Basic technical requirements for chemical injection (Draft) National Food and Drug Administration Note [2008] No. 7

 

National Food and Drug Administration Note [2008] No. 7

Basic technical requirements for chemical injection (Trial)

 

The technical requirements are applicable to injections of various registered categories of chemicals. This technical requirement mainly aims at the outstanding problems existing in the research, development, production and use of chemical injection. On the basis of following the general evaluation principles, through analyzing the main factors that may affect the safety of clinical use of injection, and combining with the listing basis of varieties, the key points and corresponding technical requirements in the evaluation of chemical injection are proposed.

1、 The necessity and rationality of the choice of chemical injection dosage form

（1） The necessity and rationality of choosing the route of injection

In order to evaluate the necessity and rationality of dosage forms, the following factors should be taken into consideration

　　1.Physicochemical properties, stability and biological characteristics of drugs

The physicochemical properties (solubility, PKA, partition coefficient, hygroscopicity, crystal form, etc.), stability (stability to light, humidity and heat, stability in solid and liquid state and compatibility stability) and biological characteristics (absorption, distribution, metabolism, elimination, etc.) of drugs can provide guidance for the selection of dosage forms. In some cases, the selection of dosage forms may even be limited.

　　2.The need of clinical treatment

On the basis of clarifying the physicochemical and biological properties of the drug, the dosage form should be selected according to the clinical treatment needs. For example: for bleeding, shock, poisoning and other emergency treatment of drugs, need to take effect quickly, usually choose injection.

If oral drugs can meet the clinical needs, it is not suitable to develop injectable preparations except for special needs; If intramuscular injection can meet the clinical needs, intravenous administration should be avoided as far as possible.

　　3.Compliance of clinical medication

It includes the convenience of doctors and the compliance of patients.

In addition, the feasibility and cost of industrial production should be considered.

For the varieties changed from other routes of administration to injection routes, and the varieties changed from ordinary injections to special injections, the safety, effectiveness and quality controllability of the modified dosage form and the original dosage form should be compared and analyzed to clarify the characteristics and advantages of the modified dosage form.

（2） Evaluation principle of rationality of different dosage forms of injection

Injections generally include large volume injections (more than 50ml), small volume injections (less than 20ml) and powder injections. When selecting and determining the dosage form, it is necessary to consider the sterility assurance level, impurity control level, process feasibility and clinical convenience of various dosage forms, so as to select the optimal dosage form.

For the injections that have been put on the market at home and abroad, according to the current understanding of the rationality of the selection of different dosage forms of injections, if the listed dosage form is the optimal dosage form, the first choice for the development of products is the listed dosage form; If the marketed dosage form is not the optimal dosage form, it is not suitable to copy the dosage form.

For injections that are not listed at home and abroad, or products whose dosage forms are changed according to injections that have been listed at home and abroad, on the basis of following the general principles of dosage form selection and considering the level of sterility assurance, the following principles should be followed in dosage form selection:

　　1.First of all, we should consider the level of sterility assurance of the sterilization process that can be used for the selected dosage form. In principle, the first dosage form should be able to use terminal sterilization process and SAL ≤ 10-6.

　　2.For the varieties that have sufficient evidence to prove that terminal sterilization process is not suitable and clinical injection is necessary, the dosage form with sterile production process can be considered. Generally, aseptic production process is limited to powder injection or part of small volume injection.

　　3.If there is no sufficient basis for the mutual modification among large volume injection, small volume injection and powder injection, the sterility assurance level of the modified dosage form shall not be lower than that of the original dosage form.

 

2、 Rationality and necessity of chemical injection specifications

（1） General principles for specification of drugs not listed at home and abroad

　　1.According to the usage and dosage determined by clinical research, it can be determined from the perspective of convenient clinical medication and meeting the needs of clinical medication, and it can be revised with clinical research.

　　2.The feasibility of the process (e.g., the limitation of solubility, production equipment, etc. may be considered).

（2） General principles for specification of drugs marketed abroad and / or in China

The product specifications shall be determined according to the usage and dosage specified in the manual, from the perspective of convenient clinical medication and meeting the needs of clinical medication, and shall comply with the relevant national regulations.

For injections that have been listed at home and abroad, according to the current understanding of the rationality of the selection of injection specifications, if the listed specifications are reasonable (the imitated product has no detailed clinical research data, and the rationality of the specifications is uncertain), the same specifications of the same dosage form that have been listed should be selected. The following requirements shall be met for those who copy domestic and foreign products and add specifications, change the specification selection of dosage form products and add specifications to the products on the market:

　　1.The selected specifications should be within the usage and dosage range specified in the manual, generally not less than the single minimum dosage or greater than the single maximum dosage.

　　2.Generally, the selected specifications should be conventional specifications (for example, the volume of small volume injection is 1, 2, 5, 10, 20 ml; The volume of large volume injection is 50, 100, 250, 500ml, etc.

　　3.The selected specifications should be clinically necessary and convenient for doctors, nurses, patients and pharmacists to manage drugs.

4.There should be sufficient data to show that the new specification is safe and effective in clinical use, especially when the drug concentration changes. If the new specification involves the change of drug users / dosage, the safety and effectiveness of the new specification should be evaluated systematically.

 

3、 Quality control and source of raw and auxiliary materials for chemical injection

（1） Quality control of API

　　1.Injections not listed at home and abroad

The quality of API for injection not listed at home and abroad should meet the general requirements of API for injection, and the following issues should be focused on:

(1) When applying for clinical application, we should pay attention to the quality of the samples used in the non-clinical safety study of the route of injection. The type and content of related substances of API used for preparing clinical research samples shall not exceed the relevant indexes of non-clinical safety research samples.

(2) When applying for production, we should pay attention to the quality of clinical research samples and the safety research results of impurities. In principle, the limit requirements of related substances in the quality standards for API marketing shall not exceed the test data of clinical research samples and safety evaluation samples. Relevant technical requirements can refer to "technical guidelines for the study of chemical drug impurities".

(3) The API used for powder direct sub packaging should be sterilized by reliable methods in the process. The refining, drying and packaging of API should be carried out in class 100 environment. The quality should meet the requirements of sterility guarantee. The sterility test and bacterial endotoxin test should meet the requirements.

　　2.Injections listed abroad and / or in China

(1) Those who apply for injections by purchasing approved API for injection shall provide detailed information on the legal source and quality control of API, including manufacturer, approval number, quality standards, inspection report, purchase invoice, supply agreement, etc. If it is an imported API, the import registration certificate shall also be provided.

(2) If the newly developed API is applied for injection, the API shall be applied together with the preparation, and the normative and complete application materials shall be provided according to the requirements of API for injection. It is a necessary condition for the approval of clinical registration of injection preparation that the API meets the requirements after technical evaluation.

(3) If there are API for injection on the market, the API for injection with legal source shall be used to declare the injection.

If there is no API for injection on the market, it is necessary to refine the API and formulate internal control standards to meet the quality requirements for injection. When applying for registration, in addition to providing relevant supporting documents, the selection basis of refining process, detailed refining process and its verification data, and quality comparative research data before and after refining should be provided. The main goal of refining is to reduce the impurity content and make it meet the requirements for injection. Therefore, the standard impurity research should be carried out on the refined samples according to the requirements of "technical guidelines for impurity research of chemical drugs".

　　3.Post marketing drug changes API

After the injection is approved for marketing, if the manufacturer or quality standard of the API needs to be changed, it shall be reported according to the supplementary application.

（2） Quality control of accessories

　　1.Basic principles of auxiliary material selection

(1) Excipients meeting the requirements for injection should be used;

(2) On the premise of meeting the needs, the types and dosage of excipients for injection should be as small as possible;

(3) The common excipients for injection should be used as far as possible.

　　2.Use approved excipients for injection

For the use of approved excipients for injection, detailed information on the source and quality control of excipients shall be provided, including the manufacturer, the quality standards implemented, the inspection report, the purchase invoice and the supply agreement. If there is an approval number, the approval number shall also be provided. For imported excipients, the import registration certificate shall also be provided.

　　3.Use of excipients not yet approved for injection route

For the use of excipients that have not been approved by the State Food and Drug Administration for production or import according to the route of injection, the new excipients and preparations shall be declared together, except for the following circumstances.

(1) For the excipients produced by foreign companies and used in injections listed abroad, but not officially approved for import, the registration certificate of imported drugs may not be required when applying for clinical research, but the foreign pharmaceutical basis, quality standards and inspection report of the excipients shall be provided. Before the preparation is approved for production, the excipients used shall be registered for import.

(2) For the excipients that are used in injections but are not produced or imported according to the standard products for injection, the excipients that are not used for injection can be refined to meet the requirements for injection, and the internal control standards can be formulated. The detailed refining process and its selection basis as well as the formulation basis of internal control standards shall be provided in the application materials. If necessary, relevant safety tests should be carried out.

　　4.Drug excipients changed after marketing

After the injection is approved for marketing, if it is necessary to change the relevant contents of excipients, such as manufacturer or quality standard, it shall be reported according to the supplementary application.

In order to reduce the microbial load of injection before sterilization as much as possible, the corresponding microbial control of raw and auxiliary materials should be considered.

 

4、 Study on rationality and feasibility of chemical injection prescription and preparation process, especially the selection and validation of sterilization process, process stability, etc

（1） Prescription Research

The study of injection prescription should include the investigation of prescription composition (API, excipients), prescription design, prescription screening and optimization, prescription determination, etc.

　　1.Study on the composition of prescription

(1) API: the physical and chemical properties (such as appearance color, pH, PKA, melting point, moisture, solubility, oil / water partition coefficient, etc.) and biological properties (such as stability under physiological environment, stability under light, heat, humidity, oxygen, etc.) of API should be investigated and analyzed in detail before prescription design the pharmacokinetic properties, side effects and therapeutic window were analyzed.

(2) Excipients: the physicochemical properties and reasonable dosage range of the excipients to be used should be investigated and analyzed, the compatibility between drugs and the excipients to be used and between different excipients should be investigated and analyzed, and the interactions between excipients and excipients and between excipients and drugs should be understood, so as to avoid the prescription setting and select the excipients with adverse interactions. For the lack of relevant research data, compatibility research should be carried out.

If the dosage of excipients exceeds the conventional dosage and there is no literature support, it is necessary to carry out necessary pharmacological and toxicological tests to verify the safety under the selected dosage. The safety of excipients with different routes of administration should be fully proved.

　　2.Prescription design

Prescription design should be based on the above research on drugs and excipients, according to the characteristics of specific dosage forms and the needs of clinical application, combined with relevant literature and specific work practice, several basic reasonable prescriptions should be designed first, and then combined with the research on preparation technology, the appearance, color, clarity, pH, content, related substances, bacterial endotoxin or pyrogen, etc.  Insoluble particles and so on were used as evaluation indexes to investigate different prescriptions. The preliminary prescription was determined by investigation, and the key factors affecting the quality of the preparation were identified.

　　3.Prescription screening and optimization

Prescription screening and optimization is based on the prescription design, aiming at the key factors affecting the quality of the preparation, various experimental designs (such as comparative method, orthogonal design, uniform design, etc.) are used to further optimize the type and dosage of key excipients. Besides appearance, color, clarity, pH, content, related substances, bacterial endotoxin or pyrogen, insoluble particles, stability evaluation should also be included.

The stability evaluation of the prescription research stage is mainly carried out through the influence factor test, and the compatibility stability research is also needed for those who need to use special solvents when giving drugs, or need to use other solvents to dilute and prepare solutions (such as intravenous powder injection and small water injection) before use. In addition, whether the stability of the preparation meets the requirements ultimately needs to be determined through accelerated and long-term stability investigation.

　　4.Determination of prescription

Through prescription screening, quality study and related stability study, the prescription can be basically determined. For injections that need clinical trials, the final determination of the prescription should be combined with the results of clinical trials and the data accumulation results of samples above the pilot scale during the clinical period, and the prescription should be further revised and improved when necessary.

（2） Study on Preparation Technology

　　1.Selection of preparation technology

Injection preparation process should be based on the characteristics of dosage forms (large volume injection, small volume injection, powder injection), based on the research and analysis of the common preparation process of specific dosage forms, combined with the physical and chemical properties of specific drugs and excipients (such as nitrogen filling, oxygen removal and other measures should be adopted in the process of easily oxidized drugs), the appropriate preparation process should be selected. If the conventional preparation process cannot meet the needs, it is necessary to improve the process and provide sufficient experimental basis.

In general, the preparation process should include the pyrogen removal process. For some varieties that are not suitable for pyrogen treatment in the process, the bacterial endotoxin content of raw and auxiliary materials can be strictly controlled, or the pyrogen treatment of raw and auxiliary materials can be carried out separately.

　　2.Determination of process parameters

After the selection of the basic preparation process, the specific process parameters should be determined through experimental research in combination with the physical and chemical properties of the drug, preparation equipment and other factors. In the research process, we should pay attention to the influence of each process on the product quality, and determine the key links of the preparation process. For the key links, the effects of preparation conditions and process parameters on the product quality (appearance, color, clarity, pH, content, related substances, bacterial endotoxin or pyrogen, insoluble particles, etc.) should be investigated, and the corresponding quality control parameters and indicators should be established according to the research results.

　　3.Process validation

The selected preparation process should be verified. The verification includes the verification in the process research stage and the verification in the scale-up production stage.

The verification of process research stage is to verify and evaluate whether the process itself is stable and easy to control by analyzing the preparation process of multiple batches of samples and the quality of intermediate products and final products.

In the stage of scale-up production, the process validation is mainly to investigate the feasibility of the preparation process in large-scale production, and to verify and evaluate whether the process is suitable for industrial production. At least three batches of pilot scale products should be prepared under the determined process conditions, the process control of the preparation process should be evaluated, and the product quality and quality uniformity should be evaluated. The equipment of pilot production should be consistent with that of mass production. If the process equipment used in the actual production is different from the pilot scale, the process verification should be carried out again.

　　4.Sterilization process and validation of injection

Sterilization of injection is an important process to ensure the quality and safety of the preparation. In order to ensure the effectiveness of sterilization and the level of sterility of the preparation, the selection and validation of injection sterilization process should comply with the following principles:

(1) Large volume injection

① The terminal sterilization process should be adopted. It is suggested that the over kill method (F0 ≥ 12) is the first choice. If the product cannot tolerate the over kill condition, the residual probability method (8 ≤ F0 < 12) can be considered, but the SAL of the product after sterilization should not be greater than 10^-6, Other processes with F0 value less than 8 are not approved in principle.

② If the product cannot tolerate the terminal sterilization process conditions, the prescription process should be optimized as far as possible to improve the heat resistance of the preparation. If it is really intolerable, other dosage forms should be considered instead of large volume injection.

③ Process validation: standardized sterilization process validation should be carried out, and part of the validation can be combined with the production line validation. It mainly includes the following tests:

Determination of microbial contamination level before sterilization, including determination of contamination bacteria and their heat resistance in products before sterilization;

Heat penetration test;

Microbial challenge test: the heat resistance and quantity of the biological indicator used should pose a necessary challenge to the sterilization process, and the heat resistance of the biological indicator should be greater than that of the common contaminating bacteria in the product. The microbial challenge test may not be carried out if the over kill method (F0 ≥ 12) is used.

(2) Powder injection

Generally, the aseptic level of powder injection can be guaranteed by filtration and sterilization under aseptic system environment, or by direct sub package process. The SAL of powder injection with aseptic production process should be no more than 10^-3. This mainly depends on whether the aseptic production process is produced and verified in strict accordance with the requirements of GMP.

① Lyophilized powder injection

The equipment verification and environmental monitoring in the validation of aseptic production process of lyophilized powder injection are the routine contents of GMP requirements of lyophilized powder injection production line;Medium filling verification is a systematic verification of equipment, environment and personnel operation, which is a key means to determine the level of sterility assurance.

Routine process validation tests include:

Validation test for simulated filling of culture medium: at least three batches of culture medium should be filled online. See Table 1 for the batch number of each batch. Sterility test should be conducted for each bottle of product. See Table 1 for the standard for judging whether the test is qualified or not.

Adaptability verification test of sterilization and filtration system: including compatibility test of filtration system, integrity test of filter membrane before and after filtration, and microbial interception test of filter membrane when necessary.

② Sterile powder injection

The quality assurance of aseptic powder injection mainly depends on the basic conditions of aseptic production line and strict quality control of each link of production process.The control and validation requirements of production process are consistent for different aseptic subpackaged products.Strict implementation of GMP requirements is an important quality assurance for the production of sterile powder injection.

The main work of process validation is the validation test of medium filling.The batch number, batch number and qualified standard of filling are shown in Table 1.

 

Table 1: batch size of medium filling test and criteria for judging qualified

Batch (bottle) 3000 4750 6300 7760

The number of allowed bacteria (bottles) 0 ≤ 1 ≤ 2 ≤ 3

(3) Small volume injection

① The terminal sterilization process should be the first choice, and the relevant technical requirements are the same as that of large volume injection.

② If there is sufficient evidence to prove that the terminal sterilization process can not be used, and it is necessary for clinical injection, the sterile production process can be considered, and the relevant technical requirements are the same as freeze-dried powder injection.

③ It is suggested that the filtration sterilization process should be modified to terminal sterilization process, and the technical requirements are the same as that of large volume injection;For the varieties that can not use terminal sterilization process, it should be modified to aseptic production process, and the technical requirements are the same as freeze-dried powder injection.

For small volume injection produced by aseptic production process, the verification of production line should be combined with aseptic production process.

In the process of injection production, in addition to choosing the appropriate sterilization process, the contaminated microorganisms in the product before sterilization should be strictly monitored, and various measures should be taken to reduce the level of microbial pollution to ensure that the final product meets the requirements of sterility.In addition, in order to judge the impact of sterilization process on product quality, the quality comparative study before and after sterilization should be carried out. The inspection items should be comprehensive, and the relevant methods should be verified.

 

5、 Study on quality of chemical injection and formulation of quality standard

The general requirements for injection quality research and formulation of quality standards can be found in the technical guidelines for the standardization process of the establishment of quality standards for chemical drugs, with special attention to the following issues:

　　1.Determination of quality research content

For injections, the key research items usually include: pH / pH, osmotic pressure, clarity and color (or clarity and color of solution), related substances, bacterial endotoxin / pyrogen, sterility, heavy metals, insoluble particles, content determination, etc.

In addition, the dry weight loss or moisture content of powder injection should be checked;Abnormal toxicity, pressor substance and depressor substance should be examined for injections from fermentation sources such as antibiotics;If antioxidant, bacteriostatic, stabilizer, solubilizer and other excipients that may affect the safety and effectiveness of the product are added in the injection prescription, quantitative inspection should be carried out according to the specific situation.

　　2.Methodology research

The routine items of injections can usually adopt the methods contained in the current edition of Pharmacopoeia, such as pH / pH, clarity and color (or clarity and color of solution), weight loss on drying / moisture, osmotic pressure, bacterial endotoxin / pyrogen, sterility, abnormal toxicity, pressor substances, depressor substances, insoluble particles and heavy metals.At the same time, we should also consider the special situation of the drug under study, pay attention to whether the Pharmacopoeia method is applicable, and whether impurities and excipients affect the test results.If necessary, the method should be revised to meet the needs of the drugs studied, but there should be corresponding experimental or literature basis.If the method is different from the current edition of Pharmacopoeia, a detailed methodology study should be carried out to clarify the basis of method selection, and the feasibility of the selected method should be confirmed through corresponding methodology verification.

The test methods related to specific varieties, such as related substances inspection and content determination, should refer to the relevant technical guiding principles, such as the guiding principles for the validation of analytical methods for chemical drug quality control, the technical guiding principles for the study of chemical drug impurities, and the basic technical guiding principles for the study of chemical drug preparations,After detailed methodology validation, the feasibility of the selected method was confirmed.

　　3.Formulation of quality standards

(1) Determination of project

Generally speaking, the main items of injection quality standard are: drug name, content limit, character, identification, pH value / pH value, osmotic pressure, clarity and color (or clarity and color of solution), related substances, weight loss on drying / moisture (powder for injection), bacterial endotoxin / pyrogen, sterility, insoluble particles, heavy metals, visible foreign matters, loading / loading differenceContent (potency) determination, category, specification, storage and validity.Antibiotics should also include abnormal toxicity, pressor substances and depressor substances.In addition, it should be determined whether necessary test items should be set for auxiliary materials such as antioxidants, bacteriostatic agents, stabilizers and solubilizers according to the research results.

Special attention should be paid to whether the items related to product safety and effectiveness in quality standards are comprehensive.

(2) Determination of limit

The limits of some routine examination items of injections have been stipulated in the current edition of Pharmacopoeia, which can be used as a reference.

The determination of the limits of the test items related to specific varieties, such as related substances, needs to be based on experiments or literature. For specific requirements, please refer to the relevant technical guidelines such as the technical guidelines for the study of chemical drug impurities and the basic technical guidelines for the study of chemical drug preparations.In order to ensure the safety of products, the rationality evaluation of impurity limits for different types of products is considered as follows:

First, for injections not listed at home and abroad, the determination of impurity limit should be based on the results of impurity safety evaluation.

 

Second, for injections and their modified dosage forms that have been listed abroad but not in China, the determination of impurity limit should be based on the control requirements of impurity test results and quality standards of foreign listed products (focusing on their sources). In principle, the control of impurity limit should not be lower than the requirements of foreign listed products.If the control requirements of foreign listed products cannot be met or the quality control information of foreign listed products cannot be obtained, the corresponding safety research should be carried out according to the requirements of injections not listed at home and abroad, so as to provide the basis for the determination of impurity limit.

Third, for domestic injections and their modified dosage forms and salt products, the rationality of the limit must be determined through quality comparative study with the listed products (in principle, the original products).In principle, the type and content of impurities should not be more (higher) than those of products on the market. At the same time, in order to ensure the consistency of product quality between batches, attention should be paid to improving the quality standards, such as increasing the inspection requirements for known impurities and single impurities.If the impurity type or content of the developed product is increased compared with the listed product, it is necessary to screen the source of raw materials, optimize the product prescription and preparation process, and reduce the impurity content to the quality control limit of the listed product, so as to ensure the safety of the injection.If it still can not meet the requirements, the necessary safety research should be done.If the basis for determination of impurities in the products on the market is not sufficient, systematic impurity studies should be carried out according to the requirements of injections not on the market at home and abroad.

　　

6、 Study on the stability of chemical injection

The design of stability study should be based on different research purposes, combined with the physical and chemical properties of raw materials / excipients, the characteristics of injection forms, and the specific prescription and process conditions.Through the systematic analysis of the stability information obtained from different experiments, the storage conditions, packaging materials / containers and expiration date of the drug were determined.

　　1.Design and content of stability study

For the sample batch and scale, packaging and storage conditions and inspection time of injection stability research, please refer to technical guidelines for chemical drug stability research. The inspection items usually include properties, pH value / pH value, clarity and color (or clarity and color of solution), related substances, drying weight loss / moisture (powder for injection), bacterial endotoxin / pyrogen, etcSterile, insoluble particles, visible foreign bodies, content (potency) determination.If there are antioxidant, antibacterial agent, stabilizer and other excipients in the injection prescription, the changes of these excipients should be investigated in the stability study.

The research contents of injection stability include influencing factor test, accelerated test and long-term test. For specific contents, please refer to technical guidelines for stability research of chemical drugs.In addition, freeze-thaw test should be carried out for injection to ensure its stability at low temperature.For the injection powder which needs to be used after dissolution, the stability under clinical conditions should also be investigated;For the drug preparations packed in semi permeable containers, such as multi-layer co extrusion PVC soft bag injection, the accelerated test should be carried out at 40 ℃± 2 ℃ and rh20% ± 2%.

　　2.Evaluation of stability research results

(1) Determination of storage conditions

Generally, the results of influencing factors, accelerated test and long-term test should be comprehensively analyzed and determined in combination with the possible situations in the process of drug circulation.

For generic injections, it should be determined according to the results of the stability study and the storage conditions of the same kind of products on the market.In principle, the stability of generic drugs should not be lower than that of the same products on the market.If the stability of generic drugs is lower than that of the products on the market, the storage conditions or validity period should not be adjusted directly, but the stability of generic drugs should be improved by optimizing the prescription process and improving the quality of raw materials and excipients.

(2) Determination of packaging materials / containers

The materials that can be used as the packaging materials / containers for injection should be selected to study the compatibility of the packaging materials / containers and preliminarily determine the selection range of the packaging materials / containers;On this basis, the rationality of the packaging materials and containers is further verified according to the results of influence factor test, accelerated test and long-term test.It should be noted that some samples should be placed horizontally and upside down in the process of stability inspection, so as to observe the compatibility of the contents and the rubber plug comprehensively.

Since the tightness of the container plays an important role in ensuring the performance of the sterilized / sterilized products, the tightness of the container should be investigated in the stability test.

(3) Determination of validity period

The validity period of injection should be determined by the results of long-term test.The validity period determined shall not exceed the last time point when the tested data are still within the limits specified in the quality standard.

 

7、 Technical requirements for non clinical safety evaluation of chemical injection

Because the injection preparation is usually directly and completely injected into the blood (including the main drug, excipients, impurities, etc.), the exposure and absolute bioavailability are high, and the safety risk is relatively high.Therefore, on the premise of meeting the necessity and rationality of dosage form selection, the safety evaluation is the focus of non clinical evaluation.

（1） Injections not listed at home and abroad

For injections that are not on the market at home and abroad, comprehensive toxicological studies should be carried out by the clinically planned injection routes (such as intravenous injection, intravenous drip, intramuscular injection, subcutaneous injection, etc.), including general pharmacology, acute toxicity, long-term toxicity, genetic toxicity, reproductive toxicity, carcinogenicity, special safety test of injections, etc,Attention should be paid to the consistency between the mode of administration and the mode of clinical use, and it can reflect the safety of the drug under the mode of clinical administration.It is suggested that the toxicokinetic study should be carried out at the same time of long-term toxicity test.

（2） Drugs changed from other route of administration to route of injection

When the route of administration is changed from oral administration to injection administration, new safety concerns may arise due to drug exposure, changes in tissue distribution or the production of new metabolites and / or impurities.Therefore, on the premise that the efficacy, safety and pharmacokinetic characteristics of the original route of administration are clear, the pharmacokinetic study should be carried out to compare the injection route with the original route of administration,The toxicological test (including toxicokinetic test) was designed reasonably to compare with the original route of administration.During the experiment, we should pay attention to whether there are new toxic target organs, whether the degree of toxic reaction is increased, whether it can be recovered, and the relationship with the dosage or exposure.

（3） Safety evaluation related to impurities

The types and contents of impurities in the toxicological study samples of injections not listed at home and abroad should be much lower than those in clinical trial samples or products on the market. In the study, attention should be paid to the toxic reactions related to impurities, so as to provide basis for the determination of impurity limit.Due to the possible differences in toxic reactions between animals and humans and the limitation of clinical trial sample size, the safety data of new drugs may still be limited when they are applied for marketing, and the impurity limit formulated based on this may not fully guarantee the safety of products. Therefore, it is necessary to continue to monitor adverse reactions after marketing and analyze the causes of new adverse reactions,If it may be related to impurities, we should try to reduce the content of impurities, or carry out more in-depth toxicological study on impurities.

If the impurity safety of the marketed product is known, the impurity type and content of the developed product should not be more (higher) than that of the marketed product;If the type and quantity of impurities are more than those of the products on the market, the formulation and preparation process should be optimized to reduce the impurity content to the specified quality control limit.If it still fails to meet the requirements, the relevant impurities shall be determined qualitatively. Combined with the chemical structure of the impurities, the relevant tests (such as toxicological studies using samples containing impurities or pure impurities) and / or literature shall be provided as the basis for determining the impurity limit.If the impurity safety of products on the market is unknown, systematic impurity safety research should be carried out according to the requirements of drugs not on the market at home and abroad.

If there is no specific data of impurities in the listed varieties, and it is uncertain whether the type and content of impurities are consistent with the listed varieties, the related impurities should be identified. For those who are worried about the safety, the samples containing impurities or pure impurities should be used for relevant toxicological research, so as to provide the basis for the determination of impurity limit.

 

（4） Safety evaluation of special injection preparation

The characteristics of some special injections (liposomes, microspheres, microemulsions, etc.) may lead to changes in the absorption, tissue distribution, elimination and other pharmacokinetics of the main drug compared with ordinary injections, resulting in changes in the nature and degree of toxicity.Therefore, when developing special dosage forms on the basis of ordinary injection forms, comparative pharmacokinetic studies should be carried out first, and further toxicological studies should be determined according to the results.

（5） Safety evaluation of excipients for injection

The safety of injection excipients should be supported by experiments and / or literature.For the newly developed excipients for injection, the change of excipients from other routes of administration to excipients for injection, and the dosage of excipients for injection exceeding the common range, in addition to the corresponding toxicological research on the preparation, the safety information of excipients should be obtained through the relevant toxicological research on excipients.

（6） Focus of special safety test for injection administration

The special safety tests of injection include vascular irritation, muscle irritation, allergy, hemolysis and so on.In the relevant research and evaluation, we should pay attention to whether the concentration of the test drug is not lower than the clinical concentration, and pay attention to the influence of the number of administration, volume and speed on the test results.In addition, we should pay attention to the histopathological examination of irritation test and the test results of positive control group of allergy test.

When the test drug in the special safety test of injection administration appears positive results, it is recommended to use the same kind of drugs that have been listed as the control, and further comparative study should be carried out. According to the results of comparative study and the clinical application of the drugs that have been listed, the clinical safety risk and acceptability of the positive results should be analyzed and judged.

　　

8、 Technical requirements for clinical research of chemical injection

The clinical study of injections should meet the basic requirements of the current administrative measures for drug registration and other regulatory documents.On this basis, we should carefully analyze the drug background information (such as clinical research and application information at home and abroad), clarify the purpose of clinical research, and determine the follow-up clinical trial design and implementation process according to the research purpose.

（1） Injections not listed at home and abroad

Systematic pre marketing clinical trials (including phase I-III) should be conducted to obtain sufficient safety and effectiveness information and evaluate the risk / benefit ratio of clinical application.

For the drugs changed from other routes of administration to injection (including intramuscular injection to intravenous injection), we should also pay attention to the comparative study with the original route of administration, including the comparative study of human pharmacokinetics, indication positioning, exploration of dosage and administration scheme, safety, etc.

Similar to the clinical research rules of other new drugs, the clinical research of injections that are not listed at home and abroad should pay attention to the following characteristics: ① purpose: before the clinical research of such drugs is carried out, it is necessary to formulate a detailed clinical research plan according to the research purpose, and achieve the purpose of product development through a series of step-by-step and interrelated clinical research.② Exploratory: due to the lack of marketing experience and data, the indications, usage and dosage, safety, effectiveness and other aspects of such drugs need to be carefully explored.③ Systematic: the clinical research of this kind of drugs is a logical, step-by-step, phased and gradual process. In this process, the information of early small-scale research is used to support the larger and more purposeful follow-up research.④ The unity of generality and individuality: in systematic clinical research, we should not only follow the common technical requirements and management requirements, but also adopt more flexible research methods according to the specific characteristics of drugs, so as to avoid risks to the greatest extent and obtain the maximum research efficiency.

（2） Injections listed abroad but not in China

　　1.It has been listed abroad and has systematic clinical research and evaluation information

The main purpose of clinical research on this kind of drug is to verify whether the safety and effectiveness of the drug used by Chinese people are consistent with the information obtained abroad, and whether the indications, usage and dosage approved abroad are still applicable to Chinese people.

The specific purpose and design of the clinical study should be determined according to the specific situation of the variety, after comprehensive analysis of the results of preclinical study, foreign clinical data and drug race differences.In general, human pharmacokinetic studies and necessary clinical trials should be carried out.

　　2.But there is no systematic clinical research and evaluation information

The specific purpose and design of this kind of drug should be determined according to the amount and cognitive level of foreign clinical information (excluding undisclosed information and information related to intellectual property protection), as well as the consideration of drug racial differences, combined with the basis of preclinical research.

In the case of no access to any foreign clinical information, clinical trials should be carried out according to the clinical research ideas and Strategies of drugs not listed at home and abroad, so as to comprehensively and systematically explore the safety and effectiveness of their application in Chinese people.

（3） Injections on the market in China

　　1.It has been on the market in China and can obtain systematic clinical research and evaluation information

The clinical research of this kind of drugs should be based on the existing clinical information, combined with the preclinical research basis.

Based on the following premise: 1) it is consistent with the indications, usage and dosage of the products on the market, and the safety and effectiveness of the products on the market has been fully verified and recognized;② It contains the same active ingredients as the products on the market (the main dosage is the same), and the clinical dosage is the same;③ The prescription is reasonable, the excipients will not bring security risks, and the preparation factors will not affect the drug behavior in vivo;④ The factors affecting the safety of the product (such as the type and quantity of impurities) were fully evaluated, and there was no potential safety hazard.Only through pharmaceutical control, it can achieve the same safety and effectiveness as the products on the market, and generally avoid clinical research.

If any of the above conditions can not meet the corresponding requirements, the necessary clinical trials should be carried out according to the specific situation.

　　2.It has been listed in China, but no systematic clinical research and evaluation information has been obtained

According to the specific situation (refer to the existing clinical research and marketing information that does not involve intellectual property protection), the specific trial purpose and trial design should be determined, and the necessary clinical trials should be conducted to further verify its safety and effectiveness.

If the drug has a more extensive clinical application basis, the occurrence of adverse reactions is acceptable, clinical research focuses on the validation of its effectiveness.If the basis of clinical application of drugs is relatively weak and the evaluation of their safety is lack of sufficient information, we should refer to the general principles of clinical research of drugs not listed at home and abroad, and combine with the existing clinical research and application information to conduct systematic research and evaluation on their safety and effectiveness.

（4） Special injection

Special injections refer to preparations that may affect the pharmacokinetics of drugs in vivo, such as liposomes, microspheres, microemulsions, etc.

　　1.Unlisted special injections in China

Because special injections may lead to significant changes in pharmacokinetic behavior in vivo compared with ordinary dosage forms, clinical trials of such drugs should be carried out according to the general principles of drug research and development not listed at home and abroad, whether they are listed abroad or not, in order to fully evaluate their safety and efficacy.

If common injections have been put on the market in China, we should pay attention to the differences in pharmacokinetics and tolerance between them, and on this basis, carry out systematic clinical studies to evaluate the safety and efficacy of special injections.

　　2.Special injections on the market in China

It is generally believed that the quality control of special injections should be carried out through standardized process and method.Therefore, although there are similar products on the market in China, this kind of products should also be combined with the preclinical research basis and the safety and efficacy information of the products on the market, and necessary clinical trials are needed to verify its efficacy and safety.

If the pharmacokinetic behaviors of the two drugs are basically the same, only confirmatory clinical trials can be conducted to confirm their efficacy and safety;On the contrary, clinical trials should be carried out according to the general principles of drug research and development which are not listed at home and abroad.

 

9、 Technical requirements for generic chemical injections

For generic injections, the safety, effectiveness and quality control information of marketed products is an important basis for research and evaluation. Whether the above information is sufficient or not determines the depth and breadth of the research work of this kind of injections.

（1） The clinical research and evaluation information of the marketed product system can be obtained

On the premise of ensuring that the quality of generic products is not lower than that of marketed products, we can bridge the clinical research and application information of marketed products to evaluate the safety and effectiveness of generic products.Therefore, the research and evaluation of imitation products should focus on the quality comparison with the listed products and improve the quality control requirements.

　　1.Focus on the selection of specifications

Generally, the specifications of the imitated products should be consistent with the specifications of the same variety on the market. At the same time, it should also be determined according to the usage and dosage specified in the manual from the perspective of facilitating clinical medication and meeting the needs of clinical medication, and should comply with the relevant national regulations.

　　2.Strengthen the quality control of API and excipients

See the third part of the technical requirements for the use principle and quality control requirements of API and excipients.

　　3.Pay attention to the similarities and differences between the prescription and preparation process and the products on the market

If the prescription process of the developed product is consistent with that of the marketed product, and the quality of the API, the specification and quality of the excipients are also consistent, the clinical study is generally not required on the premise that the quality of the developed product is consistent with that of the marketed product.

If the prescription process of the developed product is not consistent with that of the marketed product, but the quality of the API is consistent, the excipients used are commonly used in injection preparations, and the dosage is also within the range of conventional dosage. The preparation process is a conventional process, which is generally considered to have less impact on the safety of the developed product.However, due to the interaction between excipients and excipients, and between excipients and main drug, it is necessary to carry out corresponding non clinical safety studies, mainly including animal systemic allergy test, hemolysis test and local irritation test.If the excipients used in the development of products are not commonly used in injection preparations, or their dosage exceeds the conventional dosage range, or the preparation process is a special process, in order to verify the influence of prescription process on product safety, it is necessary to conduct non clinical safety research first, and then conduct corresponding clinical research.

In particular, it should be noted that the technical requirements for the prescription, preparation process, process stability, and sterilization process verification of imitation products should conform to the current cognition and general principles, and should not be simply compared with the products on the market.If according to the current cognition, the prescription process of the listed products still needs to be improved, on the basis of determining its imitation value, the imitation of the product should be improved through sufficient research.

　　4.Pay attention to quality comparative study and improve quality control methods

For the general principles of quality research and quality standard formulation of generic drugs, please refer to the technical guidelines for generic drug research, and pay attention to the following issues:

(1) Quality comparative study is an important method to judge the "consistency" or "equivalence" of the quality of developed products and listed products. At the same time, through quality comparative study, we can comprehensively understand the quality characteristics of products, and provide the basis for improving the quality control methods of developed products.

For injection, impurity study is an important content of quality control study.If the content of impurities in the developed product exceeds the national standard, or the developed product contains new impurities not contained in the marketed product, it is necessary to analyze the safety of impurities and provide relevant data, and carry out relevant safety tests when necessary;If the limit of impurities is not specified in the national standard, the impurity content of the developed product shall not be higher than the measured value of impurities of the same kind on the market, and the types of impurities shall not be increased. Otherwise, the safety of impurities shall be analyzed and relevant data shall be provided, and relevant safety tests shall be carried out when necessary.If it is difficult to obtain the products on the market for quality comparative study, and the national drug standards need to be improved, the quality study of generic products should be carried out according to the technical requirements of new drugs and the technical guidelines for the study of chemical drug impurities.

(2) The formulation of quality standards should comply with the general principles of "technical guidelines for the standardization process research of the formulation of chemical drug quality standards", and pay attention to the analysis of the results of quality comparative studies, the perfection of national drug standards, and the characteristics of developed products.

On the basis of national drug standards, according to the requirements of product characteristics and quality improvement, we should constantly improve the testing items, optimize the testing methods, and strictly limit the requirements, so as to better control the consistency of product quality between batches and within the validity period, so as to better ensure the safety and effectiveness of products.For example, for intravenous preparations, if the national standard does not include relevant substances, bacterial endotoxin or pyrogen test, it should be updated generally;If the specificity and sensitivity of the relevant substances contained in the national standard are not enough, it should be studied and optimized.

　　5.Stability study

For the imitated injections, the stability should not be lower than that of the same kind of injections already on the market. For example, more stringent storage conditions are needed, or the quality of the products developed within the validity period of the products on the market does not meet the requirements.

At the same time, it should be noted that: (1) generally, the test items in the quality standard can not be deleted only based on the stability research results of three batches of samples, for example, the stability research results can not show that there is no obvious change in the related substances, that is, the related substances inspection is not included in the quality standard（2) It is not only based on the results of stability study to relax the limit requirements of some items in the quality standard（3) The period of validity should be determined according to the results of long-term sample retention test. Generally, the period of validity should not exceed the time of long-term sample retention.

　　6.Requirements of preclinical safety study and clinical study

As the special safety test of injection administration is related to specific varieties, this study should be carried out in general.

The requirements of other preclinical safety studies and clinical studies should be determined according to the results of pharmaceutical studies.

（2） Unable to obtain the clinical research and evaluation information of the marketed product system

When the clinical research and application information of the marketed product system cannot be obtained as the basis for the safety and effectiveness evaluation of generic products, comprehensive quality control, safety and effectiveness research of generic products should be carried out according to the idea of new drug research and development.

　　1.If the listed products have been widely used in clinical practice in China, the information of adverse reactions is relatively complete, and the adverse reactions are acceptable, we should focus on the validation of effectiveness, the quality comparison with the safety indicators of the listed products, and the improvement of quality control requirements.Based on the improvement of pharmaceutical research, necessary clinical trials were carried out to verify its effectiveness, and the instructions were further improved according to the results of clinical trials.

　　2.If the marketed products are not widely used in clinical practice in China, or have not been well monitored for adverse reactions, and have little information on their safety, comprehensive and systematic pharmaceutical, pharmacological toxicological and clinical studies should be carried out to verify their effectiveness and safety, and on this basis, a reliable quality control system should be established, and the instructions should be improved.

　　3.If the same products are listed abroad, the technical requirements can refer to the technical requirements of drugs that are listed abroad but not yet listed in China.

（3） Special injection

Because the quality of such injections and the in vivo behavior of the active ingredients are greatly affected by the prescription and process, it can lead to differences in the morphology, particle size and distribution of the active ingredients, resulting in differences in the in vivo distribution and elimination of drugs, even though the marketed products have systematic clinical research and evaluation information,Clinical studies are also needed to verify the clinical therapeutic consistency between the developed products and the products on the market.

 

10、 Technical requirements for contents of instructions and labels of chemical drug injections

Drug instructions are technical documents that contain important scientific data, conclusions and other information about the safety and effectiveness of drugs, such as pharmacy, pharmacology, pharmacokinetics, toxicology and clinical medicine, to guide the safe, correct and rational use of drugs.When writing and revising instructions and packaging labels, it is necessary to pay close attention to the source of instructions information and collect relevant information scientifically and reasonably on the basis of complying with the relevant provisions of the State Food and Drug Administration (e.g. SFDA Order No. 24 "Regulations on the administration of drug instructions and labels").

First, for drugs that are not on the market at home and abroad, the instructions should be written according to the results of systematic and standardized clinical trials and non clinical trials.The information collected in the manual should not exceed the scope of the completed test, especially the indications, usage and dosage, and the safety related information should be as comprehensive as possible.

Secondly, for the innovative preparations that are given by injection instead of other routes, their instructions should be mainly written according to the system of the injection itself and the results of standardized clinical trials and non clinical trials.Indications, usage and dosage should not exceed the scope of the completed test, but the safety related items should be included in the original dosage form.

Thirdly, for the chemical injections and their simple modified dosage forms that have been listed abroad but not in China, if there is systematic clinical research and evaluation information in foreign countries, the instructions are mainly written with reference to the instructions listed abroad (for doctors) and combined with the information obtained from domestic confirmatory clinical trials,It should be noted that the indications, usage and dosage should not exceed the scope of domestic trials.

Fourth, for the chemical injections and their simple modified dosage forms that have been listed abroad but not in China, if there is no systematic clinical research and evaluation information in foreign countries, the instructions should be mainly written according to the results of systematic and standardized clinical trials and non clinical trials conducted in China, but the relevant safety information of foreign products should be included.

Fifthly, if there is systematic clinical research and evaluation information for domestic listed chemical injections and their simple modified dosage forms, the instructions are mainly written with reference to the latest version of the instructions listed in China.The varieties that need clinical research should be improved by combining with the information obtained from their own clinical trials.

Sixthly, if there is no systematic clinical research and evaluation information for domestic chemical injections and their simple modified dosage forms, the instructions should be mainly written according to the results of clinical trials and non clinical trials conducted by the developed products, especially the indications, usage and dosage. However, attention should be paid to the existing clinical safety information of the same kind in China.