With the gradual implementation and enforcement of China’s new Drug Administration Law and its related guidelines, higher requirements have been placed on the comprehensiveness of the research work involved in the entire process of drug development. Through understanding and analyzing the instances of hairpinning encountered in the course of our work, we found that such defects generally present common features. We have summarized the possible hairpin content that may be encountered during the NMPA registration process for APIs in the order in which the declarations were prepared. (Please note that, in view of the review process is often affected by a variety of factors, so for the same problem may appear in different teachers review the different scales, the content of this paper is for reference only, if you have a specific project problems, please contact us.)
Typical defect 1: Certification documents do not meet the requirements
Not provide overseas approval listed certificate of imported APIs and GMP compliance certificate, or has provided the certification documents are defective. Such as notarized certification, or the certificate has expired, or address information is inconsistent.
General Requirements:
The following combinations are available for certificates:
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- WHO format CPP
- Non-WHO format CPP + GMP (notarized certification)
- CEP+GMP (notarized certification)
- FSC + GMP (notarized certification)
- API’s DMF number + GMP + CPP of the formulation produced using the API (notarized certification)
- GMP/compliance with ISO9000 quality management system documents + proof of permission to market and sell (only for foreign chemical APIs managed as food)
- Other available documents
What needs to be paid attention to: Is the CPP in paper or electronic version? If it is a paper original and meets the WHO format and other requirements, it does not need to be notarized; if it is a paper copy, it needs to be notarized and certified; electronic CPP (eCPP) can not be notarized and certified, but it needs to be provided with validation information. GMP needs to be notarized and certified. Some CPPs contain GMP information, and can be submitted without GMP certificate, but need to state that the CPP already has GMP-related information.
Typical defect 2: Insufficient basis for the selection of starting materials, some varieties of the declared route is too short, and the selection of starting materials is unreasonable.
General requirements:
Based on the consideration of full control of drug quality from the source, the applicant should refer to ICH Q11 and the relevant technical requirements of the European Union to reasonably select the starting materials, combined with the understanding of the production process to reasonably determine the production steps under GMP conditions, provide the relevant supporting research data on the selection of starting materials, and reach a consensus with the drug review body. If there are multiple manufacturers of the same starting material, the corresponding quality control requirements should be formulated in conjunction with the preparation process adopted by the manufacturer.
The declared process should cover all the synthesis steps that have a critical impact on the safety or / and efficacy. For example, the use of genotoxic substances or the generation of the step, affect the stereochemistry of the API step. The starting materials for complex chemical synthesis should be combined with their sources, physicochemical properties and production processes, etc., to formulate reasonable starting quality standards, and provide supplier audit reports, combined with information on the actual process provided by the supplier, to clarify the toxic reagents/solvents etc. introduced by the production process, and to further strengthen the analysis and control of impurities.
Typical defect 3: Insufficient structure confirmation study, insufficient to prove the structure of the compound
General requirements:
Some imported APIs are too simple for structural confirmation, often only IR, NMR (1H NMR 13C NMR), mass spectrometry and PXRD; lack of elemental analysis (or elemental analysis of the structure of a large deviation), thermal analysis, as well as for the three-dimensional configuration and specific crystalline research information. According to the Circular on Technical Requirements for Pharmaceutical Research and Evaluation of Chemical Drugs Listed Overseas and Not Listed in China (for Trial Implementation) (No. 21 of 2021), the applicant may analyze the chemical structure of the API comprehensively by combining the process route and various analytical testing methods. For APIs that may be combined with stereo configuration, polycrystalline type, water of crystallization and/or solvent of crystallization, etc., it is recommended to adopt suitable analytical test methods to confirm the structure.
Typical defect 4: Inadequate analysis of the impurity profile of APIs; insufficient detection capability of the analytical method of the substance concerned; insufficient basis for impurity control and limit formulation.
General requirements:
The applicant should refer to ICH Q3A and other relevant guidelines for impurity research, comprehensively analyze the source of impurities, conduct removal and transformation studies, reasonably formulate the control strategy, and provide complete information and data on impurity profiling. At the same time for long-term and accelerated test degradation of impurities beyond the identification limit of attribution research, attention to the impact of factors under the test conditions of the degradation of impurities research, enhance the understanding of the degradation pathway, and develop a reasonable limit.
In other words, for the analysis and control of impurity profiles, the applicant can comprehensively analyze potential impurities and sources of impurities in conjunction with the API’s production process, reaction mechanism, structural features and their degradation pathways, pharmacopeial standards and/or other literature. For organic impurities, the establishment of the corresponding analytical method and the use of the corresponding impurity control for systematic validation of the analytical method, to prove that the analytical method used is indeed effective in detecting the corresponding impurities; for residual solvents, the establishment of the corresponding GC method and validation; for inorganic impurities, the establishment of the corresponding control items (eg, heavy metals, etc.) Here, it is necessary to pay attention to the adequacy of the study of the process control, and whether there is a Continuity.
Typical defect 5: Incomplete assessment and study of potential mutagenic impurities in APIs, and imperfect control strategy.
General requirements:
The applicant should refer to ICH M7 and S9 to carry out research on mutagenic impurities and formulate a reasonable control strategy. The assessment of impurities should be comprehensive, including process impurities and degradation impurities that may exist in the starting materials, intermediates, reaction by-products, solvents or reagents in the process route. Except for the impurities for which sufficient toxicity data are available and conclusions can be drawn based on references, please note that literature search, database search, etc. cannot be a simple substitute for software evaluation. For mutagenic impurities, scientific and reasonable detection methods should be explored when necessary, and the sensitivity of the methods should match the purpose of the test and the limits of the impurities demonstrated. Risk control strategies and the basis for limit setting should be provided.
Typical defect 6: Incomplete control of quality standards for APIs; unreasonable limit setting or insufficient basis for limit setting
General requirements:
The applicant should refer to ICH Q6A and other relevant guidelines to establish product quality standards. Based on the structure of the API type, key quality attributes to establish the quality standards of APIs, where the main special attention should be paid to a few control items such as the existence of some APIs crystal shape, salt formation ratio, particle size and particle size distribution, related substances, isomers impurities, etc. These items need to be controlled. The applicant should conduct a comparative study of pharmacopoeial methods, to determine reasonable analytical methods, with reference to the ICH guidelines for the development of reasonable acceptable limits of API quality standards, and according to historical batch test data, with reference to the stability of the study data to prove the limits of quality standards. In addition, quality standards for APIs for injection should generally include microbiological limits and bacterial endotoxin checks.
Typical defect 7: Controls
General requirements:
In addition to quality standards and COA, working controls used for content determination should be provided with a calibration assignment process; or homemade impurity controls should undergo the necessary structural confirmation.
Typical defect 8: Omission of key inspection items in the stability study
General requirements:
When submitting an application for registration of APIs, the applicant should generally provide 3 batches of samples 6 months accelerated test and not less than 6 months long-term test stability study information (including typical charts). If a specific crystalline API is specified, failure to examine the crystalline form in the stability study will also result in hair fill; for liquid APIs, the applicant should carry out package compatibility studies.
References:
[1] Circular on Technical Requirements for Pharmaceutical Research and Evaluation of Chemical Drugs Listed Outside China and Not Listed in China (for Trial Implementation) (No. 21, 2021) (cde.org.cn)
[3] Circular of the Drug Review Center of the State Drug Administration on the Publication of the Circular on Common Issues in Pharmacology and Related Technical Requirements for Pre-meeting Pharmacy of Phase III Clinical Trials of Innovative Medicines of Chemical Drugs (Trial) (No. 23 of 2023)(cde.org.cn)
[4] Technical Guidelines for Preparation and Structure Confirmation Studies of Chemical Drug APIs (cde.org.cn)
