First-line interpretation! What do researchers think of the Technical Guidelines for Pharmaceutical Change during Clinical Trials of Innovative Drugs (Chemical Drugs)

Introduction: The author, as a first-line new drug developer, will interpret the key content of the Technical Guidelines for Change of Pharmacy during the Clinical Trial starring Innovative Drugs (Chemical Drugs) in practical practiceRecently, CDE issued important guidelines for comments, namely, "Innovative Drugs (Chemical Drugs) Clinical Trials Pharmaceutical Change Technology Guidelines" (draft for comments), the draft is in the Pharmaceutical Review Center in 2019 through two organizations of nearly 20 innovative drug research and development representative enterprises on the basis of in-depth communication and exchange, and on the current domestic innovation drug development of the hot degree, the development of this guiding principle can be said to send carbon in the snow! !---- In this, the author, as a first-line new drug developer, will interpret the key content of this guiding principle from the practical practiceRevealing the law of the development of innovative drugs, it is suggested that "change" is inevitable This Guiding Principle first of all clearthes the development law of innovative pharmaceutical research, that is, "with the characteristics of graduality, stage and uncertainty, the breadth and depth of its research with the progress of clinical trials continue to advance." As far as the author's own experience is concerned, the development of innovative drugs is very different from generic drugs, the degree of its development is not only limited by the constraints of API and formulation technology, to a large extent by the pre-clinical/clinical data on its development progress of the reactionThrough feedback from preclinical/clinical data, API and formulations also need to adjust the quality (sometimes "put" quality) to bridge and support subsequent clinical trialsBased on this, the Guiding Principles clearly "the pharmaceutical research objectives of different stages of innovative drugs are different, which determines that the research process is bound to be accompanied by a large number of pharmaceutical changes." Here, CDE clearly pointed out that the development of innovative drugs will inevitably be accompanied by a "large number" of pharmaceutical changes, is "a large number"! But China's innovative drug development, the number of changes are in various ways down, it seems that the number of changes less, the more can prove the depth of pharmaceutical research, and even the innovative drug research as a generic drug to do! It seems that there is nothing wrong with it, but many times the control is too hard, data accumulation will be relatively small, often will not expose safety issues, and once in the follow-up major changes, quality changes, it is difficult to support the follow-up clinical work! In addition to the above introduction of the law of innovative drug development and the clear recognition of change, the Guiding Principles re-emphasize "thinking based on risk assessment"! The author believes that "risk-based" is the core of the whole life cycle of innovative drug development, whether it is a small step or a big step, there must be a "risk-based" assessment awareness, objective assessment of changes to drug quality, clinical trial subject safety, clinical trial results of the possible impact, can not let the department's indicators assessment to influence the objective risk assessment! Following the risk assessment, the general principleof "General Principles" is clearly stated: "When pharmaceutical changes occur during clinical research of innovative drugs, the applicant shall follow the principles of risk assessment and scientifically assess the possible impact of the change in the light of the proposed clinical research phase of the change, the characteristics of the variety, the knowledge of the drug and the preliminary study of the change." The following points need to be slowly realized: 1) early clinical research stage changes are relatively frequent, but the key clinical research stage pharmaceutical changes should be carefully considered, pay attention to the convergence of data in multiple dimensions; 2) focus on the subject population, based on benefit-hazard analysis for scientific pharmaceutical changes; 3) small molecule variety changes relatively better control, high-end preparations need to be carefully changed; PS1: Significant changes are changes that are assessed to significantly affect 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 resultsPS2: General change s is a change that may have no significant impact on the quality of clinical samples, the safety of clinical trials and the bridgeability of the results of the trial, and the applicant may conduct relevant research at his discretionFor example, "significant changes" in API should focus on the impact of changes on the key physical and chemical properties of API (associated agents) and impurity behavior (associated quality), and the reasons for this change may be the following, namely, changes in production sites, changes in processes, standard changes, changes in packaging-storage, etcHere is an example of the significant changes listed in this Guiding PrinciplesExamples of significant changes in production sites include, but are not limited to, replacement or addition to production sites (except for changes to simple chemical synthesis small molecule production sites in the early clinical phase)Experience exchange: production site changes, mostly accompanied by equipment changes, in order to coordinate the degree of correlation between equipment and process, it is inevitable to adjust the processFor example, the size/material of the reactor changes and the contradiction between the amount/production, whether the oar/anchor meets the requirements of the stirring state, whether the cooling mode can control the reaction temperature range steadily, and so on.And these problems in the premise of site changes, it is easy or even certain to occur, and with the adjustment of the process, there will be a certain challenge to product qualityIn terms of example routes for significant changes, including but not limited to: 1) changes in the synthetic route, and may have a significant impact on the behavior of API impurities and key physical and chemical characteristics2) Change the preparation method (e.gchemical synthesis and fermentation process replacement, solid phase and liquid phase polypeptide synthesis replacement, etc.)Experience Exchange: Synthetic route changes, very troublesome.Not only will the synthesis side invest heavily, but the quality department also needs to cooperate with the intervention, and if early clinical trials are good, if the critical clinical phase has been reached, such a large change needs to be very careful! Conditions, including but not limited to: 1) production processes and parameter changes that may have a significant impact on API impurity behavior and key physical and chemical properties For example, changes in fermentation and extraction processes that may affect the quality of API (e.g changes in strains, changes in purification principles); 2) Change the sterilization process of sterile api Experience exchange: reaction conditions change, even under the condition of the constant route, impurity spectrum is bound to change (sometimes not detected does not mean non-existent), especially in the last step of the condition changes, to be carefully considered! And the raw material sedative crystallization conditions, crushing parameters change, must have quality control and preparation verification! Sometimes even small changes or current cognitive deficiencies, it is easy to have quality problems, even accidents! Examples of significant changes include, but are not limited to: 1) cutting key inspection items (refers to inspection items related to safety, effectiveness and quality controllability) 2) Relax the acceptable limits for key inspection items 3) Change the key inspection project analysis method (different principles) (e.g., the use of TLC method instead of HPLC method to determine the relevant substances, dry weightlessness instead of residual solvent inspection) Experience exchange: The guiding principles of the introduction of major quality standards examples, in fact, are a core issue, is the standard "put" First of all, the relaxation of the standard is conducive to the later quality inspection procedures and workload, but is the so-called "good harvest is not good to put", want to relax the standard, need a large amount of data accumulation proof and part of the interpretation of the work, to prove that "put" on the quality of the finished product is no problem! Therefore, this is a major change, there is no excuse! Examples of significant changes include, but are not limited to: 1) The altered packaging may interact with API (generally non-solid API) 2) Strict storage conditions due to safety reasons or the use of packaging materials/containers with better protection performance 3) Change seduing packaging materials or containers for the protection of performance degradation Experience exchange: for generic drugs, the final packaging storage is mostly fixed, but rarely change sit uin, but the innovative drug is different, is in the process to understand the variety, and constantly adjust Especially in the late clinical stage, many varieties have reached the production department, they are to consider the cost, will put forward a variety of cost reduction proposals, the author believes that, if there is not sufficient data support, do not easily in the final product operation, after all, or innovative drug stage, has not yet to the time of cost! Of course, special varieties are excluded For example, "significant changes" in preparations for formulation changes need to focus on the impact of changes on the performance of the drug preparation, safety-related indicators to carry out assessment and research The reasons for this change may be the following, i.e site changes, prescription changes, accessories-related changes, process changes, standard changes, packaging-related changes, formulation/dosage form changes, etc Here is a brief look at the significant changes in the Guiding Principles Examples of significant changes in site-to-site include, but are not limited to: addition or replacement of production sites (in the early clinical phase, except for general oral preparations using conventional prescription processes) Experience exchange: site issues, similar to raw materials, no longer repeated Examples of prescription-significant changes include, but are not limited to: 1) prescription changes that may have a significant effect on the quality of the preparation (e.g significant changes in key accessories type/model/dosage, etc.) 2) Changes (including replacement or addition) of injections come with a special solvent prescription Experience exchange: Prescription changes that may affect the functionality of the accessory or the process of preparation materials, which in turn affect the performance of the preparation, or may introduce new impurities or other safety hazards that affect the safety of the subject Such changes occur, if necessary, need to re-carry the raw material compatibility research, select appropriate preparation performance-related indicators, safety-related indicators for the prescription before and after the change of products to conduct a comprehensive quality comparison, as appropriate, to carry out stability studies, the external ingredients-related examples of major changes include, but not limited to: 1) changes may affect the performance of the preparation of the endothemetinternal control standards (e.g accessories granularity and distribution affect the preparation in vitro solute) 2) The preparation process and quality standardof of the new accessories have changed (reference to the corresponding parts of the API may be referred to for example of major changes) Experience Exchange: This kind of problem is similar to THE API, can refer to the API change assessment and research principles, the change support related research, not to repeat here Examples of significant changes include, but are not limited to: 1) changes in process principles (e.g replacement of dry and wet legal particles) 2) Change the process operation or parameters of key steps (e.g sterilization mode and parameter changes) Experience exchange: As mentioned above, the risk of introducing new impurities is very high, such as some sulfonate drugs, you have to be very careful about the genetic toxicity problem after the process change, and the change in the key step process, if it is "put", also requires clear quality data support, as well as the process verification process Examples of significant changes include, but are not limited to: 1) cutting key inspection items 2) Relax the acceptable limits of safety, preparation key performance-related testing items (e.g., relax impurity limits, relax the solubility limits) 3) Change the analytical principle of key inspection items (e.g., NIR instead of HPLC to determine content) Experience exchange: mainly quality standards "put" the problem, similar to raw materials, no longer repeated Examples of packaging-related changes include, but are not limited to: 1) The changed packaging container system may affect the accuracy of the dose of administration or delivery (e.g changes in the valve or drive of the dispenser) 2) Changes to protect the packaging container system for degraded performance 3) The changed packaging may interact with the formulation 4) Use a packaging container system with better protection for security reasons Experience Exchange: When the formulation packaging container system changes, the functional changes in the packaging container system after the change (protecting the function of the drug and the delivery of the drug function) and the possibility of interaction between the drug and the packaging material are fully assessed Changing the formulation packaging container system may affect the functionality of the packaging system and the stability of the preparation The degree of influence is related to the nature of the drug, the route of administration of the formulation, the characteristics of the prescription process of the dosage form, the expected function of the formulation packaging container system, and the possibility of interaction between the drug and the packaging material Examples of dosage form/specs- major changes include, but are not limited to, "high-end preparations" - the risk of the effects of the specification changes on the preparation is high Experience exchange: for the early clinical stage using conventional prescription process production of ordinary oral preparations, according to the original specifications of prescription and other proportion of the new specifications, such as preparation performance, safety-related indicators and stability did not change significantly, can be regarded as a general change, otherwise should be regarded as a major change; Summary above, that is, for the author in the study of the "guiding principles" on the basis of their own work experience to explore; But let go of the spirit of burden, which is from the innovative drug development of scientific, progressive, uncertain and other characteristics to explore these issues, developers in the promotion of varieties at the same time, or can not forget the compliance issue Don't clearly change but "hide" changes in various ways, clearly compliance but amplify risk-pushing projects Different point of view, comment area see .