Dialectical unification of injection API, preparation process and quality research (dry goods)

Guide: Today we will talk about a few key links in the research and development process of injection consistency evaluation, to help everyone fill the pit! The dialectical unification of the research on the use materials of injectables, preparation synths and quality was made clear from March 5, 2016 (opinion of the General Office of the State Council on the evaluation of the quality and efficacy of genericdrugs) to May 14, 2020 (CDE issued the technical requirements for the evaluation of the quality and consistency of therapeutic efficacy of chemical injections), and clarified the implementation period, technology and technology of the consistency evaluation of injections. Requirements and declaration information templates; from 13 June 2019 (21st batch of reference preparations) to 19 May 2020 (29th batch of reference preparations), a total of 374 varieties of injections (21% of the market editing varieties), 895 regulations, the selection of reference preparations is increasingly clear.
from the enterprise injection consistency evaluation acceptance number and the most popular injection varieties can be seen, Qilu Pharmaceutical, Yangzijiang, Sichuan Collum, Jiangsu Hengrui, Yichang Renfu, Jiangsu Hausen and Zhengda Tianqing injection receiving numbers are more than 20.
in addition, in the most popular TOP10 list, to anti-inflammatory anti-infective category of large-capacity varieties are the most popular, fierce competition. as of April 22,
, 32 varieties of injections have passed or passed consistency evaluation, of which powder needles and water needles account for about 80% of the market, is the focus of our research and attention.
the main work modules and case sharing of injection consistency evaluation today we will talk about a few key links in the research and development process of injection consistency evaluation, to help you fill the pit! The relationship between the four links of reference analysis, original package screening, process research and compatibility research is shown in the figure below.
several links are relatively independent and interrelated, and are complementary and dialectically unified.
(i) the quality of API is the most critical factor in the evaluation of injection consistency, especially for sterile products, so how should we choose the API that meets the requirements? Case Sharing: Below, let's take a cephalosporine species as an example of the process of raw material screening.
(1) crystal type - XRD results: manufacturers 1 and 2 of the API crystal type and the original development agent is relatively consistent.
(2) Dissolution Time Results: The dissolution time is slightly different from the original study, and there may be differences in crystaltype, particle size distribution and crystalitism.
(3) crystallise results: With the increase of the electron glass scanning magnification, you can more clearly see the difference between apiand and the original development agent: the original development agent particles are significantly smaller than the API, and the surface of the manufacturer 1 API is more compact, so the dissolution time will be longer.
(4) particle size distribution results: particle size, the particle size of each manufacturer's API is greater than the original study reference ratio, from the side of the explanation, why the manufacturers of API dissolution time is longer than the original study.
(5) other physical and chemical indicators results: the quality of the raw materials of each manufacturer and the original development agent is not much different, indicating that the salt-forming process of raw materials and the original development agent is relatively close.
(6) impurity analysis in the analysis of impurities need to focus on three aspects, but also the current most supplemented part: genetic toxic impurities, elemental impurities, residual solvent.
we study the following impurities according to the production process of API and the characteristics of beta-lactam antibiotics: Through the above case study, we summarized the screening process of API as follows: (1) First, we are looking for a compliant and qualified supplier of raw materials;
(ii) the selection of accessories in the type and dosage of accessories, mainly based on the original research drug specification, patent research, reverse analysis results and the general dosage to determine.
some injections contain organic solvents, which can be dissolved on API, but the content of organic solvents often affects clarification and crystalline.
case sharing: the amount of accessories in the selection of butanol as an accessory, it is during the stability period, the clarification of the preparation is influential.
, we examined the amount of accessories: Conclusion: The test results showed that the concentration of the auxiliary sbutanol had no obvious effect on the organic solvent residue of the preparation, but it had a more obvious effect on the clarification of the solution and the crystal of the compound after replevened. it is appropriate
to finally determine the concentration of 15% and 20% of the excipients.
(iii) the production process also affects the stability of the preparation.
case sharing: a preparation has two accessories, by testing the different additions of two accessories, to optimize the preparation production process.
see the following table: Conclusion: The test results show that the different feeding sequence has a significant effect on the relevant substances of the formulation, according to the amount of reference preparation accessories added To and B, the increase of impurities significantly and the asignificant surplus of accessories A.
adjust the amount of accessories in the 95%-105% range, and carry out in-depth study of the input method, so as to reduce the increase of impurities by unique feeding method, so that it meets the requirements of consistency evaluation.
(4) package material case sharing: the preparation is relatively sensitive to moisture, the preparation in the accelerated conditions of the placement process, the substance and the solution of the clarification degree and color changes obviously, after the exclusion of raw materials and accessories and other factors, finally determined to be the impact of the package material.
Conclusion: It can be seen from the above table that the moisture of the plug has a significant effect on the stability of the preparation.
laboratory in the freeze-dried process, in addition to the preparation of its own moisture control, the use of unconventional plug treatment to control the moisture of the plug, thereby reducing the rubber plug moisture migration on the effect of preparation quality.
the quality improvement and technological innovation in the process of injection consistency in the process of how to accurately and efficiently evaluate the quality consistency of injection, not excessive study of impurities, but also to ensure the full study, in the two to find a balance between the two, it is worth our thinking and concern.
in response to increasingly stringent review requirements, we must carry out quality improvement and technological innovation in such fields as coating material compatibility research, genetic toxic impurity detection, polymer quantification and structural identification.
we share our experiences in these three areas of research.
(i) compatibility research to do package material compatibility research, first of all to determine the overall research ideas, we mainly refer to the following decision tree for the formulation of the program and the implementation of the plan.
summarize the above strategy, it is not difficult to see that risk assessment is the most important part of compatibility research.
, before doing the study of the compatibility of the package material, one is to summarize the type of package material, the material, the use of steps in the production process, the pre-treatment before use, contact conditions with the liquid (e.g. contact time, temperature, etc.); Such as ISO, GMP, formulation (especially additive types and dosage) and processing processes, product compliance statement (USP/EP/21CFR, etc.), inspection reports and supplier verification data, etc., the quality of the package and its manufacturer's quality assurance system to conduct a comprehensive assessment, the priority of the selection of standard compliance, quality assurance system perfect package material.
at the same time, the final research plan is determined in the context of risk classification of different routes of administration and the likelihood of the interaction of preparations with packaging components.
the following for the study flow chart: (2) genetic toxic impurities detection strategy of the limit of genetic toxicimpurities are mostly very low, the sensitivity of detection requirements are very high, so the use of temperament and liquid quality and other equipment, resulting in an increase in detection costs.
how to ensure the adequacy of research on toxic impurities based on resource savings and increased research efficiency, we use high-tech tools such as Derek and Sarah software as a solution based on expert advice.
, Derek software is based on an expert knowledge system to predict the toxicity of compounds; Sarah is a statistical model to predict compound-causing mutations.
the combination of these two software, it is possible to carry out risk assessment on some compounds with genotoxicity warning structures and determine their research plans and strategies.
technology technology polymer is the allergen that causes the reaction of beta-lactam antibiotic rapid hair hair, and the study of polymer is one of the key points of antibiotic quality control.
the current commonly used gel filter chromatography (molecular blocking chromatography), ion exchange chromatography, inverting chromatography, capillary electrophoresis to detect polymers, which mainly gel filter chromatography.
in recent years, there have also been reports of liquid-quality technology to detect polymers, but only the total amount of polymer impurities can be detected, it is not possible to separate and identify the structure of a single polymer, let alone to quantify each polymer.
we have established a joint laboratory with the Sazu Mass Spectrometry Innovation Center to develop 3D chromatography technology, separation and structural identification of polymers.
provide technical reference for enterprises to improve process, dosage form research and development, quality improvement, and ensure the safety of patients' medication.
can also provide a scientific basis for raising pharmacopeia standards.
instrument equipment is shown in the following image: