NMPA Generic Drug Registration Guidelines

In recent years, the scientificity and standardization of China's NMPA's regulatory system for generic drugs have made significant progress. The NMPA's registration of generic drugs has become a comprehensive test covering various aspects such as product quality, clinical effectiveness, understanding of regulations and the preparation of application materials.

Challenges in NMPA's Generic Drug Registration

Selection and acquisition of reference listed drugs (RLD)

RLD is the starting point for generic drug development and the basis for subsequent registration success. However, in practical operations, enterprises often face challenges selecting and acquiring RLDs.

The catalogue of RLD published by NMPA may have some issues such as incomplete varieties or outdated updates. Without a clearly recommended RLD, enterprises can only make their own judgments on whether to use domestic or foreign marketed products as substitutes, which undoubtedly increases compliance risks.

Even if the RLD is clearly defined, obtaining RLDs remains a challenge for enterprises. Especially for imported original drugs, the procurement process involves import approvals, supply chain stability and procurement cycles. As a result, some enterprises have to rely on a third-party agency to purchase overseas, which not only increases costs but may also impede the smooth progress of subsequent consistency evaluations.

Bioequivalence trial

The bioequivalence trial (BE trial) is the core link for determining whether the in vivo effects of generic drugs are consistent with those of the RLD. According to the technical guidelines of the NMPA, most oral solid preparations need to undergo a BE trial to obtain consistency evaluation certification.

(1) Technical design difficulty

For some highly variable drugs, sustained-release preparations, or other special dosage forms, companies often have difficulty setting the trial parameters. Even a slight mistake can lead to trial failure and even affect the entire registration cycle.

(2) Ethical review and limited trial resources

BE trials involve healthy subjects and require approval by the ethics committee. Currently, the number of qualified BE trial institutions in China with good GCP standards is limited. In addition, BE trials are expensive, and for some drug varieties, repeated trials may be required, further increasing the cost.

Pharmaceutical research and application document writing

The NMPA requires that registration materials for generic drugs be logically clear, complete in content and based on sufficient evidence.

(1) Process development

Enterprises should not just provide process flow and equipment parameters, but also provide development logic, process optimization trajectory and control strategies for key process parameters.

(2) Impurity research

Enterprises need to explain the source, control strategy, analysis method validation and toxicological assessment of each impurity.

(3) Stability study

Enterprises not only need to submit regular long-term/accelerated data, but also provide sufficient sample batch data according to ICH requirements.

(4) Quality standards establishment

Enterprises need to explain the scientific basis and detection capabilities of each indicator.

(5) Pharmaceutical equivalence

Enterprises usually need to provide dissolution curve comparisons, multi-media data and similarity factor analysis to prove substantive equivalence of the generic drug.

Regulatory updates and review standards are uncertain.

The NMPA and CDE have released a large number of technical guidelines and notification announcements, covering aspects such as BE trials, pharmaceutical research, special formulations and review processes. Even if enterprises strictly follow the current technical guidelines, they may still be required to provide supplementary materials or even re-conduct research due to different interpretations by reviewers or minor policy adjustments. For small and resource-limited enterprises, once the registration path is misjudged, they often cannot withstand the pressure of time and cost.

Our Suggestions

Proregulations has conducted in-depth research on pharmaceutical regulatory laws and regulations in multiple regions, including the United States, China and the European Union. Targeting the difficulties in NMPA's generic drug registration, we suggest enterprises consider the following factors when planning.

1. Establish a comprehensive registration plan

Organize cross-departmental assessment meetings at the early stages of the project, focusing on core elements such as RLD procurement, the rationality of BE trial design and product indication consistency, to formulate registration strategies and reserve alternative plans. For issues that may involve new technology determination, communicate with CDE as early as possible to avoid directional deviations.

2. Ensure deep research and reliable data

Generic drugs need to undergo a series of experiments and data support to prove their equivalence in quality, safety and efficacy to the RLD. We suggest that enterprises avoid simplifying processes to save costs during the pharmaceutical research stage and must rigorously determine key quality attributes (CQA) and process critical control points (CPP). For core indicators such as stability, impurities, release rate and content consistency, enterprises should ensure data reliability through systematic verification of multiple batches and time periods.

3. Utilize CRO and registration advisors to optimize the application process

For enterprises that are not familiar with the operation process and logic of BE trials, the more specialized parts can be handled by experienced teams. Especially in aspects such as BE trial scheme design, selection of clinical centers and setting of data statistical methods, highly professional and review-oriented thinking is required.

4. Communicate actively with regulatory agencies

Enterprises should flexibly utilize the Q&A channels and technical consultation meetings of CDE to communicate potential issues in advance, actively seek regulatory feedback, reduce uncertainty and increase the success rate of registration.

Our Services

Proregulations has extensive global experience in pharmaceutical compliance and specializes in providing customized and scalable solutions for pharmaceutical companies. Our services include:

• Regulatory consultation and interpretation
• Regulatory training
• Pharmaceutical marketing strategy development
• Gap analysis
• Application document preparation and submission
• Risk management
• Compliance assessment
• Maintain good interactions with the NMPA and CDE

With increasingly strict regulatory requirements, the complexity of NMPA generic drug registration is also increasing. Partnering with Proregulations, let us provide you with professional and efficient compliance services to safeguard the launch of your generic drugs, reduce regulatory risks and gain a competitive edge on the market. If you are interested in our services, please contact us.

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