Preliminary knowledge: promotion of pharmaceutical research on innovative drugs from phase I to phase III (preparation)
Last Update: 2020-06-19
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< br / > preparation technology has been affecting the quality of domestic drugs, not only generic drugs, but also innovative drugsIn the pharmaceutical research of class 1 new drugs, due to different purposes and requirements in different stages, the process and quality standards given are also different, and the core is not only "safety", but also "effectiveness" and quality controlThe domestic approval system makes the pharmaceutical research from phase I to phase III different, and the quality standard can be further improved at this stageThis manuscript is based on this summary as follows< br / > 1Dosage form and product composition < br / > phase III requirements: provide the prescription composition of unit dose of clinical samples, and specify the name, dosage, function and executive standard of auxiliary materialsIf premixed excipients are used, their composition shall be specified as much as possible for coating materials and capsule shellsThe ingredients used in the preparation but finally removed shall also be listedIf special solvent is attached, its composition shall be provided according to the above requirementsFor special preparations, clinical sample formulations and dosing devices should be similar to commercial products< br / > PS: compared with the requirements of phase I clinical pharmaceutical research, phase III emphasizes "clarifying the name, dosage, function and executive standard of excipients", and requires certain information for premixed excipients and special preparations (phase I is not explicitly required)The prescription and drug delivery device only emphasize to keep the similarity, and do not require consistencyHowever, I think that the enterprise still tries to be consistent as far as possibleAfter all, it is phase III< br / > 2Product development < br / > phase III requirements: brief description of dosage form, specification, prescription and process development processFor the preparation with high risk of drug package interaction (such as inhalation preparation, injection, ophthalmic preparation, oral solution, etc.), necessary compatibility research information (such as extractable, extractable, etc.) shall be provided For the products that need to be prepared on the spot, relevant research information of dilution compatibility stability and preparation method shall be provided For drug use in a specific population (such as children), the drug composition, dosage form and dosing device (if any) shall be safe and suitable for that specific population < br / > PS: pay attention to whether there are significant changes in dosage form, prescription, specification and production process If there are, bridging research content must be provided Meanwhile, for sterile preparations, if there are changes in sterilization process, the rationality of the changes should be explained The most concerned issue in this part is "change", which further reflects the development idea of pharmaceutical products with clinical safety as the core and supporting and serving clinical use Sufficient information should be provided and sufficient research should be made on the key quality attributes that may affect the clinical application effect < br / > 3 Production < br / > manufacturer < br / > phase III requirements: list all manufacturers' names and complete addresses related to clinical sample production (including production, packaging, inspection and release) If more than one manufacturer is involved, the responsibilities of each manufacturer shall also be listed < br / > PS: the same as the problem of API, one manufacturer usually can complete the sample supply of phase I clinical samples; when entering phase III clinical phase, the clinical sample supply work increases significantly (in case of encountering varieties with process difficulties...), it is easy to have multiple manufacturers jointly produce Therefore, it is necessary to provide information to all manufacturers for filing < br / > batch prescription < br / > phase III requirements: provide clinical sample batch prescription (indicate batch or batch range if possible), and list the name and dosage of each component If there is excessive addition, please give instructions The solvents used in the prescription but need to be removed finally should also be listed < br / > PS: after the completion of prescription screening, optimization, determination, small test, pilot test, transfer, etc., with the start of clinical sample supply, batch prescriptions will naturally form Here, it should be noted that after the completion of multiple batches of clinical sample batches, it is necessary to summarize at any time as much as possible, and it is better to form a report to facilitate the understanding of the prescription; at the same time, it is necessary to pay attention to the problem of change, and fully evaluate the level of change < br / > production process and process control < br / > phase III requirements: provide production process flow chart and process description of clinical samples, as well as relevant process control If unconventional production process is adopted, it shall be described in detail For sterile preparations, more detailed sterilization process and process control shall be provided < br / > PS: the content of this part is the conventional requirements for the production process Compared with the NDA declaration, the description of the production process, including the necessary process control requirements, still allows enough flexibility, so as to smoothly connect in the subsequent product development, scale-up and the completion of commercial production The process flow chart and process description are completed at the time of initial phase I clinical application, but process control is not strongly required After all, phase I clinical samples are required to "provide qualified samples"; sterile preparations are only required to provide assurance measures in phase I; rather than conventional production processes, Generally, it is necessary to determine whether it is an unconventional production process by combining the properties of APIs, preparations and process itself, which requires the applicant to have an in-depth understanding of the product characteristics and process objectives to be applied for < br / > control of key steps and intermediates < br / > phase III requirements: if the key steps of production have been determined, the control range of process parameters of key steps shall be provided; if the preparation intermediates have been controlled, the standard shall be provided For the preparation intermediates, if they need to be stored, the storage conditions and storage time shall be specified, and supporting research results shall be provided if necessary < br / > PS: generally, key intermediates are determined comprehensively according to product characteristics and process conditions Quality standards and inspection control are required for key intermediates In phase I, the requirements for intermediates are relatively low, with the focus on finished products However, in phase III, for key process parameters and key intermediates, it is better to form standards and control, which is conducive to the later NDA < br / > process validation / evaluation < br / > phase III requirements: generally, process validation information is not required If unconventional production process is adopted, sufficient information shall be provided to evaluate the stability and controllability of the process If unconventional sterilization process is adopted, sufficient information shall be provided to evaluate the sterility assurance level of the product < br / > PS: similar to the research mode of API, the corresponding process of phase I ~ III clinical samples of new drugs is in the confirmation stage as a whole Due to the limitation of production batches and batches, few of them can enter the verification stage Of course, if there are enough batches and large enough batches, process validation can be formed, which is the best for pharmaceutical research However, schedule and cost shall be considered < br / > 4 Excipients control < br / > phase III requirements: if the excipients used are in accordance with the pharmacopoeia standard, the manufacturer, basic information (such as model, source, component, etc.) and specific Pharmacopoeia standards (such as CHP, USP and EP) shall be listed Ph.Eur , Japanese Pharmacopoeia JP, etc.) If the auxiliary materials used are in accordance with other industry standards or enterprise standards, the specific standards shall be listed and the methods adopted for main projects shall be described For new excipients that have not been used in preparations at home and abroad, relevant information shall be provided or related declaration shall be made in accordance with related declaration requirements For human / animal derived excipients, it should be declared that there is no safety risk < br / > PS: the problem of excipients has been one of the important factors that have seriously restricted the development of domestic preparations Not only at home, but also globally, the attention of excipients has increased over the years For innovative preparations, it is very likely to use new excipients that have not been used in preparations at home and abroad At this time, it is necessary to provide relatively complete information in accordance with the related declaration requirements to ensure the safety and effectiveness of the new excipients In principle, the use of new excipients should be declared at the time of clinical application < br / > 5 Quality control < br / > Quality Standard < br / > phase III requirements: provide release standard and shelf-life standard (if applicable) of the preparation in the form of a table, including test items, methods (only the method types, such as HPLC method) and tentative limits Generally, the detection items should at least include identification, degradation products and content determination In addition, it should also include specific examination items and limit requirements for dosage form (such as dissolution / disintegration time limit of oral solid preparation, content uniformity test, pH value of injection, bacterial endotoxin and sterility test, etc.) If special solvent is attached, the quality standard of special solvent shall be provided < br / > PS: phase I requirements are relatively loose, only the preliminary quality standards are required Explain the acceptable limits, analysis methods and representative Atlas of inspection items However, in phase III, it is usually necessary to provide specific analytical methods for the main control items listed in the quality standards; if chromatographic methods are used, it is often necessary to clarify the chromatographic conditions, including column type, mobile phase system, elution procedure, detector type and parameters, etc < br / > analytical method < br / > phase III requirements: provide specific analytical method (if chromatographic method is used, chromatographic conditions shall be specified) < br / > PS: in phase I, only suitable quality control items and analysis methods are required according to the dosage form and product characteristics However, by the end of phase III, the guidelines have clearly required analytical methods, which must be specific < br / > validation of analytical methods < br / > phase III requirements: summarize the validation results of methodology in the form of tables, and provide typical atlas If Pharmacopoeia method is selected, confirmation information on applicability of Pharmacopoeia method shall be provided < br / > PS: phase I requires that in the early stage of drug development, it is not necessary to submit comprehensive and complete validation data of analytical methods, but at least provide validation information of key items such as specificity and sensitivity of methods In phase III, the analysis method should be verified accordingly However, due to different applicant's R & D and registration application strategies, some enterprises may not carry out systematic methodology verification before entering the clinical phase III trial, only part of the verification information < br / > batch analysis < br / > phase III requirements: update the batch analysis summary, including non clinical safety study batches (if necessary), phase I / II clinical sample batches, stability batches and batches that can represent phase III clinical samples The batch number, batch number, prescription process (available in the form of code), production place, production date, purpose, analysis method (available in the form of number or version number), control limit and measured results shall be indicated Provide the test report that can represent the phase III clinical sample batch < br / > PS: in phase I, it is required to provide the test report of key research batches (such as safety research, stability research, clinical research, etc.), but in phase III, it is required to summarize the information of all previous key batches, especially the registration related and clinical related batches, so as to form a large summary, which can clearly understand the stability of the process and the overall trend of impurities < br / > impurity < br / > phase III requirements: provide impurity information existing in the preparation but not covered under s.3.2, including impurity name and / or code, structure, degradation path, safety support limit, etc For the impurities beyond the identification limit that have not been clarified in the structure, it is also necessary to provide information such as relative retention time, whether it is used as specific impurity control in the standard, safety support limit, etc < br / > PS: in phase III, the impurities that exist and are not listed in the API should be supplemented first Here, the most important is degradation related impurities Based on the in-depth study of degradation pathway, it is convenient for applicants and reviewers to fully understand various degradation impurities including potential degradation products, and it is also easier to define the safety support limit of various degradation impurities Even for the specific impurities with unknown structure, special attention should be paid to collect relevant information, such as the relative retention time under different chromatographic conditions, whether it is used as specific impurity control in the standard, safety support limit, etc < br / > basis for quality standard formulation
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