CDE Drafts Technical Guidelines for Post-Approval Changes of Chemical Drugs

China’s Center for Drug Evaluation (CDE) has drafted a technical guideline for post-approval changes of chemical drugs and sought comments from stakeholders. CDE released the "Technical Guidance for the Management of Post-Approval Pharmaceutical Changes in Chemical Drugs (Draft for Public Comments)" on June 9, 2025. The guideline is intended to implement the requirements of the ICH Q12 international guidelines and optimize the management process for post-approval changes in chemical drugs in China. This guidance introduces the Post-Approval Change Management Protocol (PACMP) mechanism, providing a standardized path for change management, reducing the burden of repeated reviews, and enhancing regulatory efficiency.

Because this guidance is a draft for comments (formal comments were to be submitted by the start of July), it may well have gone through further changes before implementation.

Scope of Application and Prerequisites

Applicable Entities:

Marketing Authorization Holders (MAH) or raw material registrants for chemical active pharmaceutical ingredients (API) and formulations.

Applicable Change Types:

API: Changes in synthetic routes, process parameters, quality standards, etc.
Formulations: Changes in formulation processes, manufacturing sites, packaging materials, etc.

Prerequisites for Submitting a PACMP:

The company must have a robust quality management system and strong capabilities in quality risk management.
The risks associated with the changes must be controllable and verifiable through research to potentially reduce the original change classification (e.g., from Category III to Category II).

Exclusions:

No specific change plan or only conceptual descriptions.
Changes requiring clinical data support (e.g., indications, routes of administration).

PACMP Application Process

Two-Step Process:

Step 1: Submission and Approval of the Plan
Companies submit a PACMP application to the CDE, including a description of the changes, risk assessment, research plan (e.g., comparative analysis, stability studies), and acceptance criteria. Upon approval, the CDE will specify the reduced classification for the changes.
Step 2: Implementation and Reporting of the Plan
After completing the research and validation as per the approved plan, companies can submit the change application under the reduced category (e.g., through a filing system) without resubmitting complete data.

Linkage with Registration Applications:

New drug marketing applications can include a PACMP simultaneously (incorporated into CTD Module 3.2.R).
For marketed drugs, submission is through a supplementary application pathway.

Technical Documentation Requirements

Proposed Pharmaceutical Changes and Reasons

Content of Changes: Clearly describe the differences before and after the change, preferably in a tabular comparison format (e.g., process parameters, quality standards, manufacturing sites).
Reasons for Changes: Explain the necessity of the changes (e.g., optimizing production efficiency, compliance with new regulatory requirements). Provide an implementation timeline with specific milestones for the change plan.

Supporting Information

Provide comprehensive evidence demonstrating the company's full understanding of the change risks, including the following seven aspects:

Quality Management System: Prove compliance with GMP requirements, with no significant inspection deficiencies in the past three years (e.g., data integrity issues).
Historical Experience Data: Provide historical data from the same or similar products (e.g., process validation, stability studies) to mitigate risks.
Risk Assessment: Identify potential impacts of changes on product quality (e.g., changes in impurity profile, dissolution behavior) and develop control strategies. If multiple changes are involved, assess cumulative risks and interdependencies.
Manufacturing Process Information: Provide data from development batches or pilot-scale batches, with preference for commercial-scale samples; small-scale data may increase risks due to scaling effects.
Control Strategy Assessment: Analyze whether existing quality standards are applicable or need adjustment (e.g., adding new test items).
Ongoing Verification Plan: Commit to continuous quality monitoring post-change (e.g., stability testing, process performance confirmation).
Other Conditions: Such as supplier audit reports, comparison of quality standards for raw materials before and after changes.

Proposed Research Plan for Changes

Comparative Studies: Conduct comparative analyses of materials and products before and after changes (e.g., APIs, excipients, packaging materials), using commercial-scale samples.
Testing and Validation: When routine quality control (e.g., content, impurities) is insufficient; additional characterization is required (e.g., polymorph analysis, dissolution curve comparison, extractables studies). Process validation may be necessary for changes in critical steps.
Analytical Methods: Provide detailed testing methods (e.g., HPLC conditions) to demonstrate their effectiveness in assessing the impact of changes.
Acceptance Criteria: Clearly define quality indicators (e.g., impurity limits, dissolution) and statistical criteria (e.g., f2 factor ≥ 50).

Proposed Reduced Change Management Category

Explain the current classification change under existing regulations (e.g., major/medium/minor).
Propose the reduced category and rationale (e.g., through research proving controllable risks, changing Category III to Category II).

Other Information

Type of Change: Distinguish between one-time changes and recurring changes (the latter must ensure controllable cumulative impacts).
Implementation Commitment: Declare that research results post-change must meet PACMP standards and be reviewed by regulatory authorities before marketing.
Timeline: Provide an estimated schedule for implementing the change (e.g., completion of stability testing).

Dynamic Management and Revision

Adjustments During Implementation

If research reveals higher risks than anticipated, execution must be suspended, and the plan resubmitted.
Only when tightening standards or adding testing methods, filing through an annual report is permissible.

Regulatory Communication

The CDE encourages companies to discuss technical details in advance through communication procedures during the plan design phase.

Industry Impact and Value

Benefits for Companies

Efficiency Improvement: Pre-approved plans reduce implementation time for changes.
Cost Optimization: Avoiding repeated submission of materials reduces R&D and compliance costs.
Enhanced Flexibility: Suitable for companies with multi-site production and continuous process improvements (e.g., continuous manufacturing).

Significance for Regulatory Authorities

Risk-Graded Management: Concentrate regulatory resources on high-risk changes through PACMP.
Alignment with International Standards: Enhance the competitiveness of domestic companies in the global supply chain (e.g., change management for exported drugs is more easily recognized internationally). Change management for companies in ICH member countries is more readily accepted by the NMPA.

Further Information

To read the original announcement about the draft Technical Guidance for the Management of Post-Approval Pharmaceutical Changes in Chemical Drugs released by the Center for Drug Evaluation (CDE) on June 9, 2025, please click here.

If you are a pharmaceutical company with questions about how the PACMP mechanism affects your product registration or post-approval changes in the China market, please contact Cisema.