New Developments in China’s Drug Change Management Regulations

The Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) recently released the Acceptance Review Guideline on Biological Products Changes (for Trial Implementation). It is the latest development in China’s regulations of drug change management since the promulgation of the newly amended Drug Administration Law in 2019 and more than 20 regulations and technical guidelines. It is essential for pharmaceutical companies doing business in China to fully understand these new developments in order to comply with the regulatory requirements for drug change management.

国家药品监督管理局药品审评中心（“药审中心”）于近期发布了《生物制品变更受理审查指南（试行）》。这是中国药品变更管理法规在2019年新修订的《药品管理法》及20余部配套规定和技术指南出台后的新发展。在中国开展业务的医药企业有必要充分了解这些新发展，以遵守药品变更管理的监管要求。

A. Latest Developments in China’s Drug Change Management Regulations
中国药品变更管理法规的最新发展

The legal framework of China’s drug change management is primarily set out under the following five laws and regulations: Drug Administration Law, Drug Registration Regulation, Administrative Measures on Drug Postmarketing Changes (for Trial Implementation) (the Measures on Drug Postmarketing Changes), Administrative Measures on the Supervision of Drug Manufacturing, and Good Manufacturing Practice for Drugs. These laws and regulations establish the general principles of drug change management in China, categorize and manage drug changes according to time of occurrence and types of changes, and require sponsors, marketing authorization holders (MAHs), and drug manufacturers to obtain approvals and submit notification filings or annual report filings, as applicable.

中国药品变更管理法规的基本框架主要由以下五部法律法规构成：《药品管理法》、《药品注册管理办法》、《药品上市后变更管理办法（试行）》（“《药品上市后变更管理办法》”）、《药品生产监督管理办法》以及《药品生产质量管理规范》。这些法律法规建立了中国药品变更的总体原则，根据变更发生的时间和变更的事项进行分类管理，并要求申办者、药品上市许可持有人（“持有人”）和药品生产企业获得相应的批准、进行备案或者提交年度报告。

1. Premarketing Change Management
上市前的变更管理

a. Drug Change During Clinical Trial
临床试验期间的变更

Article 29 of the Drug Registration Regulation requires that whenever there is a clinical trial protocol change, non-clinical or pharmacological change, or new discovery during drug clinical trial, the sponsor shall evaluate its impact on the safety of the study subjects. If it is believed that there is no impact on the safety of the study subjects, the sponsor may implement such change directly and report in the safety update report during the clinical research and development; if there may be additional safety risks to the study subjects, the sponsor must submit a supplementary application.

《药品注册管理办法》第二十九条规定，药物临床试验期间，发生药物临床试验方案变更、非临床或者药学的变化或者有新发现的，申办者应当评估对受试者安全的影响，认为不影响受试者安全的，可以直接实施并在研发期间安全性更新报告中报告，可能增加受试者安全性风险的，应当提出补充申请。

b. Drug Change During Review and Approval of Marketing Authorization Application
审评审批期间的变更

For any change during the review and approval of a marketing authorization application, Article 40 of the Drug Registration Regulation provides that where there is a significant change that may impact the safety, efficacy, and quality controllability of drugs, the applicant shall withdraw the original registration application and conduct a supplementary study before submitting a new application. For changes not involving review of technical contents, such as a change to an applicant’s name and registered address, the applicant shall notify the CDE in writing and submit supporting documents.

对于药品上市许可审评审批期间的变更，《药品注册管理办法》第四十条要求申请人对可能影响药品安全性、有效性和质量可控性的重大变更撤回原注册申请，经补充研究后再重新申报。对于申请人名称变更，注册地址名称变更等不涉及技术审评内容的变更，申请人书面告知药审中心并提交相关证明材料即可。

2. Postmarketing Change Management
上市后的变更管理

a. Determination and Communication of Drug Change Classification
变更类别的确定和沟通

The Drug Registration Regulation classifies postmarketing changes as major, moderate, or minor changes based on the risk levels of such changes on the safety, efficacy, and quality controllability of drugs. CDE has also promulgated relevant technical guidelines that help MAHs to determine the classification of changes.

《药品注册管理办法》按照变更对药品的安全性、有效性或质量可控性产生影响的风险程度，将上市后变更分为重大，中等，或微小变更。药审中心也已发布相应的技术指导原则，以便持有人确定变更类别。

If an MAH is unable to classify the drug change after conducting research and verification according to the technical guidelines, such MAH may communicate the problem to the drug regulatory authorities in accordance with the Measures on Drug Postmarketing Changes. Domestic MAHs may communicate with provincial-level regulatory authorities according to the procedures determined by such provincial-level regulatory authorities, and foreign MAHs may communicate with the CDE according to the procedures for communications during the drug registration.

若持有人根据配套变更技术指导原则进行研究验证后仍无法确定变更类别，则可根据《药品上市后变更管理办法》与药品监管部门进行沟通。境内持有人可以与省级药品监管部门进行沟通，具体沟通程序由各省级药品监管部门自行制定；境外持有人可以与药审中心沟通，具体沟通程序按照药品注册沟通交流的有关程序进行。

b. MAH Change
持有人变更

According to the Measures on Drug Postmarketing Changes, a change of MAH is a major change subject to prior approval, and it can be divided into three categories: (1) change of domestic MAH, (2) change of foreign MAH, and (3) transfer of manufacturing from overseas to China for a drug manufactured abroad but already marketed in China. For changes of domestic MAHs or foreign MAHs, the MAH after the change must file a supplementary application with the CDE. For transfer of manufacturing from overseas to China for a drug manufactured abroad but already marketed in China, the domestic applicant must file a new registration application in accordance with the requirements and procedures of drug marketing registration application; the applicant may submit pharmacological materials as well as non-clinical and clinical study materials (if applicable) that were included in the original overseas registration application. If meeting the requirements, that drug can serve as a reference listed drug.

《药品上市后变更管理办法》将持有人主体变更这一需审批的重大变更事项细分为三类：（1）境内生产药品的持有人之间变更，（2）境外持有人之间变更，和（3）已在境内上市的境外生产药品转移至境内生产的变更。其中，境内生产药品的持有人变更和境外持有人之间变更应由变更后的持有人向药审中心提出补充申请。对于已在境内上市的境外生产药品转移至境内生产的，应当由境内申请人按照药品上市注册申请的要求和程序提出新的药品注册申请，相关药学、非临床研究和临床研究资料（适用时）可提交境外生产药品的原注册申报资料，符合要求的可申请成为参比制剂。

For changes such as those to the name of an MAH, the name of a manufacturer, and manufacturing address, the MAH shall submit notification filings to the provincial-level drug regulatory authorities. For similar changes to drugs manufactured outside China, the MAH shall submit notification filings to the CDE.

此外，持有人名称、生产企业名称、生产地址名称等变更，持有人应当向省级药品监管部门进行备案。对于境外生产药品上述信息的变更，持有人应当向药审中心提出备案

c. Manufacturing Site Change
生产场地变更

The Measures on Drug Postmarketing Changes provide that where there is a drug manufacturing site change, the formulation, production processes, and quality standards of that drug shall remain the same after the change; if different, the MAH shall conduct a thorough study, evaluation, and necessary verification, and the MAH shall manage the change through prior approvals, notification filings, or annual reports.

《药品上市后变更管理办法》规定变更药品生产场地的，药品的处方、生产工艺、质量标准等应当与原药品一致；若是药品的处方、生产工艺、质量标准因生产场地变更而发生变更，持有人应当进行充分研究、评估和必要的验证，并按规定经批准、备案后实施或提交年度报告。

For a domestic MAH or manufacturer changing its own manufacturing site, or for a domestic MAH changing its manufacturer, the MAH shall conduct a study, evaluation, and necessary verification, and the MAH shall file an application for change of the drug manufacturing license with the provincial-level drug regulatory authority. A foreign MAH who changes its overseas drug manufacturing site to a new overseas site shall conduct a study, evaluation, and necessary verification, and this foreign MAH shall manage the change through a supplementary application or notification filing.

境内持有人或药品生产企业内部变更生产场地或境内持有人变更生产企业的，持有人（或药品生产企业）应当进行研究、评估和必要的验证，向省级药品监管部门提出变更《药品生产许可证》申请。境外持有人变更药品生产场地且变更后生产场地仍在境外的，应进行研究、评估和必要的验证，向药审中心提出补充申请或进行备案。

d. Other Changes
其他变更

The Measures on Drug Postmarketing Changes also govern changes to other drug registration matters, including changes to the manufacturing processes such as equipment, sources and types of active pharmaceutical ingredients (APIs), excipients, and packaging materials, technical specifications, and quality standards, as well as changes to APIs. MAHs or API registrants shall classify the changes and manage the changes through prior approvals, notification filings, or annual reports.

《药品上市后变更管理办法》规定了对于其他药品注册管理事项的变更，包括生产设备、原辅包材料的来源和种类、生产环节技术参数、质量标准等生产过程变更，以及原料药变更。持有人或原料药登记人应当确定变更管理类别，经批准、备案后实施或提交年度报告。

The Measures on Drug Postmarketing Changes also regulate the management of changes that have occurred prior to the effective dates of the Drug Administration Law and Drug Registration Regulation. Under the following two circumstances, it is not necessary to submit a new application for such changes: (a) if the MAH or the manufacturer has implemented the changes by following the previous regulations and technical requirements governing the management of manufacturing process changes, and the MAH or the manufacturer studied, validated, and proved that the changes would not affect the drug quality; or (b) if the manufacturing processes have been approved by or re-registered with the regulatory authorities.

《药品上市后变更管理办法》还特别规定了《药品管理法》和《药品注册管理办法》实施前已发生的变更的处理方式，指明在以下两种情况下，无需按照新的变更管理规定及技术要求进行重新申报：（a）持有人或生产企业按照原生产工艺变更管理的有关规定和技术要求经研究和验证证明不影响药品质量的已实施的变更；或（b）经过批准或再注册中已确认的工艺。

e. Procedures for Changes
变更程序

According to the Measures on Drug Postmarketing Changes, for major changes, an MAH shall file a supplementary application with the CDE, submit study materials, and implement such changes after approval. For moderate changes, an MAH shall submit the notification filings to the CDE or provincial-level drug regulatory authorities; upon submission of the requisite notification materials, the notification filings are deemed to be complete and the moderate changes can be implemented. For minor changes, an MAH shall describe the changes in an annual report.

根据《药品上市后变更管理办法》，对于重大变更，持有人应向药审中心提出补充申请，提交研究资料，经批准后实施；对于中等变更，持有人应向药审中心或省级药品监管部门备案，按要求提交备案资料后即完成备案，可以立即实施相应变更；对于微小变更，持有人应在年度报告中载明。

B. Liabilities for Drug Change Management Violations
违反药品变更管理规定的法律责任

Drug registration applicants, MAHs, and manufacturers can be liable for any violation of drug change management regulations. Potential penalties for violating companies include a warning, order to correct, confiscation of illegal gains, drugs, APIs, excipients, packaging materials, and manufacturing equipment, monetary penalty, order to cease business and operation, access restrictions, and even revocation of drug approvals, drug manufacturing licenses, and drug distribution licenses. The responsible persons may face confiscation of illegal gains, monetary penalty, debarment, and even detention.

药品注册申请人、持有人、生产企业违反药品变更相关管理规定需承担相应法律责任，企业可能面临警告、责令改正、没收违法所得、没收药品、原辅包材料和生产设备、罚款、责令停产停业、准入限制乃至吊销药品批准证明文件、药品生产或经营许可等处罚，相关责任人员可能面临没收违法所得、罚款、禁止从业乃至拘留等处罚。

C. Conclusion
结语

Pharmaceutical companies doing business in China now have more clarity on the rules with respect to drug change management, but these companies also face more regulatory requirements and compliance challenges after the promulgation of Drug Administration Law in 2019, Drug Registration Regulation in 2020, the Measures on Drug Postmarketing Changes in 2021, and many implementing technical guidelines. Accordingly, pharmaceutical companies should thoroughly understand the regulatory requirements and closely monitor the development in this area. If you have any questions on any of the above topics, please do not hesitate to contact us. 

随着2019年《药品管理法》、2020年《药品注册管理办法》、2021年《药品上市后变更管理办法》以及诸多配套技术指导原则的相继颁布，一方面，医药企业处理药品变更问题时得以更加有章可循，另一方面，医药企业也将面临新的监管要求与合规挑战。为此，医药企业应深入了解监管要求，并密切关注这一领域的发展。若您对上述话题有任何疑问，欢迎随时联系我们。

© Arnold & Porter Kaye Scholer LLP 2021 All Rights Reserved. This Advisory is intended to be a general summary of the law and does not constitute legal advice. You should consult with counsel to determine applicable legal requirements in a specific fact situation.