How to write CTD data when the generic drug completes the BE trial report production

In September 2010, the State Food and Drug Administration issued a notice on matters related to the preparation of chemical drug registration application materials in the CTD format (Guo Shi Yao Jian Zhu [2010] No.
387), encouraging the writing and submission of application materials in the CTD format
.
Since April 2011, the Center for Drug Evaluation has also successively issued a number of relevant requirements for the technical review of CTD format application materials
.
This article discusses how to compile and organize the application materials according to the CTD format when completing the bioequivalence test (BE test) application for production of imitation oral solid preparations for the reference of drug registration applicants
.

1.
The basic situation and main problems existing in the declaration of production materials
for imitation oral solid preparations.
For a long time, China has implemented a two-batch system for imitation oral solid preparations, that is, the registration applicant first applies for a clinical trial (BE trial), and Submit pre-clinical pharmacy research data, after the technical review is passed, the State Food and Drug Administration will issue a clinical research approval document, and the registration applicant will entrust a clinical trial institution with the approval document to conduct a BE trial.
After the BE trial is completed, the trial report will be directly submitted to the drug review The center will be issued a production approval by the National Bureau after the technical review is passed
.


When the registration applicant completes the BE trial application and production, the technical data submitted often only include the BE trial-related data, that is, the 28-32 data or BE trial data specified in Annex 2 of the "Drug Registration Management Measures", as well as the clear requirements of the clinical approval document Need to supplement research related pharmaceutical information
.
Few companies submit complete pharmaceutical research materials at the same time as they report production
.


We know that pharmaceutical research and BE testing of oral solid preparations are part of the entire research and development work, and the two cannot be completely separated
.
The reasonable feasibility of the formulation process needs to be further verified by the BE test on the basis of sufficient pharmaceutical research work
.
In addition, after the equivalence conclusion is obtained in the BE test, the feasibility of the production process under large-scale production needs to be further verified, the quality standard may also need to be further revised and improved, and further stability investigation data can be obtained.

.
If only the relevant materials for the BE test are submitted when applying for production, it will be difficult to support a sufficient and appropriate evaluation of the safety, effectiveness and quality controllability of the product, which will affect the efficiency of the registration review
.

2.
Basic considerations for compiling and sorting out the application materials in CTD format
As mentioned above, it is difficult to fully support the technical evaluation of generic oral solid preparations when only providing BE test-related materials when applying for production.
Complete pharmacy and BE research materials should be submitted
.
Compile and organize the application materials in CTD format.
The following methods are recommended:
1.
Write and organize all pharmaceutical research materials in CTD format
.

The registration applicant shall compile and organize all pharmaceutical research materials in a complete and standardized manner in accordance with the relevant requirements of the CTD format
.
Compared with other declared production materials, when applying for the production of imitation oral solid preparations, the CTD format application materials shall not only meet the basic requirements of the State Food and Drug Administration Note [2010] No.
387, but also pay special attention to the following points:
(1) The application materials shall include relevant supplementary research materials on the remaining issues in the clinical approval document
.

(2) In the product development data, provide detailed data from small-scale to pilot-scale, and then to large-scale production formulation process research, specify the research process, the changes in the formulation process during the research work, and provide relevant supporting verification materials, and Clarify the changes in the formulation of preparations during the clinical period and provide research data to support the changes
.

(3) In the product production materials, provide detailed information on the prescription process and production conditions of the BE test samples
.
The BE test samples should be produced in the actual production line of the preparation or in the pilot workshop that meets the GMP requirements.
The batch production records, batch analysis reports and main production equipment models, production plants, and key technologies of the BE test samples should be provided in the application materials.
Parameters, explain in detail the similarities and differences between the production equipment, process and batch size of the BE test samples and the planned production line, analyze whether these differences will affect the quality of the product, and provide corresponding research and verification data
.

(4) In terms of preparation quality control, during the clinical period, the preparation quality standards should be further studied and improved based on the quality comparison research results of the original developed preparations, the current review technical requirements, and the latest editions of the standards included in the domestic and foreign pharmacopoeias
.
In the preparation quality control data, in addition to the research data provided in the CTD format, the changes in the quality standards during the clinical period and the further research work should be explained, and relevant research verification data should be provided
.

(5) In terms of stability, complete experimental research data should be provided, including follow-up long-term retention sample stability investigation data during the clinical period, and post-marketing stability research commitments and research plans should be provided
.
If there is a change in the formulation process, the accelerated test of the product after the change and the long-term retention sample stability inspection should be repeated
.

2.
Provide standardized and complete BE test data
.

Standard and complete BE test materials shall be provided when applying for production
.
The domestic technical guidelines on BE testing were promulgated earlier, and the guidelines on the management of test samples, post-prandial bioequivalence testing and other aspects of the guidelines are not clear enough, and there is still a gap between the criteria for determining Cmax equivalence and international standards
.
Therefore, in order to improve the quality of generic drugs and achieve the goal equivalent to the quality of the original product, it is recommended that registration applicants and testing institutions can refer to the technical guidelines of FDA and EMA on BE testing and the CDE website in recent years on the basis of the guidelines issued in China.
Relevant electronic journals published here, standardize the design and implementation of BE tests, and standardize the sorting of test application materials
.

3.
Sustained-release preparations and other special preparations are modified and perfected during the clinical period
.

Special preparations such as sustained-release preparations, due to the characteristics of their dosage forms, even if sufficient pharmaceutical comparison studies have been carried out with the original product before the clinical trial, the prescription process may need to be further modified and improved during the clinical period based on the in vivo test results.

.
In other words, for the preparations prepared according to the original clinical prescription process, the BE test results may not have the expected sustained-release characteristics and bioavailability.
It is necessary to combine the information provided by the in vivo test results to modify the prescription process and then re-run In vivo testing may even require multiple formulation process adjustments and in vivo testing of products after modifying the formulation process to obtain a product that is bioequivalent to the original formulation
.
In this case, the registration applicant should fully explain the modification and improvement of each prescription process, the basis for the modification of the prescription process, the corresponding in vivo test results, the final prescription process, and the scale-up production verification in the product development materials.
The BE test data section should also provide data on each in-vivo test (including pre-test) conducted to support the full evaluation of the safety and effectiveness of the variety (bioequivalence with the original product), quality controllability, and improve registration The efficiency of the review
.