Friday, 26 July 2024 / Published in News, NMPA Registration in China, Pharmaceuticals & DMF

China Active Pharmaceutical Ingredient Post-Market Changes Guidance

China Active Pharmaceutical Ingredient post-market changes now have guidance in the form of a set of questions and answers which were issued China’s Center for Drug Evaluation (CDE) on June 7, 2024.

This Q&A outlines the necessary research when changes are made to Active Pharmaceutical Ingredients (APIs) according to change guidelines “The “Measures for the Administration of Post-marketing Changes of Drugs (Trial)” and the “Technical Guidelines for Pharmaceutical Change Research of Listed Chemical Drugs (Trial)”. Generally, minor API changes have minimal impact on formulations. Thus, formulation holders should prioritize evaluating medium and major API changes and production site changes, conducting the necessary studies.

Detailed Procedures for Post-market Changes in APIs:

1. Manufacturing Process Changes:

Quality Consistency: If the quality of APIs before and after changes remains consistent, relevant supporting documentation (such as approval of supporting documents, filing and adoption of supporting documents) and comparative studies of 1-3 batches are required.

Inconsistent Quality: If there are changes in quality, a thorough comparison of formulation quality (dissolution profiles, impurity profiles) must be conducted. This involves testing multiple batches for comparative research and providing 3-6 months stability data.

2. Production Site or Batch Size Changes:

Describe the changes in APIs and provide relevant supporting documents.

Document the change and ensure consistency in impurity profiles and key properties.
Any associated changes in manufacturing parameters or equipment should be assessed for their impact on both API and formulation quality.

3. Registration Standards Changes:

Evaluate the impact on the formulation’s internal control standards.

If no changes are required to the standards, report the changes in the annual report.

If internal control standards need to be tightened, document and validate these changes.

4. Storage Conditions and Shelf-Life Changes:

If changes are due to product quality issues, conduct comprehensive quality comparison studies and stability assessments, and evaluate whether to annualize, file, or file a supplemental application in conjunction with the results of the study.

If no quality issues exist, document the changes in the annual report.

5. Packaging Material Changes:

Assess the potential impact of packaging changes on the API and formulation.

Submit relevant documentation if the change is likely to affect product quality.

Changing API Suppliers:

1. Consistent Quality:

Provide detailed documentation of the change.

Conduct comparative quality studies on 1-3 batches of the new and old APIs.

Perform stability studies for at least three months to ensure the new API maintains product stability.

2. Inconsistent Quality:

Conduct a comprehensive quality comparison and stability assessment.

Multiple batches of the formulation made with the new API must be tested.

Bioequivalence studies may be required if critical quality attributes (e.g., dissolution profiles) differ significantly.

3. Impact on Registration Standards:

Ensure the internal control standards align with the new API supplier’s standards without lowering the overall quality control level.

Comprehensive documentation and validation of changes to the internal control standards are required.

Research Recommendations:

The guidelines suggest following the basic principles outlined in the “Post-Marketing Change Management of Drugs (Trial)” for research.

Comparative dissolution curve studies should follow the guidance provided in the relevant Q&A on dissolution curves.

Specific circumstances might require additional research beyond the listed recommendations, tailored to the nature of the API change and its impact on the formulation.