After drugs are approved, it is common that the drug marketing authorization holders (MAH)/manufacturers intend to use a more advanced manufacturing technology and device for drug production. There are also chances that MAHs want to change the manufacturing site of the approved drugs. The changes, depending on their categories, should be approved, notified, or reported to the corresponding regulator.
In China, post-approval changes or variations to chemical drugs are divided into three categories according to risk levels.
Risk level: 1. Changes for supplemental application and approval > 2. Changes for notification > 3. Changes to be documented in annual report
Categories of Post-approval Changes
Category | Competent Regulator | Changes |
Changes for supplemental application and approval | National Medical Products Administration (NMPA) |
|
Changes for notification | For domestic drugs: local medical products administration;
For foreign drugs: Center for Drug Evaluation (CDE), NMPA |
|
Changes to be documented in annual report | NMPA |
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Notes: The category of changes should be determined case by case.
DMF Requirements
According to the Change Items of Approved Chemical Drugs and Application/Reporting Dossier Requirements, MAHs should submit the following documents to the corresponding authority.
1. Copy of the approval document and its annex of all the past applications or reporting.
2. Certification documents
For overseas marketed drugs, the MAH should submit the authorization document for the drug change, notarization document, and their Chinese translations.
If the overseas MAH appoints a Chinese legal corporate as its local agent, then the MAH should also provide the appointment letter, notarization document and its Chinese translation, as well as a copy of the agent’s business license.
3. Information relevant to inspection and testing.
4. Revised drug quality standards, manufacturing technology list, medication package inserts, sample draft of the label, and elaboration on the revision.
5. CMC research documents
The MAH should carry out CMC research according to the technical guidelines relevant to post-approval changes to chemical drugs.
Following the specific requirements for different change categories, the MAH should submit all or some of the literature and the CMC research & trial documents, as well as the necessary relevant documents in the original NDA/ANDA dossier.
6. Pharmacology & toxicology research documents
The MAH should conduct pharmacology & toxicology researches according to relevant guidelines.
Following the guidelines’ specific requirements for different change categories, the MAH should submit partial or all the documents on pharmacology & toxicology documents, and necessary domestic and international literature.
7. Clinical research documents
The MAH should carry out clinical research according to national drug regulator’s guidelines on clinical post-approval changes to chemical drugs.
Following the guidelines’ specific requirements for different change categories, the MAH should submit the corresponding documents.
If required, the MAH should conduct clinical trials according to relevant regulations and technical guidelines. If not required, the MAH should provide relevant clinical documents.
Cases
The following are specific cases of post-approval changes. Again, the category of changes should be determined case by case, and the following table is only for reference.
Case 1: Adding a new supplier of the starting material, and the manufacturing process of starting material and quality standard of API are the same | Case 3: Add a new step in the manufacturing process | ||
Which classification does the change belong to? | Minor change | Moderate change | Major change |
Is pre-approval by China authority needed? | No, it can be reported in the annual report. | No, the change only needs notification instead of application for approval. If China NMPA has any different opinion, question or inspection requirement about this change notification, it will make an inquiry within 30 workdays, then the relevant materials should be submitted before the change is implemented. If no such inquiry is received, the change can be implemented directly.
Besides, the change information should be included in the annual report. | Yes. Major changes are subject to Supplemental Application, and can only be implemented with China NMPA’s approval. The change can only be implemented with China NMPA’s approval. The official timeline is as below: 1. Format review and acceptance: 5 wd; 2. Technical review: 60 wd; 3. Administrative procedure: 20 wd; 4. Approval issue: 10 wd.
Besides, the change information should be included in the annual report. |
Research and validation requirements | 1) Conduct the testing on the API batches produced with the starting material by the new supplier to confirm the specification is the same; 2) Conduct the long-term stability test with the first batch of samples after the change. | (1) Provide the batch manufacturing record of one batch of samples after the change.
(2) Carry out quality comparability studies on the pre-change/post-change samples to demonstrate that the samples are consistent in impurity profile and critical physicochemical properties and comply with relevant guidelines.
(3) Test 1-3 batches of samples after change. The results should comply with the specification requirements.
(4) Carry out accelerated stability testing and long-term stability testing on one batch of samples after change. When submitting the notification, please provide the stability study data for at least three months and make a comparison to the stability of the pre-change product. The post-change samples should not be less stable than pre-change samples. | (1) Provide the batch manufacturing record of one batch of samples after the change.
(2) Carry out quality comparability studies on the pre-change/post-change samples, focusing on the comparison of impurity profiles and critical physicochemical properties of the samples. The results should comply with requirements of relevant guidelines.
(3) Test three consecutive batches of samples after the change. The results should comply with the specification requirements.
(4) Carry out accelerated and long-term stability testing on three batches of samples after change. When submitting the application, provide the stability study data for three to six months and make a comparison to the stability of the pre-change product. The post-change product should not be less stable than pre-change product. |
BaiPharm Regulatory Affair Director Mona Zhang and Regulatory Affair Consultant Mia Li also contributed to this article.
Get in touch with BaiPharm if you’d like to know more about China's drug regulations.
