Summary of reissued materials by the Review Center

Requirement 1: The internal control standard shall not be lower than the national and international pharmacopoeia standards

Q1.

Raw material internal control reporting standards not available in pH control should be based on batches of data, increasing the pH control

Q2.

In the original application materials, the internal control standard of raw materials is free of arsenic, and the control of arsenic should be increased based on multiple batches of data

Q3.

The content limit of the internal control standard of raw materials in the original application materials is wider than that of BP , and the content limit should be tightened based on multiple batches of data

Q4.

The internal control standard of raw materials in the original application materials does not have impurity D control, and BP controls according to the single item of known impurity, and the impurity is an isomer

Q5.

Tighten the control limits of unknown single impurities and total impurities in the internal control standards of raw materials, not lower than the limits of the current national pharmacopoeias, and increase the solution clarity and color check items

Requirement 2:Relevant requirements in methodological research

Q1.

For known impurities controlled by the self-control method, a correction factor should be provided

Requirement three:Genotoxic impurities research

Q1.

According to the synthetic process route of the API, and through the corresponding software evaluation, literature search and chemical property analysis of the compound, according to ICH M7 , the type and structure of genotoxic impurities (mainly by-products and isomers) that need to be controlled are proposed, and the possible existence The development of analytical methods and control strategies for genotoxic impurities (including potential genotoxic impurities)

Requirement four:Study on the Impurities of Optical Isomers

Q1.

According to the structure of the starting material, determine the optical isomer impurities that may be introduced, develop analysis methods as known impurities, and establish control limits

Requirement five:Impurity profile analysis

Q1.
  Please improve the impurity spectrum analysis and control

Combining the acceptance of the API of this product in the domestic and foreign pharmacopoeias, as well as the synthesis process route, structural characteristics, degradation pathways, and starting material synthesis process of this product, conduct impurity profile analysis (including impurities, intermediates, and by-products introduced by the starting material) , Residual solvents, metal impurities, degradation impurities, etc.
)
.
For organic impurities, establish the corresponding analysis method and use the corresponding impurity reference substance to systematically verify the analysis method to prove that the analysis method used can indeed effectively detect the corresponding impurities; for the residual solvent, establish and verify the corresponding GC method; For inorganic impurities, establish corresponding control items (such as heavy metals, etc.
)

Requirement six:ICH Q3A Impurity Control Limits

Q1.
  Please conduct related substance research in combination with impurity spectrum analysis, conduct qualitative research on unknown impurities in the API that exceed the identification limit, and establish reasonable limits in combination with necessary safety analysis;At the same time, the limit for other single impurities is strictly limited to 0.
1%
.

Original dossiers API fails to ICH Q3A conduct research and impurity control should be in accordance with ICH Q3A research and control, namely in the identification of unknown single hybrid control below the limit, otherwise the limit by more than identified impurity identification studies and develop reasonable limits
.

Requirement Seven:Whether the analysis method is appropriate

Q1.
The  raw material impurity A has been increasing during the stability investigation, and it was close to its control limit at 6 months
.
It is suggested that the detection method of the raw materials is not very suitable (mainly the solvent system), please carry out the description of the system
.

Because the solvent system affects the stability of the test product solution, which leads to an increase in impurity A , rather than the stability of the raw material itself, the detection method should be modified and corresponding methodological research should be carried out
.

Requirement eight:Preparation requirements for API control (such as raw material particle size control)

Q1.
  Please formulate the particle size control requirements of the raw materials of this product according to the particle size of the raw materials used in the BE test batch samples and other process verification batch samples, and make it clear in the process description
.
Supplement the inspection method verification of the raw material particle size and the particle size stability check
.

The particle size of the raw material drug in the original application materials was not controlled.
Because of the BE batch samples and process verification batch samples, the particle size control requirements of the raw materials were formulated, and the particle size detection method was established and verified
.

Requirement Nine:Bulk drug testing items or results difference requirements

Q1.
  There are differences in the control items for residual solvents between the API manufacturer standards and the self-inspection standards provided.
Please explain why
.

The in-factory inspection is in accordance with the content under the Chinese Pharmacopoeia for residual solvents, which leads to inconsistencies with the supplier’s factory inspection content.
It should be consistent with the supplier’s internal control standards, because the residual solvent is related to the supplier’s synthesis process
.

Q2.
For  the same batch of APIs currently provided, the isomer test result provided by the supplier is 0.
1% , while the test result provided by the applicant is not detected.
It is recommended to re-study the isomer test method of this product to confirm The reliability of the detection method for isomers of this product
.

Re-development of detection methods and methodological research
.