Nmpa, injection consistency evaluation is finally coming?!

In order to implement the opinions of the general office of the State Council on the evaluation of quality and efficacy consistency of generic drugs (GBF [2016] No 8) and the announcement on the evaluation of quality and efficacy consistency of generic drugs (2018) No 102), to promote the evaluation of quality and efficacy consistency of chemical injection generic drugs, the State Food and drug administration has organized the drafting of technical requirements for evaluation of quality and efficacy consistency of chemical injection generic drugs (Draft for comments), application data requirements for evaluation of quality and efficacy consistency of listed chemical injection generic drugs (Draft for comments), which are now submitted to the society Public consultation will be held Technical requirements for consistency evaluation of quality and efficacy of generic drugs for chemical injection (Draft for comments) I General requirements the applicant should have a comprehensive understanding of the domestic and foreign listing background, safety and effectiveness data, monitoring of adverse reactions after listing, and evaluate and confirm its clinical value 2、 The applicant of the reference preparation shall select the reference preparation in accordance with the procedures for selection and determination of reference preparation of chemical generic drugs issued by the State Administration, and carry out the consistency evaluation research with reference to the technical requirements and relevant technical guidelines at home and abroad 3、 Technical requirements for prescription process (1) the type and dosage of excipients in the prescription injection should generally be the same as that of the reference preparation (RLD) The same dosage of excipients means that the dosage of generic excipients is 95% - 105% of the dosage of corresponding excipients of the reference preparation If special solvent is attached, it shall be consistent with the special solvent prescription of the reference preparation The applicant may submit a prescription different from the reference preparation bacteriostatic, buffer, pH regulator, antioxidant and metal ion complexing agent, but the difference shall be marked, the reason for selection shall be explained, and the research shall prove that the above difference does not affect the safety and effectiveness of the applied product The concentration or dosage of excipients shall meet the limit requirements of FDA IID database or provide sufficient basis Refer to ICH Q8 for excessive feeding (two) production process 1 process research the research and selection of injection sterilization / aseptic process should refer to the domestic and foreign sterilization / aseptic process validation guidelines Carry out process research according to relevant guidelines, and determine the key steps and parameters of production process Attention should be paid to the following aspects: (1) in order to effectively control pyrogen (bacterial endotoxin), it is necessary to strengthen the control of the original auxiliary package, production process, etc., and it is not recommended to use activated carbon in the production of injection (2) The compatibility of the filter was studied according to the production process According to the characteristics of the solution and the production process, the compatibility of direct contact containers such as silicone tubes was studied (3) If there is overfilling of the reference preparation, the overfilling of the generic should be consistent with the reference preparation If there is any inconsistency, a reasonable demonstration should be provided 2 Process validation (1) sterilization / aseptic process validation for terminally sterilized drugs, at least the following validation reports shall be carried out and submitted: • validation of terminally sterilized drugs; • validation of the pyrogen of the internal packaging materials in direct contact with the drugs or relevant certification materials issued by the supplier; • validation of the sealing of the packaging system, and the method shall be properly verified; • Validation of retention time (including chemical and microbiological) For aseptic filling products, at least the following validation reports shall be carried out and submitted: • bacteria retention validation of sterilization process; • sterilization validation of supply solution / large package medicine if sterilization is not carried out by filtration and other methods; • sterilization validation of container sealing system directly contacting aseptic materials and products; • sterilization validation of sterilization process Verification of depyrogens or relevant certificates issued by the supplier in direct contact with the inner packaging materials of the product; • verification of aseptic process simulation test, and clear measures to be taken after the test failure; • verification of the sealing of the packaging system, the method to be properly verified; • verification of retention time (including chemical and microbiological) (2) Production process validation provides process validation data, including process validation scheme and validation report 3 Based on product development and validation results, sterilization / aseptic process control requirements are determined, such as sterilization parameters (temperature, time, loading method) / sterilization and filtration parameters (pressure difference between upstream and downstream of the sterilization filter, filter use time / times, filter integrity test, etc.), and time / retention time of key production steps The conventional central control monitoring is carried out for the microorganism load before sterilization and filtration of the material liquid adopting the sterilization and filtration process; the conventional central control monitoring is carried out for the microorganism load before sterilization of the material liquid adopting the residual probability sterilization process; the frequency can be broadened for the microorganism load before sterilization of the material liquid adopting the excessive sterilization and filtration process 4 The batch of registered samples shall be implemented in accordance with the general requirements for the production scale of registered batch of chemical generic drugs (Trial) Meanwhile, the registration batch production record and production process information form shall be submitted 4、 Technical requirements for quality control of original auxiliary package (I) API The preparation manufacturer shall fully study and evaluate the quality of API in accordance with the existing guidelines and relevant documents (including National Bureau No.7 document in 2008) in combination with API production process, revise the inspection methods of relevant substances if necessary, increase the inspection of solution clarity and color, solvent residue, bacterial endotoxin, microbial limit, etc., and provide relevant verification data to meet the requirements Injection process and quality control requirements; meanwhile, attention should be paid to the research and evaluation of elemental impurities and mutagenic impurities Preparation manufacturers need to conduct comprehensive audit and evaluation on the source and quality of APIs according to the needs of sustained and stable injection production, so as to ensure the stability of the supply chain in the subsequent commercial production If there is any change, it shall be studied and declared according to relevant technical guidelines （2） Excipients and excipients shall meet the requirements for injection, and strict internal control standards shall be formulated Except for special cases, it shall meet the requirements of current Chinese Pharmacopoeia （3） Packaging materials and containers of drugs in direct contact with each other for injection shall meet the packaging standards issued by the State Administration or the requirements of USP, EP and JP The packaging materials and containers that can guarantee the quality of drugs are selected according to the characteristics and clinical use of drugs The phase of packaging materials and containers shall be carried out in accordance with the relevant technical guidelines such as the technical guidelines for compatibility research of chemical injection and plastic packaging materials (Trial), the technical guidelines for compatibility research of chemical injection and glass packaging containers (Trial), the technical guidelines for compatibility research of chemical drugs and elastomeric seals (Trial) Capacity study According to the results of accelerated test and long-term test, the rationality of the packaging materials and containers used is determined It is suggested that the inspection of sample inversion should be added in the process of stability inspection, so as to comprehensively study the compatibility of the contents and sealing components such as rubber plug The quality and performance of the packaging materials and containers used for injection shall not be lower than that of the reference preparation, so as to ensure that the quality of the drug is consistent with that of the reference preparation 5、 Technical requirements for quality research and control (1) it is suggested to scientifically design the test according to product characteristics and relevant technical guidelines, and provide sufficient test data and literature （2） The key quality attributes (CQA) of the preparation are established according to the quality profile (qtpp) of the target product Generally, CQA of the injection includes but is not limited to the following studies: properties, identification, redissolved time, dispersion time, particle size distribution, redissolved solution properties, solution clarity, solution color, osmotic pressure / osmotic pressure ratio, pH value / pH value, water content, loading capacity, loading capacity / weight difference , content uniformity, visible foreign matters, insoluble particles, bacterial endotoxin, sterility, element impurities, residual solvents, related substances (isomers), drug substance crystal / particle size, content, etc 1 Relevant substances focus on the degradation products of preparations, including the degradation products of APIs or the reaction products of APIs, excipients and / or inner packaging materials Process impurities of APIs generally do not need to be monitored or described in the preparation According to the characteristics of the product, according to the relevant technical guidelines and the collection of Pharmacopoeia at home and abroad, scientific and reasonable selection of relevant material inspection methods, and standardized methodology verification In combination with the requirements of relevant technical guidelines, reference to the research information of reference preparation and impurity information collected in Pharmacopoeia at home and abroad, to formulate reasonable limits of related substances 2 For the presence of geometric isomers and chiral isomers, according to the research of product characteristics and production process, determine whether to set the standard 3 According to the relevant literature and reference preparation, through the analysis of production process and product degradation path, judge whether it is possible to produce potential mutagenic impurities If necessary, carry out targeted research and control according to the research results and relevant technical guidelines 4 According to the provisions of ICH Q3D, the control strategy of the element impurities in the preparation is determined through scientific and risk-based assessment, including the element impurities that may be introduced into the original auxiliary package, production equipment, etc （3） The self-developed product should be compared with the reference preparation in a comprehensive way (including the comparison of miscellaneous mass spectrometry) to ensure that the quality of the self-developed product is consistent with that of the reference preparation In principle, the reference preparation shall provide inspection data of multiple batches of samples to inspect the key quality attributes closely related to the consistency evaluation 6、 The stability research technology requires that the research contents of injection stability include influencing factor test, accelerated test and long-term test If necessary, intermediate condition test should be carried out Low temperature test and freeze-thaw test are recommended for injection that may be unstable at low temperature The clinical compatibility stability study shall be conducted according to the specification of the reference preparation For the products with poor stability, the clinical compatibility stability study shall include at least two batches of self-made samples (it is recommended that one batch shall be short-term samples), and another batch of self-made samples may be used for other products If there is significant change in the quality during the clinical compatibility, targeted comparative study shall be conducted with the reference preparation It was proved that the change range was the same as the reference preparation According to the requirements of ICH Q1b, study the light stability The accelerated test and long-term test of injection stability research should be carried out under the condition of GMP The characteristics of the declared injection products, such as product specification, container, loading capacity, concentration of raw and auxiliary materials, can be comprehensively considered The stability research scheme should be designed according to the relevant technical guidelines, and the changes that are likely to occur during the storage process may affect the quality, safety and / or effectiveness of the preparation Project If the injection prescription contains antioxidants, antibacterial agents and other excipients, the change of the content of these excipients should be investigated in the stability study Sterility test shall be carried out at the beginning and end of stability inspection, and sealing of packaging system can be used at other time points The tightness of packaging system can be tested by physical integrity test method (such as pressure / vacuum attenuation, etc.) and verified by methodology In general, stability research data of not less than 6 months shall be provided According to the results of stability study, the storage conditions were determined with reference to the information of reference preparation The stability of generic drugs should not be lower than that of reference preparation Applicants are required to submit a stability study plan and commitment The stability study plan shall at least include sample batch, sample quantity, test location, placing conditions, sampling time point, inspection index, analysis method and acceptable limit Generally, the stability test scheme of the promised batch and the