Steps in Generic Drug Development

1. Overview

According to the provisions of Annex II of the Drug Registration Management Measures, generic drugs are APIs or preparations that already have national drug standards. Such drugs have been approved for domestic production or marketing. After extensive use at home and abroad, their safety and effectiveness have been obtained. More fully confirmed.

　　 Today’s new regulations put forward new requirements for generic drugs, mainly the following points:

　　 1. Standardize the selection principle of the copied drugs, that is, the selection of reference preparations.

　　 2. Increase the inspection of the production site before approval.

　　 3. According to the CTD format requirements to provide declaration materials to make the declaration standard and unified.

　　 4. Emphasis on comparative research is one of the important methods to judge whether the quality of the two is consistent.

　　 5. Strengthen process verification, the purpose is to ensure consistent production of products of consistent quality in accordance with the declared process during mass production.

　　 6. The requirements for the crystal form are proposed. Different crystal forms have different solubility and stability.

　　Analyze the above new requirements and reference guidelines to draw conclusions:

　　 The purpose of generic drug research and development is to achieve large-scale production, emphasizing localization, in order to achieve “alternative”. The requirement is to achieve “same”. The method is a comparative study.

　　 1. Security “same”:

　　For safety, the control of oral solid preparations is mainly related substances, while liquid preparations need to control preservatives, oxidants and other substances that affect the human body in addition to related substances. Therefore, the determination of the content of preservatives must be included in the quality standards.

　　 Research content: Statically, it should include the comparison of impurity spectrum, the comparison of single impurities, and the comparison of the total amount of impurities. The dynamic comparison is the comparison of the influencing factor test and the accelerated test, that is, the stability comparison study.

　　 2. Effectiveness “same”:

For oral solid preparations, oral suspensions (including dry suspensions), the dissolution curve is the main control index [1]; for oral solutions, the selection of preservatives, flavoring agents, oxidants, solubilizers and stabilizers is very good Importantly, the control points are mouthfeel, osmotic pressure, PH, and the presence or absence of flocculation; for topical preparations (such as nasal sprays), particle size distribution, osmotic pressure, and viscosity are the main control indicators.

　　 Research content: Compare dissolution curve; particle size distribution comparison; osmotic pressure and viscosity comparison.

　　 3. Crystal form:

Depending on the crystal form, the solubility and stability of the drug may be different, resulting in different bioavailability. There are few literatures on the crystal form of a drug; the determination of the crystal form of the raw materials in the preparation is difficult; during the preparation of the preparation, there is no guarantee that the crystal form will not change.

　　 However, in view of the characteristics of generic drug research, the solubility can be explained by the comparison of dissolution curves; the stability can be explained by the comparison of influencing factors and accelerated tests.

2. Summary of generic drug R&D projects

　　 (from project establishment to declaration, the time is 10-12 months)

3. Specific steps in generic drug development

　　 (1) Product information survey

　　 (completed in about a week)

Whether there are legal raw materials provided; clinical data, adverse reaction data and product instructions and other relevant materials; domestic and imported formulation dosage forms and specifications; product quality standards (original research standards, domestic first imitation standards, pharmacopoeial standards); original research prescription composition and process research data Drug stability information; patent situation; production registration situation (the number of original product manufacturers and domestic production declaration manufacturers); reference preparation sources, etc.

　　 (2) Preliminary preparations (approximately one month to complete):

　　 1. Procurement of reference preparations

　　 1) First choice of imported or locally produced original research products;

　　 2) If the original product is not available, you can use high-quality drugs marketed in developed countries, such as the same variety marketed in ICH member countries, that is, the same variety of generic products in the United States, the European Union, or Japan. If the products of the above countries have already been imported into China, imported products can be used.

3) If a reference product that meets the above requirements cannot be obtained, a number of domestic mainstream products should be used for in-depth comparative research under the premise of fully considering the rationality of the question, and the quality of the declared product should reach the most Excellent product quality.

　　 4) If it is indeed impossible to obtain a marketed reference product that meets the requirements, under the premise of fully considering the rationality of the question, the corresponding research should be carried out in accordance with the technical requirements of the new drug research.

　　 2. Procurement of raw materials

　　You can choose samples from several manufacturers for comparison, and the purchase quality is better (providing raw material manufacturer qualifications, invoices, inspection reports, standards, purchase and sales contracts and long-term supply agreements and other supporting documents).

　　3. Procurement of chromatographic columns and reference products

　　Based on the analysis of the quality standards of raw materials and the quality standards of the inquired preparations, draft standards are drawn up. After fully understanding the chromatographic conditions of the product from the raw material supplier, purchase the chromatographic column and reference products. Including: chromatographic column model, specification, manufacturer; type of reference substance (including isomers); specification of reference substance; use of reference substance (UV or measurement included); purchase amount of reference substance (specify price).

　　 4. Purchase of accessories:

　　According to the domestic application of auxiliary materials, after a reasonable analysis of the prescription composition of the original research drug, determine the purchase of auxiliary materials (the factory does not purchase auxiliary materials, need to provide auxiliary materials manufacturer qualifications, invoices, inspection reports, standards, purchase and sales contracts and other supporting documents).

　　Choice of selection of excipients: preferred pharmaceutical grade; no pharmaceutical grade, oral preparations and topical preparations can be selected for food grade. If there is no food grade, consider replacing accessories.

　　5. Procurement of packaging materials:

After the purchase of the reference preparation, refer to the packaging material of the reference preparation and combine with the company’s situation to formulate the type of packaging material (the packaging material is not purchased in the factory, the qualification of the packaging material manufacturer, invoice, inspection report, standard, purchase and sales contract, etc. need to be provided) Proof documents): types of packaging materials (oral or injection grade); specifications of packaging materials (packaging specifications); pharmaceutical standards of packaging materials (pharmacopoeial standards or registration standards); purchase volume. This work can be slowed down.

　　(3) Research on prescription technology

　　 1. Inspection of raw materials and reference preparations

　　 (completed in about a week):

　　Determine the legal source of the raw materials and auxiliary materials; test the raw materials and auxiliary materials with reference to Pharmacopoeia standards or other relevant standards; issue an inspection report.

　　Comprehensively test the reference preparations, and the testing items should not be limited to the formulated preparation quality standards. For solid oral preparations, the dissolution curve of the reference preparations should be measured. For pharmaceutical preparations that are sensitive to PH, the pH value of the 5% suspension should be measured. For liquid preparations, the viscosity, osmotic pressure, and pH should be measured. Summary of inspection results.

　　Through this project, you can basically understand the basic performance of the preparation.

　　 2. The prescription process

　　2.1 Compatibility test of auxiliary materials

　　 (1) Oral solid preparation:

　　Through the preliminary information survey, it was learned that the nature of raw materials is relatively stable, and there are not many requirements for auxiliary materials and storage conditions:

If the prescription composition of the original research drug can be found, and the type of excipients is the same as the original research drug, this test may not be done; if the type of excipient is increased on the basis of the original research drug prescription, only the compatibility of the supplementary excipient needs to be increased Test; if the prescription composition cannot be found, an excipient compatibility test is required.

  specific methods:

Choose several kinds of excipients, mix the excipients and the main drug in a certain proportion, take a certain amount, refer to the experimental method of influencing factors in the drug stability guidelines, at a high temperature of 60 degrees, strong light, high humidity (RH75%, RH92.5% )test. Samples were taken on days 0, 5, and 10, respectively. Focus on investigating the traits, content, related substances, etc. If necessary, parallel control experiments can be performed on the drug substance and excipients, respectively, to determine whether the drug substance itself changes or the influence of the excipients.

　　If you don’t know the nature of the raw materials completely, or through information research, you know that the raw materials are unstable and have special requirements for auxiliary materials and storage conditions:

　　Even if the prescription composition of the original drug is found, it is still recommended to do a compatibility test for excipients, because the manufacturer of the original excipients has different stability and different types of impurities. In this case, the approach can be relatively simple.

Example: After searching for the prescription of the original drug, the auxiliary materials used are: XXX XXX XXX. On this basis, the raw materials and all auxiliary materials are mixed according to a certain conventional dosage, and the raw materials and blank auxiliary materials are used for parallel control. At a high temperature of 60 degrees, strong light, High humidity (RH75%, RH92.5%) test. Samples were taken on days 0, 5, and 10, respectively. Focus on investigating traits, content, related substances, etc.

　　 (2) Liquid preparation: This test is not required for liquid preparation.

　　2.2 Prescription screening

　　 (Generally, the method of single factor test is adopted, and the orthogonal method can be used when necessary)

　　Through the above-mentioned excipient compatibility test, have a basic understanding of the stability of the main drug.

　　 (1) Solid oral preparation:

　　 ① According to the conventional dosage and conventional process of the auxiliary materials, the initial performance of the preparation (such as the compressibility, fluidity of the oral solid preparation granules and the hardness, friability, moisture, etc.) of the preparation are used as indicators for preliminary screening.

　　 ② Select two to three prescription samples with qualified basic performance, perform dissolution curve measurement, compare with the original development agent, find out the gap, adjust the amount of auxiliary materials, and make the dissolution curve consistent.

③Confirm the two or three best prescription processes, make small samples respectively, and compare the original research products with influencing factors. The research project is determined according to the results of the compatibility test of excipients. Basically, the factors that are sensitive to the main drug can be selected! All factors are required to be done.

　　 ④Preliminarily determine the prescription process.

　　 (2) Liquid preparation:

　　 ①According to the basic performance of the reference preparation such as viscosity, mouthfeel, osmotic pressure, PH value, etc., the amount of auxiliary materials is selected.

　　 ②For the dosage of preservatives, if the dosage can be found in the original instruction or quality standard, you can directly refer to the dosage of the original research drug. If there is no literature, a bacteriostasis test is required and the lowest effective amount is selected.

　　Specific practice: first refer to the conventional dosage of the preservative, and then set three to four concentrations, which can be used in equal concentration. For example, the conventional dosage of X is 0.2%-1.0%, and four concentrations of 0.1%, 0.2%, 0.4%, and 0.8% can be selected for testing. Refer to the appendix of the Chinese Pharmacopoeia for test operation and judgment standards.

　　 ③ Select one or two prescription samples with qualified basic performance, and conduct the influencing factor test with the original research. The experimental items can be simplified appropriately. If only the condition of high temperature of 60 degrees is required, the stability will be preliminarily determined.

　　 ④Preliminarily determine the prescription process.

　　 3. Preliminary verification process

　　3.1 Three batches of small tests

　　 Scale up the production of three batches using the proposed prescription process, the sample scale tablets can be 1000 tablets/batch, and the liquid preparation can be 500g/batch. And fill in the production batch records.

　　3.2 Sample inspection

　　The inspection standard refers to the draft quality standard prepared by referring to the original research, domestic first imitation or domestic mainstream products, pharmacopoeia, etc. The draft should not be lower than the imitation standard. If the product is qualified, the prescription process is determined; if the product is not qualified, the prescription process is re-screened. The test results meet the quality standards and are consistent with the reference preparation, and an inspection report is issued.

　　3.3 Determine the prescription process

　　After confirming the feasibility of the proposed prescription process, determine the prescription process.

　　 4. Pilot production and process verification

　　According to the company’s conditions and relevant guiding principles, the preparation of pilot production and process verification are carried out simultaneously. Therefore, the work in the previous stage must be solid, and the test results must be accurate.

　　4.1 Pilot batch:

　　According to the requirements of the regulations and the company’s current situation, each batch is planned to be: the dosage of oral solid preparations is about 10 kg, and 10,000 tablets are converted according to this weight; the liquid preparations are also about 10 kg.

　　Regulation requirements: pilot products must be produced in the GMP workshop; the equipment used should be the same as the equipment used in future large-scale production or the principle and equipment parameters are the same; the batch size is not less than 1/10 of the future large-scale production.

　　4.2 Pilot production:

　　Produce three batches of pilot products in the workshop with a certain process; fill in the production batch records.

　　4.3 Process verification:

　　Collect and evaluate the data of the entire process design stage and the entire production process to establish scientific evidence that the process can consistently and consistently produce products that meet the quality requirements.

　　The content of the information includes: project verification, plan, approval, report, evaluation and suggestion, process verification certificate.

　　 (4) Quality research

　　In drug development, quality research is the key. With reference to the guiding principles, quality research is now divided into four parts: selection of quality research projects and preliminary determination of methods; methodological verification of quality standards; comparative study of quality; formulation of quality standards.

　　 1. Selection of quality research projects and preliminary determination of methods

　　 can be called “preliminary establishment of quality standards”, this work should be completed before the compatibility test of auxiliary materials.

　　1.1 Follow the principle of “just high, not low”. Combined with the product quality standards queried (original research standards, ChP, EP, BP, USP, JP, etc., how to query?) and the requirements of the pharmacopoeia for specific dosage forms, a draft quality standard is determined. Antioxidants, bacteriostats, stabilizers, and solubilizing agents are added to the intravenous injection prescriptions, and preservatives are added to the ophthalmic preparation prescriptions. Quantitative research should be conducted on the corresponding auxiliary materials.

　　 For the items included in the national drug standards, first of all, consideration should be given to selecting the test methods included in the standards.

　　 1.2 If there are multiple detection methods for related substances, it is recommended to conduct a preliminary comparative study to determine the method. If there is an impurity reference substance, use the impurity reference substance to confirm the feasibility of the method; if there is no impurity reference substance, a compulsory degradation test can be performed (remember that the degree of degradation is about 5%~10%, in this case it is judged Material balance makes sense), to initially determine the feasibility of the detection method.

　　 Judgment standard: when there is impurity reference substance, system suitability, resolution, effective detection, precision and reproducibility.

　　 When there is no impurity reference substance, system suitability, effective detection of degraded impurities, and material balance.

　　1.3 Preliminary establishment of draft quality standards.

　　 2. Methodological verification of quality standards

　　 is specifically divided into two aspects: preliminary verification of the method and systematic methodological verification.

　　 2.1 Preliminary verification of quality standards (complete before the pilot test)

　　①In conjunction with the screening and inspection of prescription technology, it is the process of preliminary verification of quality standards. For example, the compatibility test of the auxiliary materials, the comparison test of the reference preparation and the small test product, the test of the influencing factors of the small test product, etc., a preliminary judgment can be made on the feasibility of the method.

　　 At this time, the methodological research focuses on verifying whether the detection methods and conditions in the national standards are applicable, focusing on the specificity and accuracy of the methods. If the results of the methodological study show that the method is not applicable, the cause should be analyzed first, and the method should be adjusted by adjusting the prescription process, etc.; under some extreme conditions where the cause cannot be confirmed, the establishment of a new detection method is considered, but the new method must first follow the chemical To conduct research on the relevant guiding principles of drug quality control research, it is also necessary to verify through comparative studies that they have the same degree of control as the original method.

　　 Therefore, in principle, do not replace the existing chromatographic conditions of national drug standards. When the resolution cannot be achieved, the proportion of mobile phase can be adjusted appropriately.

　　 Discussion: In the pre-screening of prescriptions, the quality standards were not really established, and the final quality standards may be different. In this case, it is believed that the data of prescription screening can still be put into the application materials, which is not incompatible with the purpose of prescription screening, and also reflects the development process of quality research.

　　②Issuing an inspection report of three batches of small test samples.

　　2.2 Methodological verification of the system

　　On the basis of preliminary verification, a systematic methodological verification of quality standards is required. The samples used for the methodological verification shall use pilot products.

　　 Verification items (different test items for different varieties and dosage forms):

　　Characteristics; identification (physicochemical identification and spectral identification); general inspection items (according to the general principles of Chinese Pharmacopoeia preparations); microbiological test (need to carry out a complete methodological verification test); dissolution, some can be verified together with the content;

　　 Related substances (need to carry out complete methodological verification test); content determination (need to carry out complete methodological verification test), hygiene methodological verification.

　　The focus is on methodological verification of related substances and contents.

　　 The contents of substance verification include:

　　 System suitability:

　　Take a sample, prepare a solution according to the test substance concentration of the relevant substance, inject a sample, and record the spectrum. Number of theoretical plates

　　 Meet the regulations, the resolution should be greater than 2.0 or meet the regulations, and the tailing factor should be 0.8-1.2 or meet the regulations.

　　 There are known impurities and the impurity reference substance is available: the relative standard deviation of the peak area of the continuous injection of the impurity reference substance solution should not be greater than 2.0%, and the relative standard deviation of the retention time should not be greater than 1.0%. In addition, the number of theoretical plates should meet the regulations, the separation should be greater than 2.0 or meet the regulations, and the tailing factor should be 0.8-1.2 or meet the regulations.

　　Special attributes:

　　 Blank solvent interference test, blank auxiliary material test, forced degradation test (high temperature, strong light, strong oxidation, strong acid, strong base, etc.), known impurity location test, peak purity check (diode array detection, mass spectrometry detection).

　　 Limit of detection and limit of quantification:

　　 generally uses the signal to noise ratio method. If there are known impurities and the impurity reference substance is available, it must be done with the known impurity reference substance. A signal-to-noise ratio of 10:1 is the limit of quantification; a signal-to-noise ratio of 3:1 is the limit of detection.

　　 Linear range:

　　 Generally do a series of 5 to 7 concentrations, such as 40%, 60%, 80%, 100%, 120%, 150% (relative to their own control concentration). Take a sample of this series of solutions, record the chromatogram, and calculate the regression equation.

　　If there are known impurities and the impurity reference substance is available, then take the known impurity reference substance and make another linear relationship test

　　 test (with the limit of quantification as the initial concentration point), the peak area of the known impurities in the test product should be in the linear range.

　　 Precision:

　　 Including repeatability and intermediate precision. Repeatability: 6 test samples; intermediate precision: different time, different personnel, different instruments, 6 test samples, compared with the 6 data of the repeatability test.

　　 Solution stability:

  Accuracy:

　　 is generally verified by the recovery rate test. If there are no known impurities, do not do it. If there are known impurities, a sample recovery test must be done to verify the accuracy.

　　 Discussion: In the detection of related substances, impurities are to be detected, not raw materials. Therefore, it is believed that when there is a known impurity reference substance and this impurity is controlled individually in the standard, the content of methodological verification should be developed around the known impurity and cannot be replaced with raw materials. When there is no known impurity control substance, the raw material is used instead (self control, such as 1% control, 0.5% control, 0.1% control).

　　When doing the compulsory degradation test, the compulsory degradation test is also performed in parallel with blank auxiliary materials, especially those containing special auxiliary materials, such as preservatives and other auxiliary materials that absorb in ultraviolet.

　　 The mandatory degradation test is not only the content of methodological verification, but also the process of determining the degradation path, impurity spectrum and product stability of the product. The relevant guiding principles of generic drugs require that the generic product and the original drug should compare the impurity spectrum, impurity quality and degradation pathway. Therefore, it is recommended to carry out the compulsory degradation test in parallel with the original research drug (both about 5~10%), so that it can be visually compared whether the degradation pathways of the two are consistent; whether the degradation products are different; the inspection method is specific to the two. Differences (because most of the proposed methods are the original drug detection methods). The parallel comparison of destructive test research is an important method to evaluate whether the quality of the developed drug and the copied drug are the same.

　　 On the issue of material balance in the forced degradation test:

　　①First, the degradation intensity is about 5%~10%.

　　②When there is impurity reference substance, calculate the correction factor, and substitute the correction factor into the calculation.

　　 ③ Peak purity inspection (diode array inspection), the function of diode array inspection is not only the peak purity inspection, but also reflects the overall ultraviolet absorption of impurities and the main drug. You can calculate the material balance at different wavelengths (depending on the specific variety).

　　④Calculation method: By comparing with the total peak area of normal samples. Specific method: It is recommended to take a certain amount of sample to dissolve and use it as a mother liquor. Take a certain amount of the mother liquor to carry out a factor of degradation test, and then compare it with the normal sample of this mother liquor to obtain reliable results.

　　 3) Issuing three batches of pilot test report.

　　 3. Quality comparison study

　　 (Adopt pilot products)

　　Quality comparison research is an important method to judge the “consistency” or “equivalence” of the quality of generic drugs and generic drugs. It can fully understand the quality characteristics of products and provide a basis for the establishment of registration standards for generic drugs.

　　3.1 Comparative study of dissolution curve:

Generally, the method of dissolution curve comparison in four dissolution media (such as pH1.2, pH4.5, pH6.8 and water) is used. The f2 factor method (f2>50) is used to compare the curve of the original drug and the imitation product. Sex. (The choice of dissolution medium can refer to Xie Mufeng’s literature)

  Precautions:

　　 ① The content difference between the two preparations used for comparison should be within 5%.

② The time point interval selected during calculation need not be equal, but the time points taken by the two preparations must be consistent; and the calculation time points should not be less than 3; because the calculation result has characteristics that depend on the number of comparison time points, so in Dissolution rate

There should be no more than one time point above 85% (slow release above 80%). The dissolution amount should be calculated according to the cumulative dissolution amount.

　　③Except for 0, the coefficient of variation of the dissolution result at the first selected time point should not exceed 20%, and the coefficient of variation of the dissolution result from the second time point to the last time point should not exceed 10%. If it exceeds, it should be considered from the perspective of instrument suitability or sample uniformity.

　　3.2 Comparative study of impurities (this content can be done with method verification):

　　 For the inspection of related substances, the types of impurities in the generic drugs and the generic drugs may be different due to the differences in the preparation process of the drug substance and the formulation of the preparation. Therefore, a comparative study is required to analyze the types and contents of impurities in the generic drug and the generic drug.

　　①Comparative research on the compulsory degradation test and the influencing factor test can be used to compare the types of impurities, degradation pathways and size of impurities between generic and original drugs.

　　②For compound preparations, the impurities should be assigned first. Method of application: Do the mandatory degradation test of individual raw materials, blank auxiliary materials and preparations respectively.

  Requirements are as follows:

    　　A. The measured values of the types and contents of impurities in the developed products are not higher than the reference preparations.

    　　B. If the content of an impurity is higher than the reference preparation, it must not be higher than the standard limit (generally the quality standard limit of the original drug).

    c. If the developed product contains new impurities not contained in the reference preparation, it is recommended to first reduce the content or type of impurities by improving the formulation process so as not to exceed the identification limit, otherwise the impurity structure must be identified to analyze the safety of the impurities and Provide relevant data and conduct relevant safety tests if necessary.

　　3.3 Comparative study of detection methods (simultaneous with methodological verification):

　　If the research finds that some of the testing methods in the national drug standard are not suitable for the development of products, in order to further verify whether there is a problem with the testing method or the quality of the developed product itself, a comparative study can be carried out using the generic drugs.

　　 4. Development of quality standards

　　 (combined with the results of comparative studies and stability studies):

　　4.1 On the basis of national drug standards, foreign pharmacopoeia and references can be referred to to add necessary testing items.

　　 4.2 Test method: If the new method has no obvious advantages compared with the national drug standard collection method, it is recommended to adopt the national drug standard collection method because the national drug standard has been verified for a long time and has been verified by multiple units.

　　4.3 Limits: When there are various methods for reference, the limits are formulated in accordance with the principle of “higher, not lower”.

　　4.4 Formulate shelf life standards and release standards, that is, registration standards and internal control standards, and write in the application materials.

　　 (5) Stability study (pilot product)

　　 1. Influencing factor test:

　　Take a batch of the pilot test and the reference preparation, remove the inner packaging, and disperse it into a single layer under suitable conditions. Generally including high temperature (60 or 40 degrees), high humidity (92.5%, 75%), light test. Sampling and testing were carried out on the 5th and 10th days, respectively, focusing on the traits, content, and related substances. The high humidity test added moisture absorption and weight gain items.

　　The above are the general requirements for the stability study of influencing factors. If necessary, other tests can be designed according to the nature of the drug, such as examining the influence of pH, oxygen, low temperature, freeze-thaw and other factors on the stability of the drug. For drugs that need to be dissolved or diluted, such as sterile powders for injection, solution tablets, and dry suspensions, the stability under clinical use conditions should also be investigated.

　　 2. Accelerated test:

　　Take three batches of samples to be packaged in the market, it is recommended to carry out at least 15℃ higher than the long-term test storage temperature. Generally, the test can be carried out for 6 months under the conditions of 40℃±2℃ and RH75%±5%. At the end of the test period, 0, 1, 2, 3, and 6 months at the end of sampling inspection indicators. If the test product does not meet the requirements of the quality standard or changes significantly within 6 months, the 6-month test shall be carried out in the same way under the intermediate conditions of 30℃±2℃ and RH65%±5%. For the specific temperature, you can refer to the original research drug’s instructions to store an item.

　　 Discussion: Regarding the comparative study of stability tests, the regulations require that the stability of the developed product should not be lower than the stability of the product already on the market. After passing the comparison between the forced degradation test and the influencing factor test, we have a certain degree of understanding of the stability of the two.

　　 ①If the product itself is relatively stable, the reference preparation can be compared with only the samples at 0 month and accelerated 6 months.

　　②If the product itself is unstable, it is recommended to compare the reference preparation and the three batches of pilot preparations simultaneously.

　　 3. Long-term test:

　　Long-term tests are conducted under the storage conditions specified in the marketed drugs. The purpose is to investigate the stability of the drugs during transportation, storage, and use. They can directly reflect the stability characteristics of the drugs and are the ultimate basis for determining the expiration date and storage conditions.

Three batches of pilot samples were tested at 25°C±2°C and RH60%±10%. The sampling time points were 0, 3, 6, 9, 12, 18, 24, 36 months .

　　 The choice of long-term test time should be based on comprehensive consideration of product stability, comparison with the stability of the generic drug, and the proposed expiration date. When applying for registration, generally should provide no less than 6 months of long-term stability research materials.

　　 4. Intermediate condition test

　　30℃±2℃, RH65%±5% (If this condition is used for long-term test, the intermediate condition test can no longer be performed).

　　5. Evaluation of stability study results

　　According to the results of the stability study, combined with the original research, determine the packaging materials, storage and expiration date.

　　Additional note: Packing material compatibility test:

　　The selection of packaging materials refers to the original research agent, preferably the same as the original research material. For oral solid preparations, use the proposed packaging for accelerated testing and long-term testing; for liquid preparations and semi-solid preparations, it is necessary to investigate whether the ingredients in the packaging material (especially the additives) will seep into the drug, causing the product Changes in quality (such as the Lipectin plasticizer event).

　　 As far as the company’s existing conditions are concerned, this is a difficulty. Only through communication with the packaging material supplier, the packaging material supplier is requested to exercise self-control.

　　 Remarks: On February 6, 2013, CDE released the “Consultation Draft for Technical Guiding Principles of Stability Research on Chemical Drugs (APIs and Preparations)”.

　　 (6) Pharmacology and Toxicology Research

　　 1) Most studies of generic drugs only need to provide pharmacological and toxicological literature research materials. In this case, you can refer to domestic and foreign literature data to find the pharmacological and toxicological data of the drug for collation and summary.

　　 2) Topical preparations should be tested in GLP laboratories, and irritant, allergic and hemolytic tests should be performed according to the type. If fluticasone propionate nasal spray needs to be tested for irritation.

　　(VII) Writing and sorting of application materials

　　 (within 1 month after completion of stability test)

　　 1、Summary information

　　 1) Drug name.

　　 2) Proof documents. It is necessary to pay attention to the entrusted inquiry of the scientific and technological inspection report, generally entrusted inquiry in the middle of the stability test.

　　 3) The purpose and basis of the topic (there are technical guidelines for writing issued by the National Bureau, which can be written after querying the information).

　　 4) Summary and evaluation of the main research results (there are written technical guidelines issued by the National Bureau, which can be written after entering the stability inspection).

　　 5) Drug instructions, drafting instructions and related references (based on the original drug instructions).

　　 6) Samples of packaging and label design.

　　 2. Pharmaceutical research materials (Annex 2 is items 7-15)

　　Generic drugs (six types) must be written in the CTD format promulgated by the National Bureau. Other categories are recommended to be written in CTD format.

　　 1) CTD format declaration main research information summary table

　　 2) Requirements for writing information in CTD format

　　 3. Pharmacology and toxicology research materials

　　16) Summary of pharmacology and toxicology research data (based on relevant technical guidelines)

　　21) Submission of topical preparations: allergic (local, systemic and photosensitive toxicity), hemolytic and local (vascular, skin, mucous membrane, muscle, etc.) irritation and other special safety test data and literature data.

　　 4. Clinical trial data

　　28) Review of relevant clinical trial data at home and abroad.

　　29) Clinical trial plan and research plan.

　　30) Clinical Investigator’s Manual.

　　31) Sample informed consent form, ethics committee approval.

　　32) Clinical trial report.

　　The last two items are the materials required for production.

　　 (eight) clinical declaration and on-site verification

　　 1) Report the information together with the electronic declaration form to the provincial bureau, preparing for on-site verification

　　 2) Dynamic three batches of on-site process verification, sampling and re-inspection by the Provincial Institute of Drug Control.

　　(9) Clinical research

　　Solid oral preparations are bioequivalent; solutions are generally clinically free; topical preparations generally require clinical trials.

　　(Ten) declare production

　　After the completion of the clinical trial, organize the data and report to the provincial bureau.

table of Contents

　　 1. Overview

　　 II. Summary of generic drug R&D projects

　　 Third, the specific steps for the development of generic drugs:

　　 (1) Product information survey

　　 (2) Preliminary preparations (approximately one month to complete):

　　 1. Procurement of reference preparations

　　 2. Procurement of raw materials

　　3. Procurement of chromatographic columns and reference products

　　 4. Purchase of auxiliary materials:

　　5. Procurement of packaging materials:

　　 (3) Research on prescription technology

　　 1. Inspection of raw materials and reference preparations

　　 2. Explore the prescription process

　　 3. Preliminary verification process

　　 4. Pilot production and process verification

　　 (4) Quality Research

　　 1. Selection of quality research projects and preliminary determination of methods

　　 2. Methodological verification of quality standards

　　 3. Quality comparison study

　　 4. Development of quality standards

　　 (5) Stability study (pilot product)

　　 (6) Pharmacology and Toxicology Research

　　(VII) Writing and sorting of application materials

　　 (eight) clinical declaration and on-site verification

　　 (9) Clinical Research

　　(Ten) declare production