipes, the "Law of the People's Republic of China on Traditional Chinese Medicine", the Notice of the State Food and Drug Administration on the Issuance of the "Requirements for Registration Classification and Declaration of Chinese Medicines (No.
68 [2020])" and its annex "Requirements for Registration and Declaration of Chinese Medicines" and relevant policy interpretations, the basic requirements of the registration classification (Class 3.
2) and the key content that need to be paid attention to are clarified, and the "compound preparations of ancient classic prescriptions that are not managed according to the Catalogue of Ancient Classic Prescriptions" are clarified and "Chinese medicine compound preparations based on ancient classic recipes plus or minus" different requirements
.

Fourth, the main content

The body of the guiding principles is divided into three parts: overview, basic requirements and main contents
.
Emphasize that the research on the key information of ancient classics should be strengthened; Ensure the consistency of the declared preparation with the reference sample or the preparation used in clinical practice; Strengthen the quality control of the whole process to ensure that the quality of the preparation is stable and uniform
.
And from the prescription, production process, quality research and quality standards, stability research and related research five aspects of the specific requirements
are clarified.

Fifth, the issues that need to be clarified

(1) Regarding the examination of key information and expert review

Since other Chinese medicine compound preparations derived from ancient classic recipes are derived from ancient classic recipes, it is emphasized that the original advantages of traditional Chinese medicine should be given full play to strengthen the research on the key information of
ancient classic recipes.

According to the relevant requirements of the Notice of the State Food and Drug Administration on the Issuance of the "Requirements for the Registration Classification and Declaration of Chinese Medicines" (No.
68 [2020]), the Drug Evaluation Center of the State Drug Administration organized experts to conduct technical reviews of other compound preparations of traditional Chinese medicines derived from ancient classics in accordance with the drug marketing authorization review procedures stipulated in the Measures for the Administration of Drug Registration
.
Experts verify the accuracy of the key information examined by the applicant and the consistency with the ancient classics
.

(b) the requirements relating to the two situations covered by the registration classification (Class 3.
2).

"Ancient classic compound preparations of Chinese medicine that are not managed according to the ancient classic prescription catalog" should be consistent with the ancient book records, so it should be studied with reference to the "Guidelines for the Pharmacological Research Technology of Chinese Medicine Compound Preparations Managed According to the Ancient Classic Formula Catalogue (Trial)
".

"Traditional Chinese medicine compound preparations based on the addition and subtraction of ancient classic recipes" should be developed and studied on the basis of collecting and sorting out the information of the preparations used in clinical practice to ensure the consistency
between the declared preparations and the preparations used in clinical practice.

(3) About traditional crafts

The Notice of the State Food and Drug Administration on the Issuance of the Requirements for Registration Classification and Declaration of Chinese Medicines (No.
68 [2020]) requires that such preparations should be prepared by traditional processes and traditional routes of
administration.
The "traditional process" in these Guiding Principles can refer to the relevant provisions
of the Announcement of the General Administration of the General Administration on the Recordal Administration of the Application of Traditional Techniques to Prepare Traditional Chinese Medicine Preparations by Medical Institutions (No.
19 [2018]).

(4) About stability research

Regarding how long stability research data should be provided at the time of declaration, it was discussed that stability research is an important part of drug (especially new drugs) research, which is closely related
to the research content of preparation prescription research (excipient type and dosage screening, etc.
), production process research, quality and quality standard research, packaging and storage condition selection.
If stability studies reveal problems with the quality of the drug, it may involve adjusting the formulation of prescription excipients, processes, packaging and storage conditions
.
Under normal circumstances, the validity period of drugs should be based on the results of long-term stability tests, and in order to meet the actual needs of drug marketing and circulation, the validity period of drug approval should not be too short
.
Through repeated research, it is believed that in order to ensure the quality of the formulation, this guideline stipulates that "when applying for marketing, all completed stability research data should be provided, generally including research data
for 6 months of accelerated trials and 18 months of long-term trials.
" After the listing, the stability investigation should continue in accordance with the submitted stability research plan, do a good job in the prevention and control of relevant risks, and ensure the stability of drug quality
.
"

In addition, if it is necessary to use the stability research data of the preparation used in clinical practice as the supporting data of the proposed validity period of the declared preparation, the declared preparation and the preparation prescription, production process, main process parameters, excipient types and dosages, dosage forms, specifications, packaging materials in direct contact with the drug should be consistent
.

(5) Research on relevance

Other Chinese medicine compound preparations derived from ancient classics include two situations that should be studied for correlation, and the quantitative and mass transfer laws should be analyzed
according to their respective characteristics.
"Ancient Classic Prescription Traditional Chinese Medicine Compound Preparations" that are not managed according to the Catalogue of Ancient Classic Formulas" shall determine the key quality indicators of the medicinal materials, tablets, intermediates, preparations, etc.
used in the declared preparations according to the results of the correlation research, so as to ensure the consistency of the quality of the declared preparations and the benchmark samples; "Traditional Chinese medicine compound preparations based on the addition and subtraction of ancient classics" should focus on the consistency
of the declared preparations and the preparations used in clinical practice.