Medical network - February 20 September and November last year, the CFDA successively to change specifications drugs (oral solid preparation), dosage form drug (normal) oral solid preparations with the change of base drug consistency evaluation technique guide for advice, on February 17, the quality of generic drugs and drug efficacy evaluation of consistency change specifications (oral solid preparation) evaluation generally consider the quality of generic drugs and curative effect evaluation of consistency in the change of dosage form drug (oral solid preparation) evaluation generally consider the quality of generic drugs and curative effect evaluation of consistency in the change of base medicines evaluation generally consider "three official documents released in the CFDA's official website.
Generics in the quality and curative effect evaluation of consistency change specifications drugs (oral solid preparation) assessment of general considerations
To implement the state council about the opinions of the drug review of medical equipment examination and approval system reform "(guo fa [2015] 44) and the general office of the state council about the opinions of the consistency to carry out the quality of generic drugs and curative effect evaluation" (countries do hair [2016] no. 8), the spirit of the state food and drug supervision and administration bureau issued "on the implementation of the general office of the state council about to carry out the quality of generic drugs and curative effect evaluation opinion consistency > announcement of relevant matters of no. 106 (2016) and the common reference preparation oral solid preparations to select and determine the guiding principles (announcement no. 61, 2016), and other technical guidelines, this article is the guiding principle of supplementary document.
Change specifications drugs refers to the specifications listed in the United States, the European Union and Japan are not allowed to, or can not be sure the same specification reference preparation of drugs.
This document applies to generics in the quality and curative effect evaluation of consistency of oral solid preparation specifications of drug evaluation. Evaluation including but not limited to the contents described in this document.
An overview,
Part existed in our country has approved drugs to change product specifications, again for this part of the product evaluation is a generic quality and curative effect evaluation is an important part of consistency. Listed on the specification and usage and dosage of the drug on the basis of previous clinical trials determine, therefore increase the specification shall generally be based on the original usage and dosage of drug instructions. In order to strengthen the management of drug specifications, to prevent unreasonable drug specifications bring confusion to clinical medicine, the state food and drug administration issued the notice about strengthening the management of the drug specifications and packaging specifications "(food drug safety note letter [2004] no. 91), to increase the drug specifications of the supplement further put forward strict requirements, application may not change the increase of the specifications of the usage and dosage or applicable people. To change specifications of drug evaluation contents include pharmaceutical and clinical trials, etc.
Second, the evaluation content
(a) change specifications of the scientific nature and rationality
Change the specifications of drugs in the first place should be combined with the original drugs specification listed, fully demonstrated scientific nature, rationality and necessity of change the specification.
Change in the drug specifications shall be within the scope of its use the dosage of the specification, the indications in the same situation, may not change the usage and dosage of the drug approved or applicable people, its minimum specifications generally should not be less than a single drug dose, and shall not be greater than the single largest drug doses.
(2) pharmaceutical evaluation
With the varieties of the original specification reference preparation (hereinafter referred to as the reference preparation) for comparison, comparative study on the system for pharmacy, such as production enterprises and has passed the evaluation of consistency and reference formulation of the same product, also should carry on the contrast research, and the differences between the quality of the preparation and quality evaluation. The research content mainly includes the following several aspects:
1. The prescription screening and optimizing process: control reference formulation change with the specification requirements, analysis key physical and chemical properties test preparations of raw materials and auxiliary materials, prescription screening and production process optimization, packing material selection and verification.
2. Quality control: system analysis and comparison to change product specifications and reference preparation quality difference, focus on: drug dissolution curve in many medium; Spectrum of impurities and the content of impurities, such as a new impurity shall be confirmed for structural levels, quantitative determination of impurities and toxicity research; Reflect the characteristics of the dosage form other key projects.
3. The stability test: focus on character, dissolution curve and related substances, such as content of project.
(3) the bioequivalence test and clinical trials
If the specifications of drugs and reference preparation indications and usage and dosage are the same, and in the treatment of dose range, suggest to change specifications of drugs and reference preparation in the same dosage of medicine (single drug dose not exceed the maximum dose dose), bioequivalence test.
Do not meet the above conditions, Suggestions for clinical trials.
Third, other
Other matters not mentioned herein refer to administration of the state food and drug supervision and administration on the released chemical new registered classification declaration data requirements (trial) circular no. 80 (2016), "about release chemicals generics oral solid preparation quality and curative effect evaluation declaration data consistency requirements (trial) circular no. 120 (2016), the pharmacokinetic parameters for the finish evaluation index of chemical drugs generic human bioequivalence study technical guiding principles (announcement no. 61, 2016) and the quality of generic drugs and curative effect of consistency evaluation of clinical efficacy test generally considered (18 2017 notice) and other relevant documents.
Generics in the quality and curative effect evaluation of consistency change of dosage form drug (oral solid preparation) evaluation generally considered
To implement the state council about the opinions of the drug review of medical equipment examination and approval system reform "(guo fa [2015] 44) and the general office of the state council about the opinions of the consistency to carry out the quality of generic drugs and curative effect evaluation" (countries do hair [2016] no. 8), the spirit of the state food and drug supervision and administration bureau issued "on the implementation of the general office of the state council about to carry out the quality of generic drugs and curative effect evaluation opinion consistency > announcement of relevant matters of no. 106 (2016) and the common reference preparation oral solid preparations to select and determine the guiding principles (announcement no. 61, 2016), and other technical guidelines, this article is the guiding principle of supplementary document.
Change of dosage form drugs refers to the form of a drug on the market in the United States, the European Union and Japan are not allowed to, or not sure reference preparation formulations with drugs.
This document applies to generics in the quality and curative effect evaluation of consistency of oral solid preparation to dosage form and dosage was not significant change of drug evaluation. Evaluation including but not limited to the contents described in this document.
An overview,
Change of dosage form drug oral solid preparation, from the perspective of pharmacokinetics can be divided into don't significantly change the pharmacokinetic behavior and significantly change the pharmacokinetic behavior.
Referred to in this document is not significantly changed pharmacokinetic behavior of dosage forms, such as tablet, capsule, dry suspension agent and change between granules and other dosage forms; Significantly changed pharmacokinetic behavior of dosage forms, such as: common oral solid preparation to slow changes such as controlled-release dosage forms.
Second, the evaluation content
(a) change the scientificity and rationality of dosage forms
From the physical and chemical properties, biological properties and clinical medicine need, patient compliance, drug economics, compared with the original dosage forms the merits of the reference preparation aspects analysis to form the scientific nature, rationality and necessity of the drug.
(2) pharmaceutical evaluation
Compared with the original dosage forms reference preparation system test, the evaluation of both the similarities and differences and the advantages and disadvantages. Change of dosage form drug quality should with the original dosage form reference preparation quality. Evaluation content mainly includes the following aspects:
1. The prescription screening and optimizing process: control the original dosage form reference preparations with the change of the requirement of the dosage form, prescription screening and production process optimization, packing material selection and verification.
2. The control of raw materials:
Active pharmaceutical ingredients (1) analysis and determination of key physical and chemical properties under different pH conditions (such as crystal shape, solubility, particle size and particle size distribution, pKa, logP, etc.); Consistency test and the results of active pharmaceutical ingredients and accessories.
(2) analysis of test materials preparation performance related key features.
3. Quality control: system analysis and comparison with the original dosage form reference preparation quality differences. Focus on: drug in medium dissolution curve; Spectrum of impurities and the content of impurities, such as a new impurity shall be confirmed for structural levels, quantitative determination of impurities and toxicity research; Reflect the characteristics of the dosage form other key projects.
4. The stability test: focus on character, dissolution curve and related substances (especially new impurities), content determination, etc.
(3) the bioequivalence test and clinical trials
For biological equivalent LiTi basis and does not significantly change the pharmacokinetic behavior change dosage form drugs, should with the original dosage form reference preparations for bioequivalence test.
Change the change of dosage form drug pharmacokinetic behavior, suggested dosage forms with the original reference preparations for relative bioavailability studies and clinical trials.
Third, other
Other matters not mentioned herein refer to administration of the state food and drug supervision and administration on the released chemical new registered classification declaration data requirements (trial) circular no. 80 (2016), "about release chemicals generics oral solid preparation quality and curative effect evaluation declaration data consistency requirements (trial) notice" (announcement no. 120, 2016), the pharmacokinetic parameters for the finish evaluation index of chemical drugs generic human bioequivalence study technical guiding principles (announcement no. 61, 2016) and the quality of generic drugs and curative effect of consistency evaluation of clinical efficacy test generally considered (18 2017 notice) and other relevant documents.
Generics in the quality and curative effect evaluation of consistency to base medicines evaluation generally considered
To implement the state council about the opinions of the drug review of medical equipment examination and approval system reform "(guo fa [2015] 44) and the general office of the state council about the opinions of the consistency to carry out the quality of generic drugs and curative effect evaluation" (countries do hair [2016] no. 8), the spirit of the state food and drug supervision and administration bureau issued "on the implementation of the general office of the state council about to carry out the quality of generic drugs and curative effect evaluation opinion consistency > announcement of relevant matters of no. 106 (2016) and the common reference preparation oral solid preparations to select and determine the guiding principles (announcement no. 61, 2016), and other technical guidelines, this article is the guiding principle of supplementary document.
Change base drugs refers to the active pharmaceutical ingredients used in the preparation in the United States, the European Union and Japan are not allowed to use or not sure reference preparations that contain the same active pharmaceutical ingredients.
This document applies to generic indications in the quality and curative effect evaluation of consistency of the same change to base the evaluation of the drug. Evaluation including but not limited to the contents described in this document.
An overview,
Different drugs if the active ingredient is the same, only into salt forms, referred to as the change of base medicines, including change known salt active ingredient of acid radical, base, or metal ions to form of free drug into salt or changed into salt drugs to free form such as drug substances and drug products.
In principle, by changing into salt forms of drugs should not change its pharmacological action, only to change its physical and chemical properties (such as solubility, stability, etc.), to meet the needs of the storage, production or clinical drug use. But each into salt forms of medicine are with unique chemical properties and biological activity compounds, their physical and chemical properties change, can cause degree of pharmacological effects or property, the change of the process in the body (such as solubility change can affect drug absorption in the body, even in vivo pharmacokinetic process may therefore change), which affect the efficacy of drug interaction strength, sites and duration, or even a new indications toxicity, activity, or change, its clinical curative effect and drug safety. To review this kind of medicine is a generic quality and curative effect evaluation work is an important part of consistency.
Second, the evaluation content
The change of base medicines including drug substances and drug products. To change base drug efficacy and safety evaluation should be change base drugs as comparison, contrast experiment was carried out, and to evaluate both similarities and differences in the purpose and the advantages and disadvantages. The research content mainly embodied in the following aspects:
(a) change the scientificity and the rationality of the base
From the drugs of the physical and chemical properties, biological characteristics, clinical need analysis to base the scientific nature, rationality and necessity of the drug.
(2) of pharmaceutical research
Pharmaceutical research requirements and the change of base and drug control, comparison test, and the base base drugs and change medicine in the purpose of evaluate the advantages and disadvantages of similarities and differences. Change should base drug quality and to be base drug quality of the reference preparation. The research content mainly for the following several aspects:
1. The API
(1) the structure identification: according to the chemical new registration confirmation structure based on the classification of 2.1 class requirements and should provide ample evidence into salt.
(2) the physical and chemical properties: should carry on the physical and chemical properties of system research and comparing with be change base drugs, focus on the following contrast test data: solubility (different pH, different solvents, etc.), pKa (pKb), moisture absorption (critical relative humidity and moisture absorption curve), crystal type, etc. Should provide detailed as far as possible by physical and chemical properties of the literature information base drugs.
(3) quality control: should be related to the safety and effectiveness of system research and compare the purpose, focus on the material structure of conscientiousness, scientific nature and rationality of analysis method of impurities, impurity level of production and the impurities such as comparing the test data, especially if there is a new impurity and the impurity level and toxicity, the potential safety risk of base (such as mesilate) to system control, and research shows that the impurity limits for the basis.
(4) stability test: test should undertake the quality control project comparison and analysis, focus on character, crystal type, related substances and content determination, etc.
2. Preparation
(1) formulations and the component of product: different ways into salt has a great influence on the physical and chemical properties of drugs may, physical and chemical properties for the determination of dosage form selection and the production process is very important. Should focus on the basis of the choice of types and specifications, as well as the prescription composition, production technology, choice of packaging material and determine the rationality of the attention and to be change base the comparison of the reference preparation.
(2) the control of raw materials: (1) analysis and preparations of production and performance related key physical and chemical properties of active pharmaceutical ingredients (such as crystal shape, solubility, particle size distribution, under the conditions of different pH pKa, logP, etc.) and its control; Specifies whether the API and the compatibility of complementary makings test and basis; If the API and the compatibility of material test, the paper test, including test design, the indexes, the test results, etc. (2) the paper material is appropriate for the dosage used approach, the role of excipient in prescription analysis main supplementary material preparation performance related key features. If there is any change, to change the rationality of the prescription after the supplementary material, and the rationality of the prescription analysis.
(3) quality control: should be related to the security effectiveness of the objective system of research and comparison, focus on the material structure of conscientiousness, scientific nature and rationality of analysis method of impurities, impurity level of production and the impurities such as comparing the test data, especially if there is a new impurity and the impurity level and toxicity, the potential safety risk of base (such as mesilate) to system control, and research shows that the impurity limits for the basis, and the dissolution curve can reflect the characteristics of its dosage form contrast test of key projects.
(4) stability test: test should undertake the quality control project comparison and analysis, focus on the character, the dissolution curve and related substances and content determination, etc.
(3) the clinical studies
Due to the change of base medicines are on the market and used in clinical treatment, under normal circumstances, the pharmacological active ingredients in the body is the same, in principle, no longer to carry out the clinical pharmacodynamics and toxicology research.
Base drugs with the change should be analyzed compared base drugs, whether to increase the potential security risks associated with the base. Focus on: into whether the salt drug toxicity and Yin and Yang are combined into salt ions have close relationship; Into salt in the process of preparation is it possible to produce new potential toxic impurities; Whether can produce toxic metabolites in the body. When necessary, in accordance with the requirements for chemical classification of new registered 2.1 class for toxicology research.
(4) bioequivalence test or clinical trials
With the change of equivalent for LiTi base drugs, to carry out the change and the base reference drug preparations of bioequivalence research; LiTi for superior effect according to the change of base medicines, suggest to be change base drugs as the reference preparations, pharmacokinetic study, pharmacokinetic study/pharmacodynamics study and (or) the corresponding clinical trials.
Third, other
Other matters not mentioned herein refer to administration of the state food and drug supervision and administration on the released chemical new registered classification declaration data requirements (trial) circular no. 80 (2016), "about release chemicals generics oral solid preparation quality and curative effect evaluation declaration data consistency requirements (trial) circular no. 120 (2016), the pharmacokinetic parameters for the finish evaluation index of chemical drugs generic human bioequivalence study technical guiding principles (announcement no. 61, 2016) and the quality of generic drugs and curative effect of consistency evaluation of clinical efficacy test generally considered (18 2017 notice) and other relevant documents.
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