Requirements for Registration Data of Pharmaceutical Excipients (Trial) Annex 1(2019 Edition)

Requirements for Registration Data of Pharmaceutical Excipients (Trial)

Variety name: XXXXX

Registrant: XXXXX

Accessories classification:

There is no history of use in domestic and foreign listed drugs, including

.Jp 1.1The new molecular structure of the excipients and does not belong to1.2,1.3Excipients;

.Jp 1.2By the use of the history of the auxiliary materials by simple chemical structure change (such as salt base, hydrate, etc.);

.Jp 1.3Excipients obtained by co-processing of two or more excipients with a history of use;

.Jp 1.4Excipients that have a history of use but change the route of administration.

There is a history of use in domestic and foreign listed drugs, and.

.Jp 2.1Chinese Pharmacopoeia/USP/EP/BP/JPExcipients not received;

○ 2.2 usp/ep/bp/jpOne of the excipients that have been received but not used in domestic marketed drugs;

○ 2.3 usp/ep/bp/jpOne of the excipients has been collected, but not collected in Chinese Pharmacopoeia;

.Jp 2.4Excipients already included in the Chinese Pharmacopoeia.

Has a history of use in food or cosmetics, and

.Jp 3.1Excipients for oral preparations with national food safety standards;

.Jp 3.2 Excipients for external preparations with national or industry standards for cosmetics.

○Other

Proposed route of administration:○Injection ○Inhalation ○eye use ○Local and sublingual ○Transdermal ○Oral

○Other

Source:○Animals or people○Mineral ○Plants ○chemical synthesis○Microbial fermentation or bioengineering

○Other

1. registration data items

1 Basic information of registrant

1.1Name, address and production address of registrant

1.2Certifying Documents

1.3Research data storage address

2 Basic information of accessories

2.1Name

2.2structure and composition

2.3physicochemical properties and basic characteristics

2.4Domestic and overseas approval of listing and use of information

2.5Collection of Pharmacopoeia at Home and Abroad

3 Production Information

3.1Production process and process control

3.2Material Control

3.3Control of key steps and intermediates

3.4Process Validation and Evaluation

3.5Development of production processes

4 Characterization

4.1study on structure and physicochemical properties

4.2impurity study

4.3Functional characteristics

5 Quality Control

5.1Quality Standards

5.2Validation of analytical methods

5.3Quality standard formulation basis

6 Batch Inspection Report

7 stability study

7.1Stability Summary

7.2Stability data

7.3Packaging of accessories

8 Pharmacological and Toxicological Research

Text of 2. registration materials and writing requirements

1 Basic information of registrant

1.1Name of registrant, registered address, production address

Provide the name, registered address, production plant and production address of the registrant.

The production address shall be accurate to the production workshop and production line.

1.2Certifying Documents

The registrar of domestic pharmaceutical excipients shall submit the following supporting documents:

（1) Copy of the business license of the registrant. If the registrant entrusts a third party to carry out production, relevant documents such as the power of attorney, relevant information of the producer and a copy of the business license shall be submitted at the same time.

（2) For domestic registrants who apply for medicinal gelatin hollow capsules, gelatin for capsules and medicinal gelatin, they are required to provide:①For the application of medicinal hollow capsules, the legal source certification documents of gelatin shall be provided, including the approval certification documents, standards, inspection reports, business licenses of pharmaceutical gelatin manufacturers, Pharmaceutical Production License, sales invoices, copies of supply agreements, etc;②Application for gelatin capsules, medicinal gelatin, should provide the source of raw materials, types, standards and other relevant information and proof.

The overseas registrant of pharmaceutical excipients shall authorize the Chinese representative office to submit the following supporting documents:

（1) The registrant's legal production qualification documents, notarized documents and their Chinese translations. If the registrant entrusts a third party to carry out production, relevant documents such as the power of attorney and relevant information and supporting documents of the producer (if any) shall be submitted at the same time.

（2) Authorization documents, notarized documents and their Chinese translations entrusted by the registrant to the agency in China. The business license of the agency in China or the Registration Certificate of the Permanent Representative Office of a Foreign Enterprise in China of the permanent office of the registrant in China.

（3) For registration of medicinal hollow capsules, gelatin for capsules, medicinal gelatin and other bovine-derived pharmaceutical excipients for import, the main raw materials for capsule preparation must be provided.--The source, type and other relevant information and certificates of the raw materials for the preparation of gelatin, and provide government certification documents that the raw materials for the preparation come from countries where there is no mad cow disease epidemic.

It is recommended to provide relevant certification documents of human or animal-derived excipients for overseas pharmaceutical excipients.

1.3Research data storage address

The storage address of the research data of pharmaceutical excipients should be accurate to the house number. If there are multiple storage addresses for research materials, they must be submitted.

2 Basic information of accessories

2.1Name

Provide the Chinese common name of the auxiliary materials (if applicable, the name of the Chinese Pharmacopoeia shall prevail), English name, Chinese Pinyin, chemical name, former name, chemical abstract (CAS) No. If there isSOMEThe number and other names (including those included in the domestic and foreign pharmacopoeias) are recommended to be provided together.

Premixed excipients^[Note1]and co-processing excipients^[Note2]The single excipient used should be clearly defined and described qualitatively and quantitatively. Typical formulations can be submitted for illustration. The specific formulations used in practice should be included as attachments in the registration data or provided at the time of drug registration according to the usage.

Note1: Premixed excipients (pre-mixed excipient) refers to the mixing of two or more excipients by low to medium shear force, which is a simple physical mixture. The components remain as separate chemical entities after mixing, and the chemical identity of each component does not change. Pre-mixed excipients can be solid or liquid, and the physical mixing time is short.

Note2: Co-processed excipients (co-processed excipient) is a combination of two or more excipients. The physical properties of the combination have changed but the chemical properties have not changed significantly. This change in physical properties cannot be obtained by mere physical mixing and, in some cases, may be in the form of a salt.

2.2structure and composition

Provide information on the structure and composition of excipients, such as structural formula, molecular formula and molecular weight. Polymer pharmaceutical excipients should specify the model, molecular weight range, degree of polymerization and degree of substitution. There are three-dimensional structures and polymorphic phenomena should be particularly described.

Pre-mixed excipients and co-processed excipients shall submit structural information for each component.

2.3physicochemical properties and basic characteristics

Provide known physical and chemical properties of excipients, such as: properties (e. g. appearance, color, physical state), melting or boiling point, specific rotation, solubility, solutionpH, particle size, density (bulk density, tap density, etc.) and functional correlation indicators.

Pre-mixed excipients shall submit basic characteristic information such as product traits.

2.4Domestic and overseas approval registration and other related information and purposes

2.4.1Historical approval information in the territory

Provide information on historical approvals in the territory (if any).

2.4.2Information about other countries

Provide relevant information about the products to be registered as pharmaceutical excipients abroad (if applicable).

2.4.3Usage Information

MentionsProvide information on the route of administration of the excipient and the maximum daily reference dose and reference basis. If the drug using the excipient has been approved for marketing at home and abroad, the dosage form and route of administration of the relevant drug shall be provided; if the drug using the excipient has not been approved for marketing, the expected route of administration of the pharmaceutical excipient and the drug information on which the excipient is being used for registration shall be provided. If there is a non-recommended route of administration or a limited dose known by the manufacturer, it should also be specified and relevant reference instructions should be provided. The above information should be provided as much as possible.

2.5Collection of Pharmacopoeia at Home and Abroad

To provide the pharmaceutical excipients by domestic and foreign pharmacopoeia and China's national standard collection of information.

3 Production Information

3.1Production process and process control

（1) Process overview: Provide process flow diagrams according to process steps and conduct a production process overview.

（21) Process details: indicate the process parameters and solvents used according to the process flow. If it is a pharmaceutical excipient for chemical synthesis, the reaction conditions (such as temperature, pressure, time, catalyst, etc.) and its chemical reaction formula should also be provided, which should include the molecular formula, molecular weight, and chemical structure of the starting materials, intermediates, and reagents used.

Represented by commercial batches, the main process steps, the feeding amount of each reaction material and the yield range of each step are listed, and the key production steps, key process parameters and quality control indicators of intermediates are defined.

For excipients of human or animal origin, the production process of the excipients should have clear process steps for virus inactivation and removal, which must be verified.

（3) Explain the batch principle, batch range and basis of commercial production.

（4) Equipment: Provide main and special production equipment.

Production equipment data can be submitted in the following form:

List of production equipment

3.2Material Control

3.2.1Key material control information

Control of critical materials provides information in the table below.

Key material control information

Note: Such as animal sources, plant sources, chemical synthesis, etc.

3.2.2Material Control Information Detail

According to the procedures in the process flow chart, list all materials used in production (e. g. starting materials, reagents, solvents, catalysts, etc.) in the form of a table, and explain the steps used, as shown below.

Material Control Information

Note: Such as animal sources, plant sources, chemical synthesis, etc.

Provide the source of the above materials, clear reference standards, or provide internal control standards (including items, testing methods and limits), and provide methodology verification data if necessary.

3.3Control of key steps and intermediates

List the key steps (e. g., process steps for refining and purifying the final product, viral inactivation of excipients of human or animal origin/removal steps). When applicable, provide key process control and parameters, provide specific research data (including research methods, research results and research conclusions), and support the rationality of the determination of key steps and the rationality of the control range of process parameters. Where isolated intermediates exist, their quality control criteria should be listed, including items, methods and limits, and the necessary methodological validation information should be provided.

3.4Process Validation and Evaluation

3.4.1 Process Stability Assessment

Provide relevant assessment information on the stability of the excipient process, such5A retrospective report on the quality of products above the batch, etc.

3.4.2 Process Validation

Provide process validation plan, validation report and other information, if necessary, provide batch production record sample.

3.5Development of production processes

Provide the basis for the selection of process routes (including literature and/or theoretical basis).

Provide detailed research information (including research methods, research results and research conclusions) to explain the rationality of the determination of key steps and the rationality of the control range of process parameters.

Detailed description of the main changes in the production process during process development (including changes in process routes, process parameters, batches, and equipment) and related supporting validation studies. Provide a summary table of process study data, examples are as follows:

Summary of Process Study Data

Note1: Describe the purpose of producing the batch and the purpose of the sample, such as process verification/Stability studies.

Note2: Explain whether the production process of the batches listed in the table is the same3.1The processes under this item are consistent. If not, the differences shall be clarified.

4 Characterization

4.1study on structure and physicochemical properties

4.1.1Structural Confirmation Study

（11) Structural Confirmation Information

Provide relevant information that can be used to confirm or characterize the structure of the pharmaceutical excipient.

（21) Structural Confirmation Study

The structure of the product should be analyzed in conjunction with the preparation process route and various means of structural confirmation, such as the possibility of containing three-dimensional structure, crystalline water./The problem of crystallization solvent or polymorphism should be explained in detail, and for polymer pharmaceutical excipients, attention should also be paid to the molecular weight and molecular weight distribution, degree of polymerization, degree of substitution, infrared spectroscopy and other structural confirmation information. Provide purification method, purity and batch number of samples for structural confirmation; Provide specific research data and maps and analyze them.

In order to ensure the consistency of the quality of pharmaceutical excipients derived from biological products, standards need to be established./controls or compare excipients with their natural analogs. For biological products accessories, seeICHAbout Biotechnology/A guide to biological products.

To be derived from chemical synthesis or from motion./The premixed excipients of plants need to be characterized by different methods, and described quantitatively and qualitatively, including all special information.

4.1.2physical and chemical properties

Provide research data on the physical and chemical properties of excipients, such as: properties (such as appearance, color, physical state), melting point or boiling point, specific rotation, solubility, hygroscopicity, solutionpHpartition coefficient, dissociation constant, physical form (e. g., polymorph, solvate, or hydrate) to be used in the production of the formulation, particle size, source, etc.

4.2impurity study

4.2.1Impurity information

Combined with the production process of auxiliary materials, describe the impurities.

4.2.2impurity study

The impurity research should be carried out according to the molecular characteristics, source and preparation process of pharmaceutical excipients. For example, for polymer excipients, the residual monomer, catalyst and impurities brought by the production process should be studied. Evaluate the impact of impurities on the safety and functionality of pharmaceutical excipients, and control them accordingly.

4.3Functional characteristics

4.3.1 Functional characteristic information

Provide information on the functional indicators of the excipients (if applicable) in conjunction with the use of the excipients in the preparation and the route of administration.

4.3.2functional characteristics study

Combined with the use of excipients in the preparation and the route of administration, the main functional characteristics of the pharmaceutical excipients are described in detail and the corresponding research data are provided.

For example, the adhesive can provide surface tension, particle size and particle size distribution, solubility, viscosity, specific surface area, accumulation and other applicable characteristic indicators.

5 Quality Control

5.1Quality Standards

Provide quality standards for pharmaceutical excipients. The quality standards shall conform to the general technical requirements and format of the current edition of the Pharmacopoeia of the People's Republic of China, and the terms and units of measurement thereof shall be used.

5.2Validation of analytical methods

Provide methodological validation information on the project in the quality standard. For the current edition of the Chinese Pharmacopoeia/United States Pharmacopoeia/European Pharmacopoeia/British Pharmacopoeia/For the varieties already included in the Japanese Pharmacopoeia, if the standard method of the Pharmacopoeia is adopted, the methodological confirmation may be carried out as appropriate.

5.3Quality standard formulation basis

Explain the consideration of each item setting, summarize and analyze the selection of each inspection method and the basis for determining the limit. The drafting instructions of the quality standard shall include the basis for the selection of control items, method selection, inspection, purity and limit range in the standard.

6 Batch Inspection Report

Provide inspection reports for not less than three batches of production samples. If there are inspection items entrusted to other units, they shall be explained. The entrusted party of the entrusted inspection shall have relevant qualifications.

7 stability study

Experimental data and literature for stability studies. Including the use of direct contact with pharmaceutical excipients packaging materials and containers to carry out stability tests. If applicable, describe the compatibility and support studies performed on the selected package materials.

7.1Stability Summary

Summarize the sample situation, inspection conditions, inspection indicators and inspection results of the stability study, analyze the trend of each indicator, and propose storage conditions and validity.

7.2Stability data

The specific results of the stability study are provided in tabular form and the relevant maps from the stability study are attached.

7.3Packaging of accessories

Explain the packaging and selection basis of excipients, and provide sample packaging labels.

8 Pharmacological and Toxicological Research

The general need to provide pharmacological and toxicological research data and/or literature including:

（1) Review of pharmacological and toxicological research data.

（2) Test data and/or literature.

（3) Non-clinical pharmacokinetic test data and/or literature.

（4) Safety pharmacology test data and/or literature.

（5) Test data on toxicity of single dose and/or literature.

（6) Test data on the toxicity of repeated administration and/or literature.

（7) Allergy (local, systemic and photosensitive toxicity), hemolytic and local (vascular, skin, mucous membrane, muscle, etc.) irritation and other special safety test studies mainly related to local and systemic administration./or literature.

（82) Genotoxicity test data and/or literature.

（9) Reproductive toxicity test data and/or literature.

（10) Carcinogenic test data and/or literature.

（11) Other safety test data and/or literature.

Determine the research information to be submitted based on the marketing status, application, and risk level of the pharmaceutical excipients./Or literature, if a research information is not required, it should be explained under the corresponding research project. Pharmacological and toxicological studies of pharmaceutical excipients can be carried out separately or combined with pharmacological and toxicological studies of related preparations through rational design.

Description of 3. registration information

1 Based on the history of the use of excipients (in the preparation) and the availability of pharmacopoeia, the attached table1The information documents required for the different categories of excipients are listed.

2 The registration information should list all information items, according to the schedule.1Information that is not required should be described under that item of information.

3 For pharmaceutical excipients that have previously been approved in accordance with the registration procedure, such registration may be in accordance with the schedule.1Section2.4Class information requires information. Additional information may be provided as required during the review process.

4 The definition of the excipient has a history of use: the excipient has been used in domestic and overseas approved preparations and the route of administration is the same.

5 Scope of overseas approved preparations: only preparations approved for listing in the United States, the European Union and Japan.

6 For pharmaceutical excipients not covered by classification, please select“Other”According to the requirements of its registration data, the relevant registration data shall be submitted according to the history of use and the collection of pharmacopoeia.

7 If there is a history of use in domestic and foreign listed drugs, it has been included in the Chinese Pharmacopoeia,USP/EP/BP/JPReference of pharmaceutical excipients not included2.2Class to submit registration information.

8 If the same auxiliary material belongs to different classifications at the same time, relevant technical data shall be registered and submitted according to the classification with high risk level.

AttachedTable 1

Registration Information Form of Pharmaceutical Excipients

Note:+Items for which relevant information is required

-Items for which no relevant information is required

±Items for which relevant information is provided as required

Remarks:*

There is no history of use in domestic and foreign listed drugs, including

1.1The new molecular structure of the excipients and does not belong to1.2,1.3Excipients;

1.2By the use of the history of the auxiliary materials by simple chemical structure change (such as salt base, hydrate, etc.);

1.3Excipients obtained by co-processing of two or more excipients with a history of use;

1.4Excipients that have a history of use but change the route of administration.

There is a history of use in domestic and foreign listed drugs, and.

2.1Chinese Pharmacopoeia/USP/EP/BP/JPNone of the accessories received;

2.2 USP/EP/BP/JPOne of the excipients received but not used in domestic marketed drugs;

2.3 USP/EP/BP/JPOne of the excipients has been collected, but not in the Chinese Pharmacopoeia.;

2.4Excipients already included in the Chinese Pharmacopoeia.

Has a history of use in food or cosmetics, and

3.1Excipients for oral preparations with national food safety standards;

3.2Excipients for external preparations with national or industry standards for cosmetics.

Note:

（1) High-risk pharmaceutical excipients generally include: animal-derived or human-derived pharmaceutical excipients; pharmaceutical excipients for injections, ophthalmic preparations, inhalation preparations, etc. The registration data requirements for high-risk excipients can be provided on demand according to the application of excipients in specific preparations and the corresponding technical requirements, or supplemented during the review process according to the application of specific preparations and excipients in preparations.

（21) For excipients with a history of use, if the excipient exceeds the historical maximum usage of the corresponding route of administration, relevant safety data and other information shall be provided.

（31) For pre-mixed excipients, appropriate data shall be selected for registration according to their application in the preparation and the composition of each excipient in the formula.

（4) The above classification requirements for registration data are used as guidance for the preparation of data for registrants, and the Drug Evaluation Center may provide supplementary data requirements according to the needs of the technical evaluation of the preparation.

（5) According to the classification of accessories, registration data3.2.1with3.2.2,3.4.1with3.4.2,4.1.1（1) and (2) provide a set of research data.