Medical network on September 12 - to guide the applicant to change production process listed Chinese medicine research and the administration of state food and drug supervision and administration to make the listed Chinese medicine production process change research technical guiding principles, are hereby issued.
Hereby notify.
Annex: the technical guiding principle of the production process change of listed Chinese medicine
Food and drug administration
August 24, 2017
The attachment
Technical guidelines for the study of the production process change of listed Chinese medicine
An overview,
This guiding principle is mainly used for guiding the applicant to change production process listed Chinese medicine research, is for the listed Chinese medicine changes research technical guidelines (a) supplement and perfection of related content. The applicant should carry out corresponding research according to the impact of production process change on drug safety, effectiveness and quality control.
The process change of listed Chinese medicine includes: production process route, method, parameter and so on change. Medical materials production technology changes may involve pretreatment (including the net system, cutting system, gun broiled, grinding, sterilization, etc.), extraction, isolation, purification, concentration, drying, molding process changes. The change may involve only one link mentioned above, or it may involve multiple links.
Based on the characteristics of traditional Chinese medicine (TCM), as well as the change of medicinal material base or the influence extent of drug absorption and utilization of technological change can be divided into three categories: type I change belongs to a small change, the change does not cause the change of the medicinal material foundation, on the absorption of drug use will not produce significant effect; Ⅱ class changes are moderate changes, the change of medicinal material base or have an effect on the absorption of drug use, but little change; Ⅲ class change belongs to major change, the change will cause the obvious change of medicinal material base, or could have obvious influence to the absorption of drug use. Regardless of the type of change, it does not respond to the safety and effectiveness of the drug. The purpose of classification is to make it easier for the applicant to identify the change research content and conduct research effectively. However, due to the particularity of traditional Chinese medicine and the complexity of process change, the category boundaries of specific changes may not be clear, and the specific situation should be analyzed.
As the principal subject of change research, the applicant should study according to the basic requirements of the guiding principles and the relevant provisions of drug registration management and the characteristics of products. The guiding principle is to expound the relevant research on the technological change of listed Chinese medicine in the general situation from the perspective of technical evaluation. The specific requirements for the research mentioned in this guideline can be seen in the relevant guidelines. If by other scientific research to obtain sufficient evidence to prove that technological change on drug safety, efficacy and quality controllable will not have a negative impact, can not completely change research according to the requirements of this international guidelines.
Due to the particularity of injection, the change research guiding principle of listed injection is formulated separately.
Basic principles and requirements
The following principles should be followed:
(1) "necessary, scientific and reasonable" principle
The changes in the production process of the listed Chinese medicine should reflect the necessity, scientific nature and rationality of the change. The development of process change is based on the study of the process and the research and data accumulation in the actual production process. The more systematic and in-depth the previous research work, the more abundant the data accumulated during the production process, the more helpful it is to study the process change after the listing. If relevant research data are available in the early stage of quality design, it can be used as the basis for the later process change research. Applicant to cope with its product development and production process, such as the nature of the product has a comprehensive and accurate understanding, should know the cause of the change, change, and with "quality is the result of design ideas and concept to carry out the production process change study, play to the initiative, the establishment of a comprehensive, systematic quality risk management system. Through the changes before and after the product quality, stability, biological properties, such as research, to comprehensive analysis and evaluation of the results of the study, illustrates the necessity of the change, scientific and reasonable.
The production process is closely related to the production equipment. The selection of production equipment shall meet the requirements of production process. It should be established that production equipment is the concept of drug quality service. Fully consider the necessity and rationality of changing the production process to adapt to the production equipment.
(2) the principle of "safe, effective and quality control"
The chemical composition of traditional Chinese medicine is usually more complex, and its quality is guaranteed by the quality control of the whole process. Changes in the production process of traditional Chinese medicine may lead to changes in substance base or drug absorption and utilization, thus affecting drug safety, effectiveness and quality control. After the production process changes, the applicant should evaluate the impact of the changes on the safety, effectiveness and quality of the drug. The content of the design should be considered according to the specific situation of production process change and the type of change, the nature of the preparation and the influence of the change on the quality of the product.
For the complicated Chinese medicine preparation, the influence of process change on drug quality is often difficult to evaluate objectively. Keep production craft and confirmed clinical trials using samples of the production process is consistent, is to guarantee the quality of the listed drugs and clinical trials using samples are consistent, to ensure drug safety and effective important method. Technological change, the greater the degree listed medicinal substances and its absorption of the drug use and the more likely it is differences in clinical trials using samples, the safety and efficacy of listed drugs can be affected by the greater.
Better if the drug standard can't reflect the drug quality, only on the basis of drug standards before and after the changes of the comparison of the product quality is difficult to assess the influence of the change, should carry out quality research and drug standards, and improve the pharmaceutical standards of drug quality control. Chinese traditional medicine production process change research should adopt appropriate detection method based on the characteristics of products, such as fingerprint (feature maps), dissolution test, biological activity test, etc., to the quality of the sample contrast research, to reflect the changes before and after the consistency of product quality.
Change in the production process of listed Chinese medicine, to fully consider the risk of any errors or missing link, are may be safe, effective and quality control of drug adverse effect, should strengthen the research and evaluation system.
(3) study the selection of samples
The research and verification of the changes in the production process of the listed Chinese medicine should adopt the sample of production scale, which should be used to represent the actual situation of the production and the change of the production process. Before and after the change of drug quality comparative study, the general adoption of the three batches of the sample and the change of the first three batches of samples. After changing the sample stability test, three batches of samples were generally used for 3-6 months of accelerated test and long-term stability test, and the stability data of the three batches of the samples were compared with those of the previous three batches.
(4) study of association changes
The production process is closely related to production equipment, pharmaceutical auxiliary materials, specifications, etc. A change in the production process is often not independent and may involve a variety of changes. For example, the change of granulation mode may be accompanied by changes in the concentration process, auxiliary materials and specifications. In order to account for convenience, this guideline refers to a change that is associated with or associated with other changes as associated changes.
When the production process changes and the related changes such as pharmaceutical auxiliary materials or production equipment are changed, the research should be carried out in the light of the corresponding guiding principles. If the variation type of the related change is different, the study should be conducted in general according to the type of change that the technology requires.
(5) requirements for the preparation of toxic medicinal materials
In the case of the change of the prescription of toxic medicinal materials, the influence of production process change on drug safety should be paid attention to, especially the safety of the following types of preparation changes should be concerned, and relevant researches should be carried out. (1) preparation of drugs involving large drugs (highly toxic); (2) preparations for the discovery of severe toxic drugs in modern studies; (3) it involves poisonous medicinal materials [2], and preparations for the use of medicines for pediatric medicine, pregnancy and lactation; (4) the medicinal herbs that are forbidden or used by pregnant women should be used, and the function is to treat the medicine of women during pregnancy and lactation. The classification of toxicity of medicinal materials in local medicinal materials is inconsistent and based on the high toxicity classification criteria.
3. Classification of Chinese medicine production process change
(1) overall consideration
The specific situation of all kinds of changes listed in this guiding principle is based on the general considerations for the study of the change of traditional Chinese medicine, for reference only. The production enterprises should carry out corresponding research in combination with the product characteristics. The research object is different, and the research content can be different. If the ingredients of active ingredients are relatively clear, the change categories can be determined directly according to the comparison of the medicinal materials and their absorption and utilization before and after the change. Listed in the present guiding principles in the process change is mainly suitable for ordinary Chinese native medicine preparation, involving toxic herbs for prescription, strong biological activity or security window narrower traditional Chinese medicine (TCM) should be performed according to the actual situation of the corresponding research.
For the purposes of this guideline in the class is divided into Ⅱ or Ⅲ changes, if there is sufficient research data showed that changes the material basis of drugs and won't impact absorption use, can be in accordance with the requirements for Ⅰ class changes were studied. For this guiding principle is divided into Ⅰ class changes, if the data showed that the material basis for the changes to a drug or absorption use may influence, should be in accordance with the requirements for class Ⅱ or Ⅲ change were studied.
(2) classification of treatment process change before medicinal materials
The pretreatment of medicinal materials is an important part of traditional Chinese medicine production. The pretreatment of the medicinal materials should be investigated on the influence of the quality of the tablets, the follow-up intermediates and the pharmaceutical preparations.
1. Ⅰ class changes
Including but not limited to the following changes:
(1) the methods and equipment for changing the pulverization of raw materials without thermal sensitivity and volatile components are the same as the particle size distribution before and after crushing.
(2) change the size and shape of the slices, but no obvious influence on the extraction rate and medicinal materials.
(3) the individual pulverization of various medicinal herbs is mixed and crushed, and the powder rate of single pulverization is relatively high, and the powder rate and particle size before and after change are not significant.
2. Ⅱ class changes
Including but not limited to the following changes:
(1) the change of the raw material with heat sensitive and volatile components has been changed and the degree of heating has changed.
(2) the particle size of medicinal materials is changed into another powder grade in the pharmacopoeia of the pharmacopoeia.
3. Ⅲ class changes
Including but not limited to the following changes:
(1) change the method of the cautery, such as the change of the method of semi-summer in the prescription to ginger half summer.
(2) add 60Co- gamma radiation sterilization or microwave sterilization to original medicinal materials or raw powder.
(3) the particle size of Chinese medicine pulverization is changed from fine powder to super micro powder.
(3) extraction of purification process change classification
The extraction and purification process of the guiding principle includes the extraction and purification of the purification process, including the concentration and drying process of the liquid medicine. Extraction and purification process directly affect the material foundation of traditional Chinese medicine products. After the modification of the purification process, the effects of process change on the type, content and material properties of pharmaceutical ingredients are required. When the change involves critical processes or major process parameters, you should be particularly careful. In addition, the change in the extraction solvent dosage, generally carried out in accordance with the Ⅲ class changes research, to provide adequate research data to prove that if the change is not big, can press Ⅱ class changes were studied.
1. Ⅰ class changes
Including but not limited to the following changes:
(1) the static and filtration of the liquid medicine were changed to centrifuge (or centrifuge changed to hydrostatic and filtration), and the contents of solids and indexes in the liquid medicine were unchanged.
(2) does not contain volatile components, heat sensitive components of the extract, the degree of enrichment method, parameter and heated unchanged under the premise of the "multiple extraction of extract combined enrichment" changed to "each extract concentration, directly in the concentrated tank mix", or "each extract concentration, directly in the concentrated tank mix" changed to "extract merge multiple extraction enrichment".
(3) the liquid containing volatile components and heat-sensitive ingredients shorten the heating time or reduce the heating temperature.
(4) do not contain several kinds of extract volatile components, heat sensitive components (including powder and extract), by "several concrete common drying (including powder added to extract common drying)" changed to "dry" respectively, or by "several dry extract respectively" change for "common drying (including powder added to extract common drying)".
(5) changes in the temperature, time, or time required for the static storage of liquid materials due to the change of production equipment and scale, etc.
(6) when the other process parameters are unchanged, the time of alcohol sinking or water sinking can be changed, but the relative density of the liquid, the solid object and the index component of the liquid are unchanged.
2. Ⅱ class changes
Including but not limited to the following changes:
(1) changes in the heating temperature or heating time of the material containing volatile components and heat-sensitive ingredients.
3. Ⅲ class changes
Including but not limited to the following changes:
(1) change of process route, such as:
The changes in the extraction and extraction of the slices were extracted and separated.
To extract the change of the solvent.
The volatile oil is changed to not extract the volatile oil.
The process of water sinking (or alcohol sinking) is added.
The steps in the extraction or purification process are removed.
(2) change of process methods, such as:
(1) to extract the change in the way, such as changing the traditional extraction technology for continuous extraction, ultrasonic extraction or dynamic decoction extract change for the extraction of warm immersion, thermal circumfluence extraction change for countercurrent extraction, diacolation process changes for continuous hot reflux extraction or static extraction, volatile oil extraction process change for supercritical fluid extraction technology, or sweet water extraction process, etc.
The changes of the purification method, such as the change of alcohol precipitation to precipitation agent, clarifying agent or membrane separation and purification, the extraction process is changed into the purification process of macroporous adsorption resin, ion exchange or silica gel.
(3) change of process parameters, such as:
The concentration, frequency, temperature, or time of the extracted solvent.
The main technological parameters of the process of change of alcohol-sinking/water sinking technology, such as the relative density of the liquid before the hydrolyzing of alcohol, the amount of alcohol and the amount of water and the amount of water, and the temperature of the water sinking, etc.
The purification process is changed to ZTC1+1 clarifier, such as chitosan.
(4) the change column chromatography purification process of main process parameters, such as the dosage of column packing type and model, and the proportion of the sample amount, elution solvent type and dosage, eluent pH, elution end, etc.
The main technological parameters of the supercritical extraction process, such as extraction pressure, extraction temperature, extraction time, flow velocity, separation kettle pressure, separation kettle temperature, etc.
(4) classification of molding process change
The molding process has important influence on the quality of Chinese medicine preparations, the absorption and utilization of pharmaceutical ingredients and the stability of preparations. The change of Chinese medicine molding process mainly includes the production method of change preparation and technological parameter. The change of molding process is often associated with the change of the auxiliary material (source, model, grade, dosage, type, etc.) and the change of production equipment.
1. Ⅰ class changes
Including but not limited to the following changes:
(1) traditional Chinese medicine with no volatile components or heat sensitive ingredients can change the drying process, shorten the heating time or reduce the heating temperature, such as normal temperature and drying changes to reduce pressure drying and fluidized bed drying.
(2) the order of addition of raw materials in the preparation of solid preparation is changed.
(3) mix equipment type and parameters in the mixed process step, and the mixing uniformity meets the requirements.
(4) shorten the heating time of the granulation process or reduce the heating temperature, such as wet legal granulation, one-step granulation, and the change of grain of dry legal system.
(5) change the concentration of adhesive ethanol solution in wet legal granulation technology.
(6) increase the normal filtration process of the liquid medicine, or change the filter material, pore diameter and filter number of the normal filtration of the liquid medicine, and the relevant detection and the solid objects and the contents of the index components are unchanged.
(7) the treatment of volatile oil is added after the injection is changed into beta-cyclodextrin.
(8) the change of pill method, such as pan - making, extrusion and rolling, suppression, etc., or by manual pan changing into machine pellets.
(9) pills, capsules and tablets add polishing process. The coating process is changed from the coating process to the coating process.
(10) the filling process of the capsule is changed, such as filling after the powder is changed into granules.
(11) oral liquid preparations without volatile and heat-sensitive ingredients are changed from hot and humid sterilization to terminal aseptic filling process, or increase the process of hot and humid sterilization.
(12) change feeding sequence in the drip system, reduce the ingredients temperature, drop system temperature, condensate temperature and change the drop distance.
(13) adding inert gas steps to the packaging process.
2. Ⅱ class changes
Including but not limited to the following changes:
(1) oral liquid preparations containing heat-sensitive ingredients, which are changed by heat sterilization to terminal aseptic filling process; Or increase the thermal sterilization process.
(2) traditional Chinese medicine with volatile components and heat-sensitive ingredients is changed and dried.
(3) the normal filtration process of the liquid drug is changed to ultrafiltration process.
3. Ⅲ class changes
Including but not limited to the following changes:
(1) the normal pressure/decompression drying is changed into special drying methods such as microwave drying.
(2) change of the forming process method with obvious influence on drug absorption and utilization.
4. Research on the production process of traditional Chinese medicine and the requirements for the declaration
(a) Ⅰ class change research and declare the information requirements
1. Overview of varieties
(1) declare varieties were allowed to public information, including specifications, approval number, approval time, standards, and the period of validity, and past the supplement and the latest registered again, etc.
(2) briefly describe the change
If it is not declared for the first time and has not been approved, the reasons for the failure should be outlined. If there is an associated change in the process change, the situation of the associated change should be explained.
2. Change the content and reasons for change
The process of production process before and after change is illustrated in the description of words. The main changes of each step (including batch, equipment, method of production, process parameters, type of auxiliary materials and quantity of auxiliary materials, etc.) are provided in the way of words description or list. The specific items and reasons for the related changes should be explained, and information about prescription and drug specifications should be provided to clarify whether the formulation of the formulation and the drug specifications have been changed.
3. Production process change research
(1) the rationality evaluation and risk analysis of the change
Risk analysis of change content based on the principle of specific analysis. Analyze the influence of change on drug quality, determine the rationality of change and change risk.
(2) change study
Production process
Complete description of the changed production process and main process parameters.
2. Process research
In combination with the change situation, the selection basis and optimization process of production process are briefly described. The corresponding process steps and control scope of main technological parameters are listed, and the detailed process route, technological method, definition of technological parameters, and research materials for the type and dosage of auxiliary materials are provided. If the intermediate quality control changes are involved, the control standards of the intermediates should be listed. The source, level, and quality standards of the auxiliary materials should be listed in relation to the change of the auxiliary materials, and the details of the added supplementary materials shall be listed in the key points. For special auxiliary materials, the safety application limit and its basis should be explained.
Production process verification and pilot production data
In combination with the change situation, the production process verification is briefly described. If only local changes to the production process are involved, the content of the change can be studied and verified. If the whole change of production process is involved, the whole production process should be studied and verified.
Provide 3 batches of pilot study data that can represent the actual situation of production, including batch number, material quantity, semi-finished product quantity, auxiliary material quantity, finished product quantity, yield rate, etc.
(3) research on drug standards and quality
Drug standard
Provide pharmaceutical drug standard draft and draft specification, various quality control project set, summarizes the analysis methods to examine the choice and the basis, as determined by the limit of did not include standard to consider and determine the basis of the project, describe the have because production process changes as a result of changes to the project.
To evaluate whether the original implementation standard/protocol meets the current technical requirements, such as methodological research and standard revision of the system if it does not meet the current requirements.
Quality study
Provide quality test data of the research and literature, changes to the project should include the pharmaceutical standards of research and verification methodology research materials, not included in the drug standards project methodology research and validation data, etc. The feasibility of the test method can be evaluated by responding to the verification work.
Quality comparison research
Under normal circumstances, should provide changes involved in the production process quality control index of comparative research materials, change process and the sample with the original production process sample pharmaceutical standards of quality control index of the comparative study on information. When necessary, still should according to the change of the specific circumstances, dosage form, features and the characteristics of the drug, as the case to increase the appropriate test items (such as fingerprints, dissolution, biological activity test, etc.), in order to fully reflect the consistency of the sample quality before and after the process change.
(4) batch inspection report
The inspection report of three consecutive batches shall be provided with sample batch number, production time, location, bulk and other information. The data of the first three batches of samples were given, and the key indexes were compared.
(5) stability study
3-6 months acceleration and long-term retention of samples after 3 batches of modified samples are generally dealt with, and the stability of the sample before change is provided in the form of text or list. For key projects, such as content, specific test data should be listed to compare the change trend.
Provide change after the sample of the inner packing material, storage conditions, the period of validity, and combining the study of stability of samples after making changes, change the stability of the samples before and after comparison research situation, the storage conditions and the valid date of the products, such as the change after the sample of the inner packing material, storage condition, the determination of the validity of the basis.
(2) Ⅱ class change research and declare the information requirements
Such changes, in addition to the above Ⅰ class changes related work, also should undertake the following work:
1. Provide pharmacological test data as required.
2. Comparative data on clinical trials or bioequivalent studies.
(3) Ⅲ class change research and declare the information requirements
Such changes generally need to conduct a comprehensive study and verification work, the research work can be in accordance with the requirements of overall consideration in this paper, the basic ideas and methods, in addition to the above Ⅰ class changes related work, according to the need for the following work is necessary to prove that the change will not have a negative impact of drug quality, including:
1. Related pharmacological toxicological test studies.
2. Ⅱ, Ⅲ period clinical trials or bioequivalence study.
Note 1: big poisonous medicine refers to the state council "toxic drugs for medical use management method" (1988) the release of 28 kinds of toxic herbs and labeled in national and local medicinal standard big poison (or toxic) medicine.
Note 2: poisonous medicinal materials are the medicines labeled as toxic in national and local medicinal materials.
reference
1. Technical guidelines for the research on the change of traditional Chinese medicine (1)
2. Guiding principles for the raw materials of traditional Chinese medicine and natural medicine
3. Technical guiding principles of extraction and purification of traditional Chinese medicine and natural medicines
4. Guidelines for the study of traditional Chinese medicine and natural pharmaceutical preparations
5. Guiding principles of Chinese medicine and natural medicine
6. Guiding principles of the study on the stability of traditional Chinese medicine and natural medicines
7. Guiding principles of sterilization of traditional Chinese medicine
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