Regulatory Post-Approval Change Management in China

Innovative drug developers are increasingly interested in synchronizing marketing authorization applications in China. In this blog post, Wei Qu, senior regulatory manager, and Guoliang Liu, director of regulatory affairs in China, discuss recent regulatory and procedural updates for post-approval change management for pharmaceutical products marketed in China.

In March 2020, China’s National Medical Products Administration (NMPA) issued new provisions for drug regulation to reform the Chinese pharmaceutical industry. The wide-ranging provisions, known as the ”drug registration regulation,” are the first revisions to NMPA regulations since 2007. They became applicable on July 1, 2020, and introduced new procedures and requirements, such as an accelerated review procedure, a marketing authorization holder (MAH) system and a new IT platform for patient registration. In our June 2020 Regulatory Insights blog, “Focus on China – New Provisions for Drug Registration in 2020,” we highlighted key changes introduced by the regulation.

Subsequently, the NMPA issued a series of guidance documents to clarify details and facilitate step-by-step implementation of the new provisions. The guidance on post-marketing management of drugs is one of the most noteworthy changes resulting from the updated regulation.¹

This guidance outlines that, as the responsible party for post-approval variation management, the MAH should conduct all required post-approval activities effectively and within specified timelines to maintain compliance with the marketing authorization. Expectations for how the MAHs should classify post-approval variations remain less clear. Although the regulation and associated technical guidance set out principles to support MAHs, including examples of variation classifications, they are not exhaustive. For variations not specified in the regulation or guidance, MAHs must determine the classification after evaluating the relevant guidance and taking into consideration the product characteristics. The MAH can consult the Center of Drug Evaluation (CDE) when necessary.¹

Post-approval changes are categorized into three classifications in the recently issued (February 2021) technical guidance²:

1）Review and approval

Major variations require the CDE’s review and approval. These include variations to the chemistry, manufacturing and controls (CMC) or clinical aspects as specified in the technical guidance,^3,4 as well as variations to change the MAH and usage of the commercial product name. This type of variation should be submitted as a supplementary application to the CDE. After review, the CDE will issue its decision within a specified number of working days, which will vary depending on the type of change, as outlined:

2）Changes to be filed with the CDE

Moderate variations must be filed with the CDE before implementation. Examples include moderate changes to the CMC or clinical information as specified in the technical guidance, such as adding a testing item in the specification, tightening the specification or making a non-technical change. An instance of a non-technical change could involve changes to the license that are unrelated to technical review, change of local registration agent and certain packaging changes for imported drugs. For drugs manufactured abroad, the CDE publishes the change on its website within five days of the MAH submission.

3) Changes to be reported to the CDE

Minor changes to CMC or clinical information, such as changing the excipient vendor without lowering the grade and specification, or changing package size, do not require CDE approval but should be reported in the annual report submitted to the CDE classified as “changes to be reported.”

Cross-Border Collaboration

Similar to the electronics industry, the evolving Chinese biomedical industry has given rise to two types of enterprise, one with strong innovation and research and development capabilities, and the other with large-scale manufacturing abilities, capable of global production operations.

While cross-border commissioned production is a feature that is expected to expand, cross-border contract manufacturing is not yet possible in China due to the current legal and regulatory framework. Practically-speaking, this means drugs manufactured outside China must have an MAH based outside China with a local Chinese agency bearing joint responsibility. Similarly, drugs manufactured in China must have a local Chinese MAH.

This requirement remains an important consideration for any MAH planning to transfer a manufacturing site to China. The overseas MAH must transfer to a local Chinese MAH meeting domestic requirements, such as holding an appropriate Chinese manufacturing license. However, with the establishment of China’s MAH system, it is expected that cross-border contract manufacturing could become a reality in the future, which is critical to achieving globalization in pharmaceutical manufacturing and supply.

The following examples illustrate the procedures required under the new regulation to change the MAH and manufacturer:

• To change a foreign MAH to another foreign MAH (without any other changes), the incoming MAH must first be approved outside China. Upon approval, a supplementary application can be submitted to the CDE for the change of the MAH.

• Generally, in cases where the MAH change is accompanied with a manufacturing site change or other technical changes, the MAH change must be approved before the incoming MAH can submit the corresponding supplementary application or filing for other changes. In certain circumstances, it is possible to combine the change of MAH with other changes as a single application.

• Technology transfers, where the drug product was originally developed and manufactured overseas and then transferred to China for further development and commercialization, is another common scenario in which both the MAH and manufacturing site must transfer for future commercialization in China. Prior to the new regulation, the incoming MAH in China was required to submit a supplementary application to implement this type of change.⁵ However, the new regulation now requires that a New Drug Application be submitted for this type of transfer.² Relevant CMC and non-clinical and clinical data (as applicable) conducted overseas can be referenced and submitted to NMPA to support technology transfer applications. Once approved, the MAH can apply for the locally manufactured drug product to become a reference product (Reference Listed Drug), which guarantees the market position of the original drug.

Rapidly Evolving Environment

Innovative drug developers are increasingly interested in synchronizing marketing authorization applications in China and other countries. While the Chinese regulatory environment has seen progress, careful evaluation and planning by MAHs is still needed because specifics within the new regulations remain to be clarified, such as whether NMPA can accept authorization from a local MAH to an overseas company to manufacture the product or whether NMPA can accept the variation submission in China in parallel with another country. The PPD™ clinical research business of Thermo Fisher Scientific will continue to follow these developments closely and advise our clients about these new provisions, adapting as guidance emerges to offer sound regulatory solutions in China.