Technical Guidelines for Changes in Pharmacy During Clinical Trials of Innovative Drugs (Chemical Drugs) (Draft for Comments)

Guide: This guide is divided into four parts, including overview, general principles of pharmaceutical change assessment, API change research, preparation change research and so on!---- The drafting note of the Technical Guidelines for Change of Pharmacy during Clinical Trials of Innovative Drugs (Chemical Drugs) (Draft for Comments) is to implement the relevant requirements of the State Council's Opinions on Reforming the Review and Approval System for Pharmaceutical Medical Devices (No44 of 2015), and the Opinions on Deepening the Reform of review and approval system to encourage innovation in pharmaceutical devices, and further complement the relevant requirements of the Drug Administration Law and the Measures for the Administration of Drug Registration on Innovative DrugsThe Ministry drafted the Technical Guidelines for Pharmaceutical Changes during Clinical Trials of Innovative Drugs (Chemical Drugs) (Draft for Comments), and now explains the relevant information as follows: First, on the basis of preliminary research, combined with the relevant regulations and technical guidelines for pharmaceutical changes during clinical trials of chemical innovation drugs at home and abroad, the status quo of domestic chemical innovation drug declaration, and a chemical pharmaceutical medicine organization has drafted the Technical Guidelines for The First Draft of Pharmaceutical Change during clinical trials of Innovative Drugs (Chemical Drugs) to solicit the views of external expertsAnd in the department in advance discussion and improvementAfter September and December 2019, two domestic and foreign organizations of nearly 20 representative enterprises in the research and development of innovative drugs on the outline of the first draft, writing ideas, main content and other related issues of in-depth exchanges, and the basic language of the guiding principles were standardized, according to the consensus of the meeting to form a revised draftIn June 2020, the Technical Committee of our ministry reviewed the above revised draft, and formed a draft for commentsSecond, the main content of this guide is divided into four parts, including overview, pharmaceutical change assessment general principles, API change research, preparation change research and so onThe first part introduces the general law of research and development of innovative drugs, the scope of application of this guiding principle, etcThe second part introduces the general principles of the evaluation of changes in innovative pharmacyThe third part introduces the general principles of the study of API change, the example of the classification of API change and the research ideaThe fourth part introduces the general principles of the study of preparation change, the example of preparation change classification and research ideasThird, the drafting of the technical guidelines to be explained, based on the requirements of the current Measures for the Administration of Drug Registration, drawing on relevant regulations and guidelines at home and abroad, on the basis of following the law of chemical innovation drug development, focuses on the current evaluation principles of pharmaceutical changes during clinical trials of chemical innovative drugs, research ideas and research content, and gives examples of common major and general changesWhen conducting a pharmaceutical change study, the applicant may refer to these guidelines and conduct the assessment and study in the light of the characteristics of the species and the specific circumstances of the changeTo better understand the content of this guide, the following questions need to be explained: 1, taking into account the phase of innovative pharmaceutical research, the diversity and complexity of pharmaceutical changes, these guidelines provide examples of only common significant and general changesFor other forms of change that are not explicitly listed, the applicant may refer to these Guidelines for assessing principles and research ideas and work on the circumstances of the change2 Considerations for Significant Changes: Significant changes in these Guidelines are changes that are assessed to have a significant impact on the quality of clinical samples, which in turn may have a significant impact on the safety of clinical trial subjects or the convergence of clinical trial results In some cases, pharmaceutical changes may have an impact on the interface of clinical trial results before and after the change, thereby increasing the safety risk of subsequent clinical trial subjects 3 The State Drug Administration has issued the Technical Guidelines for Application of Clinical Trials for New Drugs Phase I and the Information Guidelines on Pharmaceutical Research in Innovative Drugs (Chemical Drugs) III Clinical Trials, which refer to the relevant contents of these Guidelines The technical guidelines for changes in pharmacy during clinical trials of innovative drugs (chemical drugs) (draft for comments) i, outlining the gradual, phased and uncertain characteristics of innovative pharmaceutical research, the breadth and depth of its research with the progress of clinical trials continue to advance Under the conventional development mode, the research and development process of API is ahead of the formulation, usually following the following laws: For API, the synthetic route and process of the early clinical trial stage is relatively immature, the knowledge of key quality properties such as the pharmacological properties and impurity behavior of api, based only on the pre-clinical safety test and relatively limited preparation experience, established a preliminary quality control strategy and a broader quality standard adapted to its development phase With the advancement of clinical trials and the in-depth understanding of key quality attributes, based on the need to enlarge production, improve quality, improve quality control, etc., continuously optimize the route, in-depth study of impurity behavior, strengthen the understanding of key physical and chemical characteristics and their potential impact on the formulation, and combine multi-batch production experience to adjust quality control strategies Determine the proposed synthetic route stake and process at the stage of key clinical trials (refertod in support of core safety and effectiveness evidence on the market), determine the scope of key process steps and key process parameters based on the system, develop reasonable process control and intermediate control, improve raw material stylus quality standards, packaging, storage conditions and expiration period/re-test, etc., based on historical batch (especially safety test batch, key clinical trial batch) production information, quality characteristics, stability findings, etc For preparations, in the early clinical trial stage, based on a limited understanding of the drug's own physical and chemical properties, safety and efficacy, the prescription process is usually selected for development in relatively simple formulation forms (e.g oral solution, capsules directly filled with raw auxiliary powder, etc.), based on preclinical safety tests and relatively limited preparation experience, to establish a broader quality standard adapted to its development phase, based on limited stability, compatibility (if necessary), and pre-use (if necessary) research information Follow-up with the advance of clinical trials, obtain the preliminary human data, for the drug's own characteristics and behavior in the body has a certain understanding, and initially accumulated production experience, on this basis to optimize dosage form, specifications and prescription process, strengthen the prescription of preparation symbiosis and degradation of impurities research, according to the existing knowledge and information to improve quality control In the key clinical trial stage, based on more adequate human safety and efficacy information, production information, determine the proposed commercialized dosage form, specifications and prescription process, carry out a systematic quality risk assessment, determine key process steps and key process parameters, develop reasonable process control and intermediate control, based on historical batch (especially safety test batch, key clinical trial batch) information and stability, compatibility, mating research results, improve preparation quality standards, packaging, storage conditions, expiration dates and usage Based on the above research and development laws, due to the different research objectives of different research stages of innovative drugs, it is decided that the research process is bound to be accompanied by a large number of pharmaceutical changes Pharmaceutical changes may introduce quality risks into clinical samples, which in turn may have an impact on the safety of subjects and/or the connectivity of clinical trial results, so a comprehensive and prudent assessment of the quality risks introduced by the changes and research to support the application of these changes to the preparation of clinical samples The pharmaceutical changes described in these Guidelines are changes that occur (or are intended to occur) in the production, quality control, packaging and storage conditions of clinical samples This guideline applies to pharmaceutical changes during clinical studies of chemically innovative drugs (except radiation drugs) In view of the stage of innovative pharmaceutical research, the diversity and complexity of pharmaceutical changes, this guiding principle mainly expounds the general principles of evaluation and research of changes in innovative pharmacy, gives examples of some common major changes and general changes, and briefly describes the research ideas and research contents under such changes For other forms of change that are not explicitly listed, the applicant may refer to these Guidelines for evaluation and study based on the circumstances of the change When the applicant conducts the pharmaceutical change research, he or she needs to clarify the reason sway, the matter of change and the extent of the change, combine the characteristics of the variety and the specific change content, evaluate the possible impact of the change on the quality of the drug, the safety of the clinical trial subjects, and the convergence of the clinical trial results, and carry out the corresponding research work to assess the feasibility of the change In addition, pharmaceutical changes often do not occur independently For example, changes in production sites may be accompanied by changes in production equipment and production processes, and changes in prescriptions may be accompanied or trigger changes in drug quality standards For multiple changes that occur simultaneously and are related, separate studies may be conducted in accordance with the basic thinking of this Guiding Principles, and supportive research on changes can be carried out in accordance with the change categories with high technical requirements, and attention can be paid to the possible overlay effects of multiple changes 2 When pharmaceutical changes occur during the general principles of pharmaceutical change assessment during clinical research, the applicant shall follow the risk assessment principles and scientifically assess the possible impact of the change in the light of the proposed clinical research phase, the characteristics of the variety, the knowledge of the drug and the preliminary study on the change Specifically, the clinical phase of change occurring (early clinical phase, critical clinical phase): pharmaceutical changes run through all stages of drug development, and are usually more likely to occur in the early stages In the early clinical phase, the human safety of the drug has not been fully established, and the potential impact of pharmaceutical changes on subject safety needs to be assessed mainly in combination with non-clinical safety evaluation results and early clinical research scenarios For example, whether changes in the production process of API will introduce new impurities (e.g genotoxic impurities) and whether changes in the production process of the formulation will cause changes in the amount of exposure in the body at the same dose In the critical clinical research stage, the number of subjects increased, the duration of drug use is extended, and the clinical trial results are the main basis for the assessment of risk-to-benefit ratio when the product is marketed, the pharmaceutical changes at this stage need to focus on the safety of the subjects, but also need to take into account the bridge of clinical trial results For example, based on the results of Phase II clinical trials to determine the dose of administration, in Phase III clinical phase to add new specifications, according to the characteristics of the product, through in vitro research (pharmacy-related comparison, etc.) and /or in vivo tests (e.g BE, PK, etc.) to assess the interface between the new specification and the original specification In general, in the process of innovative drug research, the more the later changes occur, the more detailed and in-depth research is required to prove the acceptability of the changes Innovative drugs need to be carefully considered after completing key clinical studies that support the market 2 The change involves the subject population: clinical trials involve different subjects, the risks that may arise from the change If the process of changing the api introduces genotoxic impurities, the risk of safety is higher for healthy subjects, and for specific subjects (e.g patients with advanced tumors), the risk is relatively acceptable based on benefit-harm analysis The same prescription changes, if used in child subjects, require careful assessment of whether the type and dosage of the changed accessories are applicable to the child population and whether there is a safety risk 3, variety characteristics: the complexity of drug structure / composition and preparation process is also an important factor to be considered in the evaluation For example, when process changes occur in compounds with more complex structures/components such as polymers, synthetic peptides, polysaccharides, bio-source extracts, etc compared to small molecular compounds, it may be relatively difficult to assess the impact of the change, and the risk control ability is relatively weak or the uncertainty of risk assessment is strong For special formulations (lipids, microspheres, etc.), the effects of changes in the prescription process may not be demonstrated by pharmaceutical comparisons alone, and in some cases in vivo bridging tests and/or necessary non-clinical safety trials may be carried out for comprehensive assessment In addition, different routes of administration, their own safety risks are also different, such as injections compared to solid oral preparations need to take full account of the risks associated with sterile 4 Existing cognitive limitations: pharmaceutical change management during clinical trials is part of the whole life cycle management of drugs, usually the more systematic and in-depth research work, the fuller the accumulated research data, the more scientific the assessment of the possible impact of the change Based on the general law of step-by-step research in innovative pharmaceutical research, there may be limitations in the cognition of key quality properties of the product during clinical research (e.g., impurity spectrum research, the effect of apipharmacologic properties on preparation quality and in vivo behavior, etc.) during clinical research, and there may be some limitations in the study of changes in clinical trial seyly Changes that may have significant potential impacts that may be significant, limited data may be difficult to assess, or cannot demonstrate consistent quality through simple pharmaceutical comparisons, and it is recommended that they be considered significant changes, conducting in-depth studies, and accumulating more sufficient data, based on risk considerations In general, pharmaceutical changes during the clinical period can be divided into significant changes and general changes, depending on the likelihood of pharmacoscology changes affecting the safety of clinical subjects and the convergence of clinical trial results A significant change is a change that is assessed to have a significant impact on the quality of clinical samples, which in turn may have a significant impact on the safety of clinical trial subjects or the bridgeability of clinical trial results Applicants should carefully assess the risks associated with such changes and conduct research to support the preparation of changes applied to clinical trial samples General changes are changes that may have no significant impact on the quality of clinical samples, the safety of clinical trials, and the convergence of trial results, and the applicant may conduct relevant studies as appropriate Third, the study of API change 1, the general principle of API change research for the change of API, should be combined with its impact on the quality of the corresponding formulation to carry out assessment and research Specifically, the focus needs to be on the impact of changes on the key physical and chemical properties of API and impurity behavior Changes in the key physical and chemical properties of API, which affect the performance of the formulation, may lead to changes in the behavior of the experimental drug in the subject's body, which in turn affects the convergence of clinical trial results (data) before and after the change, and may also increase the risk of safety of the subject; 1.1 In general, the key physical and chemical characteristics of API, such as crystal type, granularity and distribution, micromorphology, material density, solubility, etc may have an impact on the quality of clinical trial drugs These physical and chemical properties are often closely related to the final purification (or salt, crystallization) process, separation method, drying, crushing, mixing and other operational steps In some cases, significant changes in impurities in the material to be refined may also result in changes in the key physical and chemical properties of the API Therefore, after the relevant process changes, it is necessary to compare the key physical and chemical characteristics of apibefore sints before and after the change based on risk assessment, conduct stability studies as appropriate, and re-verify the structure if necessary When there is a change in the key physical and chemical properties of the changed API, the effect on the formulation process (e.g fluidity, compressibleness, mixing uniformity, solubility, etc.) and formulation properties (e.g., dissolution, collapse, content uniformity, etc.) of the formulation process should be fully assessed, and research based on the results of risk assessment, if necessary, the corresponding preparation in vivating research should also be considered 1.2 Impurity behavior In general, the type of impurities and impurity level in API are important factors affecting the safety of clinical trial drugs Impurities are usually derived from production processes (e.g solvents, reagents and catalysts, starting material introduction and process sidereactions that produce impurities) and their own health.