Optimize your post-approval CMC change management in China with the ICH Q12 tool

This blog is part of The Regulatory Navigator series, where we explore the evolving regulatory landscape with actionable insight from Parexel's experts, sharing their experience to maximize success for clinical development and patient access.

The Center of Drug Evaluation (CDE) of China's National Medical Products Administration (NMPA) issued  guidance on  October 28 2025, soliciting opinions on "Technical Guidelines for Pharmaceutical Change Management Plans after Chemical Drug Approval."¹ This regional guidance advises companies on how to implement post-approval Chemistry, Manufacturing, and Controls (CMC) changes for chemical drugs by using post-approval change management protocols (PACMP), as outlined in the ICH Q12 Lifecycle Management guideline. The ICH Q12 guideline, developed in 2020 by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), provides a framework to facilitate management of post-approval CMC changes.^{2, 3}  The NMPA began implementing ICH Q12 in August 2023, with a 24-month transition period. 

Challenges of post-approval CMC change management in China 

The NMPA uses a three-level change management system based on risk and complexity: 

• Major post-approval variations (equivalent to a Type II variation in the EU or prior approval supplement (PAS) changes in the US; defined as changes that may or not have impact on quality, safety or efficacy)  
• Medium post-approval variations¹ (equivalent to a Type IB variation in the EU, and changes being effected (CBE-30) or (CBE-0) supplements in the US; defined as changes that will have medium risk on quality, safety or efficacy)  
• Minor post-approval variations (equivalent to a Type IA variation in the EU or changes that can be submitted in the annual report in the US; defined as changes that will have minimal or no impact on quality, safety or efficacy) 

For imported drugs in China, navigating changes can present challenges as a result of the country-specific regulatory framework, and technical requirements, as outlined below:  

1. Sample testing and stability data requirements: To support post-approval CMC changes, detailed documentation is required at the submission as well as compliance with specific technical requirements. Regarding stability data, the NMPA may require a different number of batches and different testing durations compared to other regions. Specifically, if there are medium-type changes in a drug product manufacturing process, the NMPA may request data from: 

• One to three batches of immediate-release products 
• Three batches of sustained-release products 
• Specific long-term and accelerated timepoints  

The NMPA requires representative samples to be available for testing at a national laboratory for both medium and major CMC changes.¹ While the CTD/application may specify 1-3 batches, in practice, testing of 3 batches is typically expected even for medium-type changes.  

Recommended action: Advance planning is essential to compile and present appropriate data that satisfies Chinese regulators and may differ from global requirements. 

2. Timelines: The time from submission to approval of post-approval CMC changes can differ substantially between the US, EU, Japan and China. For example, review times for a change in drug substance manufacturing site for a biological product range from: 

• 4–10 months in ICH founder member countries/regions 
• 6–24 months in CPP-dependent members (i.e., countries or regions that primarily rely on the" Certificate of Pharmaceutical Product") 

The conclusions issued by the ICH founder member countries serve as the primary foundation for their respective drug registration and approval processes.  Per NMPA regulations, sponsors of imported drugs are required to obtain the foreign regional authority’s approval of a post-approval CMC change before submitting a post approval changes application to the NMPA. These regional differences complicate global approval strategies coordination and may delay product launches in the Chinese market.  

Recommended action: Plan for and obtain variation approval in the country of manufacture before initiating a submission in China.³ This sequential process can almost double the timeline for implementing changes in China. For example, a post-approval variation might receive FDA approval in six months, but when subsequently submitted in China, it faces an additional 10-month review period – extending the total variation management timeline in China to over 16 months.  

3. Supply chain management complexity:  The complexity of the supply chain management and the need for stock (often termed ‘high bridging’, ‘buffer’ or ‘safety stocks’ – held in storage to guarantee continuous market supply and prevent shortages) can impact the workload and logistics associated with post-approval variations.  

Recommended action: Ensuring a consistent supply of pharmaceutical products is crucial, and any changes in the manufacturing process must be meticulously planned to avoid drug shortages. To continue the example mentioned above, after receiving FDA approval, a US company can generally begin implementing the change immediately. However, to comply with Chinese regulations, the company needs to maintain an inventory of the pre-change product for at least 12 months to ensure uninterrupted supply to the Chinese market. This poses a significant challenge, especially for products with a short shelf life or high-volume requirements, making it almost impossible. An alternative would be to have both manufacturing processes in place during the transition, but this strategy requires complicated tracking and raises the risk of inadvertent errors.   

While global trends favor innovation and continuous process, China’s complex and differing regulatory requirements can slow this progress.  

ICH Q12 PACMP-based solutions to post-approval CMC changes in China 

The PACMP tool described in the ICH Q12 guideline offers a dual benefit: (1) it facilitates the implementation of new technologies that enhance manufacturing efficiency, robustness and effectiveness; and (2) mitigates post-approval change management issues in China by allowing for the downgrade of the ‘major’ change to ‘medium’ one.  

According to Article 79 of the Chinese "Drug Registration Regulation"⁴: 

• Medium changes can be implemented upon submission   
• Major changes require review and approval, which typically take 10–12 months (with sample testing often being the rate-limiting step) 

Therefore, if the implementation of PACMP may allow downgrade from a ‘major’ change to a ‘medium’ type, significant time reduction and subsequent pressure on the supply chain would apply. What remains unclear is whether sample testing requirements can be waived – because then the benefits would be minimal.  

To submit a PACMP in China, the following prerequisites must be met³: 

1. Quality Management System (QMS): The company must have a robust QMS in place. The applicant should provide information on whether the site has undergone domestic or international regulatory agency inspections in the past three years. The information should include details on data integrity and authenticity issues, major and critical defects identified, and any failures in inspections, along with relevant supporting documents. 
2. Platform experience: The company should leverage supporting data (prior knowledge) from the development, production, characterization, batch release, and stability of similar or relevant products to mitigate risks. 
3. Risk assessment: A risk assessment for the proposed change must be conducted and provided, identifying the potential impact of the change on product quality and outlining strategies to manage these risks. 
4. Product development and manufacturing information: Detailed information on product development and manufacturing processes should be provided, including assessment of the applicability of the approved control strategy or the need for changes to the control strategy related to the proposed variation. 
5. Continued process validation: If applicable, the company must confirm that ongoing manufacture process validation will be continued under the QMS. 

The PACMP submission process typically includes two steps: 1) submitting the protocol and 2) implementing the protocol, while the submitted protocol must be approved by the Chinese regulatory authorities before implementation. The filing materials submitted to the regulatory authorities should additionally include, but not be limited to: 

• Proof of approval of the marketing application or supplemental application containing the PACMP, along with details of any revisions to the PACMP 
• A statement confirming compliance with all acceptable criteria in the PACMP 
• Detailed information on the implementation of the proposed change, including research data, comparative study results, and analysis. If stability studies are involved, the duration of stability testing submitted to the regulatory authorities should meet or exceed the requirements for major changes 
• An updated risk assessment in the PACMP or a statement that the risk assessment remains unchanged 
• A summary of any deviations from the approved protocol during implementation and justification for these deviations 
• A CMC change summary (which should fall under the PACMP defined scope) 

In China, a PACMP can be submitted within a marketing authorization application (CTD Module 3.2.R regional information, with a note in the application form).   

Final announcement of ICH M4Q(R2) guideline updates may introduce some changes in the PACMP placement. Currently, PACMP can also be submitted post-marketing as a supplemental application, with a note in the application form. A single PACMP can address one or more changes for a product. PACMP can also be designed for repeated use to allow for specified types of CMC changes using the same principles within the lifecycle of a product. However, each PACMP should be specific to one product, and different products should have separate PACMP submissions. 

There are some exceptions to PACMP’ use for changes with high or uncertain risks to product quality. These include, but are not limited to, the following scenarios: 

1. Vague change plans, such as applying for a change in manufacturing processes without specifying the exact details 
2. Changes that impact to product quality cannot be determined through prospectively defined studies, such as changes to poorly characterized products, changes in the synthetic route of the active pharmaceutical ingredient, or changes from wet granulation to dry granulation 
3. CMC changes requiring supporting data from efficacy, safety (clinical or non-clinical), or human PK/PD studies to assess the impact of the change (e.g., certain formulation changes, clinical or non-clinical studies for new impurities, evaluation of immunogenicity/antigenicity) 
4. Changes that require revision of the safety or efficacy part in the label 
5. Changes to drug product associated with the API, excipient or package materials DMF, with a registration status of “Inactive” (i.e. not yet reviewed) in China  
6. Major changes involving a revision in ‘China approval specification’  
   
   This is a case where existing release & shelf-life specification is submitted for China regulatory agency to create a ‘China approval specification’ which becomes a part of the official approval package.
   
   The China Customs Labs may test the drug based on the ‘China approval specification’ before they can release to China market. 
7. Any changes that need a new certificate number, such as new strength  
8. Other situations with significant risks 

Conclusions  

In summary, navigating the post-marketing CMC changes for imported drugs in China requires a deep understanding of the local regulatory landscape, meticulous preparation of submission materials, and strategic planning to manage the differences in technical and procedural requirements compared to other regions. Parexel has regional subject matter experts that can help navigate those challenges.   

Despite the difficulties, the new guideline offers a harmonized global approach of leveraging ICH Q12 PACMP can significantly alleviate the issues and support the updates to pharmaceutical products in the Chinese market.¹

Contact us to leverage our deep knowledge of the APAC landscape and how to implement ICH Q12 solutions. We are always available for a conversation.  

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References 

1. Technical Guidelines for Pharmaceutical Change Management Plans after Chemical Drug Approval, 化学药品批准后药学变更管理方案技术指导原则》available in Chinese only, October 2025 
2. ICH Q12 Technical and regulatory considerations for pharmaceutical product lifecycle management - Scientific guideline, March 2020 
3. Q12 Lifecycle Management, ICH.org 
4. Provisions for Drug Registration, June 2022 

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