The official website of CDE publishes answers to 28 common questions about chemical generics, so let’s learn together on the weekend!
1. Question: What factors need to be considered when studying and controlling the particle size of the API used in the registration application for generic oral solid preparations of chemical drugs?
Answer: The particle size of the API may affect the key quality attributes and/or in vivo bioavailability of the API, etc., and the applicant should comprehensively consider the physical and chemical properties of the API and the influence on the production process and dissolution behavior of the preparation, as well as in vivo studies to formulate the control strategy of the particle size of the API. In general, for APIs with poor solubility (e.g., low solubility drugs), reasonable particle size control standards (e.g., control of D10, D50, D90, etc.) of API particle size distribution should be formulated based on the research on the influence of API particle size on the dissolution behavior of the preparation, as well as the actual particle size of the API used in key batches (e.g., BE test batch and process verification batch) to ensure the consistency of the quality of the preparation within and between batches. For APIs with good solubility (e.g., highly soluble drugs), if the research and validation are sufficient, the particle size of such APIs can also be controlled by grinding process parameters. For formulations with smaller sizes (or a low proportion of the API by weight in the formulation), the effect of the particle size of the API on the homogeneity of the mixture in the production of the formulation should also be considered. 2023-12-14
2. Question: What information should be provided if there is temporary storage of intermediates in the chemical production process?
Answer: The specific conditions, time limit and supporting research data of the temporary storage of intermediates should be provided, and the specific research should be combined with the characteristics of the dosage form, the characteristics of the process, the temporary storage time, etc. Pay attention to the rationality and comprehensiveness of the indicators. 2023-12-14
3. Question: Is it necessary to provide batch production records of actual production samples for the supplementary application for the application of generic chemical drugs, consistency evaluation and pharmaceutical changes?
Answer: Considering that the batch production records record more detailed process parameters, and the “Technical Guidelines for Pharmaceutical Change Research of Listed Chemicals (Trial)” clearly requires that batch production records of a batch of samples be provided for multiple medium and major changes, it is recommended to provide batch production records of representative batches (such as BE batches, clinical trial batches, etc.) when applying for supplementary applications for generic chemical drugs, consistency evaluation and pharmaceutical changes, which will help support the evaluation of process feasibility. 2023-12-14
4. Question: What should I pay attention to when comparing the similarity of the proportion of multi-specification prescriptions for chemical drugs?
Answer: (1) The similarity of the proportion of preparation prescriptions in the “Study on Human Bioequivalence of Chemical Drug Generic Drugs with Pharmacokinetic Parameters as Endpoint Evaluation Index” includes “the composition ratio of all active and inactive components is similar between different specifications”, which is recommended to pay attention to. (2) Highly active drugs generally refer to the content of active ingredients accounting for <5% of the core and capsule contents, and the active ingredients here should include all groups of the compound (for example, the active ingredient of amlodipine besylate tablets should be calculated based on amlodipine besylate). 2023-12-14
5. Question: How to carry out relevant research work on solvent recycling in the production process of APIs?
A: First, the risks that may be introduced by solvent recycling should be analyzed, such as the residue and accumulation of solvent-related impurities and impurities that may be introduced by the reaction steps using this solvent, with special attention to the study of uncontrolled impurities in the intermediate quality standard. Secondly, strict quality standards for recovered solvents should be formulated based on risk analysis and research to provide a basis for the formulation of standard limits. If recycled solvents must be used, the rules and rounds of recycled solvent use should be clarified and corresponding research and verification data should be provided, and it is recommended that recycling should only be carried out within the steps used. It is not recommended to use recycled solvents in the finished product refining step. 2023-12-14
6. Question: What are the concerns in the research on the filling quantity and quality standard in the inhalation solution production process?
Answer: It is recommended to conduct a comparative study on the pouring volume of the self-made preparation and the reference preparation in combination with the clinical use method (such as pouring into the atomizing cup) to determine the reasonable filling volume of this product, and add a reasonable loading standard with upper and lower limits to the quality standard. 2023-12-14
7. Question: Is it necessary to review the dissolution curve of a chemical generic based on an ICH M9 exempt bioequivalence study with the reference preparation during registration inspection?
Answer: For the registration test of the above conditions, multiple batches of self-made preparations and reference preparations should be compared and reviewed in vitro dissolution curves in a variety of dissolution media. 2023-12-14
8. Question: What are the common problems of chemical generics for oral solid preparations on dissolution curves?
Answer: The research on the dissolution curve of oral solid preparations of chemical generic drugs should be carried out with reference to the “Questions and Answers on the Study of Dissolution Curves of Pharmaceutical Changes of Listed Chemicals (Trial)”, and pay attention to the following common problems: (1) It is recommended to select a variety of dissolution media for comparison according to the requirements. In addition to the standard medium, it is usually not recommended to add surfactant to the rest of the media, and the dissolution curve research data without surfactant should be provided;(2) In addition to the standard medium, it is usually not recommended to adjust the speed of the rest of the media;(3) If it is proved that the drug is spec-dependent, the dissolution curve of different specifications can be compared at the same dose;(4) The similarity should usually be calculated using all sampling point data, and the data should not be selected (for example, skipping the data of a sampling point and selecting the following sampling point data), and at the same time, it should meet the requirements of calculating the similarity and demonstrate its reasonableness;(5) When using the non-model-dependent similarity factor method to calculate the similarityAfter the dissolution of more than 85% of the two samples or the plateau is reached, the subsequent sampling point data will not be calculated. (6) It is recommended to evaluate the inter-assay consistency (e.g., f2) and intra-assay uniformity (e.g., RSD) of self-made preparations. 2023-12-14
9. Question: What should be the dissolution range of chemical generics at each time point of the extended-release formulation?
Answer: Referring to the Technical Guidelines for Pharmaceutical Research of Oral Sustained-release Preparations of Chemical Drugs, the range of sustained-release preparations of chemical generic drugs should generally not exceed 20% (i.e., ±10%) at each time point. In some cases, the deviation can be appropriately relaxed to less than 25%, and if the limit is exceeded by 25%, it may affect the in vivo behavior of the product, and it is recommended to conduct a bioequivalence test to verify the bioequivalence between the upper and lower limits. Even if the control scope of the reference preparation is broad, the generic preparation should be strictly required according to the guidelines. 2023-12-14
10. Question: How can the control limits of ICH Q3C be justified for solvents that do not have sufficient toxicological data?
Answer: ICH Q3C clarifies that for new solvents, “the supporting safety data for their marketing application shall be in accordance with the impurity control principles described in these guidelines or the API Guiding Principles (Q3A, impurities in new drug substances) or formulation guidelines (Q3B, impurities in new drug formulations), or both”. Therefore, in the absence of reliable solvent safety evaluation studies, reasonable control limits should be formulated with reference to relevant guidelines such as ICH Q3A, Q3B and M7. 2023-12-14
11.问题：How to conduct elemental impurity studies for chemical generic drug preparations?
Answer: It is recommended to establish a feasible method (the analytical method needs to be validated) with reference to the requirements of ICH Q3D, to analyze, evaluate and study the elemental impurities in chemical generic drug preparations, and to formulate a reasonable control strategy based on the research results. 2023-12-14
12. Question: Is there a need for research and control of aluminium for total parenteral nutrition (TPN) large volume injections?
Answer: Aluminum has certain nephrotoxicity, so it is necessary to study and control the aluminum element in total parenteral nutrition (TPN) large-volume injection, and set a registration standard, and the control limit is not more than 25μg/L. 2023-12-14
13. Question: If there is no change in the pharmaceutical part of the re-declared chemical generic, can the registration test report of the previous declaration be used?
Answer: For chemical generics that have not been approved for non-pharmaceutical reasons and re-declared, if there is no change in the pharmaceutical part, the applicant can use the first registration test report for the re-application application, and the review process can consider whether it is still necessary to conduct a review test according to the actual situation (such as adding or revising or the original test report raises questions that need to be improved). 2023-12-14
14. Question: At present, cephalosporins and penicillin antibiotics are mostly prepared by enzymatic process, what aspects should be paid attention to in the research of potential mutagenic impurities in APIs?
Answer: Combined with the synthesis process of APIs and starting materials, a comprehensive analysis and study of potential mutagenic impurities should be carried out, and a reasonable control strategy should be formulated with reference to ICH M7 and other guidelines. Combined with the composition of the immobilized carrier provided by the manufacturer, the potential mutagenicity impurities (such as glutaraldehyde) introduced into the finished product should be analyzed and studied. In addition, if there is a possibility of multiple lifetime doses, the impurity limit should be calculated using the acceptable intake shorter than the lifetime dose, and the duration of treatment should be reasonably determined with reference to relevant guidelines. 2023-12-14
15. Question: What are the specific requirements for the writing of microbial limit test methods for drugs with antimicrobial activity (e.g., antibiotics and other antimicrobial drugs, etc.) that need to be included in the quality standard for microbial limit testing?
Answer: It is recommended to describe the test method in detail in the quality standard according to the verification results of the method applicability test, and clarify the removal, neutralization or inactivation method of antibacterial activity, the preparation method of the test solution, etc., if the membrane filtration method is used, the type, dosage and number of rinsing solution should be clarified, so as to ensure the operability of the test method. 2023-12-14
16. Question: What are the common problems with chemical stability studies?
Answer: (1) The stability investigation plan was not designed in accordance with ICH Q1 and the Technical Guidelines for the Stability Research of Chemical Drugs (APIs and Preparations), and the test design was unreasonable, such as: (1) only long-term tests were carried out without accelerated tests, (2) the long-term stability test was carried out at 20°C without basis, (3) the liquid preparations using semi-permeable packaging materials were not investigated under low humidity conditions, and (4) the investigation conditions were not comprehensive, such as the humidity was not clarified. (2) The sampling point is not designed according to the stability investigation plan, such as the sampling point is not designed for 3 months in the long-term test. Sampling points specified in ICH Q1 and the Technical Guidelines for Stability Studies of Chemical Drugs (APIs and Preparations) must be sampled, and on this basis, individual time sampling points can be added according to the needs of the study, but they cannot be replaced or changed at will. (3) The stability investigation and study was not carried out with reference to the storage conditions of the reference preparation, such as the storage conditions of the reference preparation were stored at room temperature or below 30 °C, and the imitation product was only used at 25 °C for long-term stability test. For this category, a long-term stability test should be performed at 30°C. 2023-12-14
17. Problem: The problem that needs to be paid attention to in the stability study of chemical generics in use
Answer: The in-use stability study is to investigate the stability of the drug after the package is opened, and provide data support for the use period and storage conditions of the drug after the package is opened. Multi-dose packaged drugs, or drugs with a protective secondary package, should be studied for in-use stability. The packaging form of the test sample should be consistent with the packaging to be marketed. If different sizes of packaging or different specifications are declared at the same time, the in-use stability study should be carried out with the packaging or specification with the highest exposure risk and the most sensitive to time changes, and sufficient basis for selection (including necessary test data) should be provided. As far as possible, the actual clinical use should be simulated or more harsh conditions should be used, and the investigation period should fully cover the longest clinical use cycle. Simulation operations should be carried out at the corresponding interval time points with reference to the usage methods specified in the instructions and combined with the actual clinical use. The index should reflect changes in the quality of the sample, i.e., those that are susceptible to changes during placement that may affect its quality, safety, and/or validity, and should cover physical, chemical, biological, and microbiological properties. The corresponding inspection indicators should be set according to different dosage forms. The test plan should be formulated and the test results should be analyzed and evaluated with reference to the instructions of the reference preparation and the characteristics of the self-made samples to determine whether it is necessary to indicate the expiration date and storage conditions after the opening of the package in the instructions and labels. If there are abnormal results, reasonable analysis and interpretation should be carried out. 2023-12-14
18. Question: What should be paid attention to when changing the dosage of excipients that may affect absorption in the general oral solid preparation of marketed chemical drugs?
Answer: Mannitol or sorbitol may be added as a filler and surfactant (such as sodium dodecyl sulfate) as a solubilizer in the preparation of ordinary oral solid dosage forms, because the above excipients may affect the absorption of the drug, and the dosage of ICH M9 is managed separately. It is recommended to refer to ICH M9 when changing the dosage of mannitol, sorbitol and surfactant in the general oral solid dosage of marketed chemical drugs, and strict requirements. 2023-12-14
19. Question: Can the change of sucrose in ordinary oral preparations to flavor be classified as a medium change according to the type of flavor change?
Answer: The dosage of flavor correction in the preparation is small (generally no more than 2%), and the risk caused by its change is also small, so the “Technical Guidelines for Pharmaceutical Change Research of Listed Chemicals (Trial)” classifies the change of flavor correction as a minor change or medium change. The dosage of sucrose in ordinary oral preparations is generally relatively large, and sucrose may have the effects of fillers and binders in addition to the role of flavor correctors, so sucrose should not be managed according to the flavor dresser, and the change of sucrose in ordinary oral preparations to flavor belongs to the type of change of excipients, which is a major change. 2023-12-14
20. Question: Changing povidone K30 to povidone K90 in ordinary oral solid preparations is a change in the technical grade of excipients or a change in the type of excipients?
Answer: The molecular weight and viscosity of povidone K30 and povidone K90 are quite different, and changing povidone K30 to povidone K90 in ordinary oral solid preparations should be a change of excipient type. 2023-12-14
21. Question: How to change the classification of the dosage of the excipients of the common oral solid preparations of the listed chemical drugs?
Answer: It is recommended that each layer of the double-layer sheet be counted separately as an independent piece, and the change of the amount of excipients in each layer is within the range of minor changes, which is a minor change, the change in the amount of excipients in each layer is within the range of medium changes, which is a medium change, and if it exceeds the medium change, it is a major change. If the change classification of the two layers is inconsistent, the highest change classification shall prevail. 2023-12-14
22. Question: What are the requirements for changing the dosage of excipients for oral sustained-release/controlled-release preparations and enteric-coated preparations of marketed chemical drugs?
Answer: The Technical Guidelines for Pharmaceutical Change Research of Listed Chemical Drugs (Trial) put forward requirements for the sum of changes of all excipients for ordinary oral solid preparations, but did not put forward relevant requirements for oral sustained-release/controlled-release preparations and enteric-coated preparations All excipient changes do not exceed 10% of the total weight of the original approved prescription, which is a moderate change, and more than a medium change is a major change. 2023-12-14
23. Question: Does the specific surface area be considered when changing the dosage of excipients for enteric-coated preparations with enteric coating mechanism of chemical drugs that have been marketed?
Answer: The specific surface area of the enteric-coated preparation with the enteric coating mechanism has a great influence on the dissolution behavior of the enteric-coated preparation, and the specific surface area of the enteric-coated preparation can be considered when changing the dosage of its excipients. 2023-12-14
24. Question: Is it necessary to verify the production process to change the production batch of a chemical that has already been marketed?
Answer: The production process should be verified for changing the production batch of a chemical that has already been marketed. 2023-12-14
25. Question: What should be paid attention to in the comparative study of pharmaceutical quality when the prescription process (including the source and model of structural and functional ingredients), production batch, and production site of special injections (such as liposomes, nanoparticles, micelles, intravenous milk, microspheres, etc.) change after marketing?
Answer: Compared with ordinary preparations, the prescription process of special injections is complex and more sensitive to pharmaceutical changes. Based on the characteristics of the preparation and product characteristics of the special injection, the impact of the changes on its pharmaceutical quality, safety and efficacy should be fully evaluated, and the content and depth of the quality comparison study before and after the changes should be determined. In addition to the items specified in the quality standards, the comparative study of pharmaceutical quality should also cover the key quality attributes related to the properties of particles, as well as the comparative study of physical and chemical stability. Key quality attributes related to particulate properties include, but are not limited to: particle size and particle size distribution, morphology and structure, surface potential, thermodynamic properties, drug loading, encapsulation efficiency, drug presence form and state, in vitro release and leakage, etc. It is recommended that critical batches (e.g., critical clinical lots, etc.) be used for data comparison before and after the change. For cases where the degree of impact of the change cannot be determined or the pharmaceutical quality attributes are significantly affected by the change, non-clinical safety studies, human bioequivalence studies and/or clinical studies are also required. 2023-12-14
26. Question: Problems related to the application of multi-dose liquid preparations and semi-solid preparations to increase the filling volume under the condition of constant concentration
Answer: Should the application for increasing the loading volume of multi-dose liquid preparations and semi-solid preparations under the condition of constant concentration be declared in accordance with the increased specifications or in accordance with the increased packaging specifications? According to the Guidelines for the Writing of Pharmaceutical Information on Instructions and Labels of Chemical Drugs (Trial), multi-dose liquid preparations and semi-solid preparations (including but not limited to oral solutions, oral suspensions, oral emulsions, creams, ointments, gels, etc.) should contain the loading information in the specification statement. Loading: Active ingredient content” should reflect the actual loading, not just the concentration information. For multi-dose liquid preparations and semi-solid preparations, the application for increasing the filling volume under the condition of constant concentration should be declared according to the increased specification rather than according to the additional packaging specification, and the reasonableness of the specification should be paid attention to. 2023-12-14
27. Question: What problems need to be paid attention to in the study of the disintegration time limit of sildenafil citrate oral disintegration tablets?
Answer: For oral disintegration tablets, the disintegration time limit is a critical quality attribute. The current edition of the Chinese Pharmacopoeia contains a device dedicated to the time limit check of oral disintegration tablets, which is unique to the Chinese Pharmacopoeia. Sildenafil citrate oral disintegration tablets were included in the British Pharmacopoeia (BP), and the disintegration time limit was studied using a common disintegration time limit device. When conducting the study of the disintegration time limit of generic drugs, it is recommended that the special device for the disintegration time limit of oral disintegration tablets of the Chinese Pharmacopoeia is preferred for the comparative study of generic drugs and reference preparations, which should meet the limits specified in the appendix of the Chinese Pharmacopoeia. If the ordinary disintegration time limit device is used for disintegration time limit inspection, it is recommended to use the two devices at the same time to conduct a comparative study of generic drugs and reference preparations, record the disintegration time and phenomenon in detail, explain the basis for not using the special disintegration time limit device for oral disintegration tablets in the Chinese Pharmacopoeia, and formulate a reasonable limit. 2023-12-14
28. Question: How should the compatibility stability and compatibility test of resorroglucinol injection and infusion pipeline be studied, and what are the issues that need to be paid attention to?
Answer: Please use the near-term samples or the samples at the end of the stability investigation to carry out the compatibility stability test (which should include the minimum and highest concentrations) according to the latest instructions for resorcinol injection (such as passing the consistency evaluation or according to the new four approved varieties), and conduct compatibility tests with infusion pipelines of different materials. The investigation items should include trimethylresorcinol content, and the compatibility and stability study with glucose infusion should also be examined with 5-hydroxymethylfurfural and methodological verification data. If necessary, conduct a systematic and comprehensive comparative study with the reference preparation. 2023-12-14
