New Regulations for Post-Market Drug Changes Remain Unclear on Cross-Border Contract Manufacturing
Writer: Jianqing Chang, Vice President of Drug Regulatory Policy, Tigermed Co., Ltd.
Editor: Justin Fischer
Following the latest revision of China's drug administration law from December 2019, drug life cycle management has become a key obligation for Marketing Authorization Holders (MAHs). Recently, the National Medical Products Administration issued regulations for post-approval changes in medicinal products (for pilot implementation). The action was intended to further regulate post-approval changes of drugs and to strengthen the responsibilities of drug MAHs in their management of post-approval changes to drugs.
New obligations for MAHs
For the entire drug lifecycle management, MAHs are now expected proactively conduct post-approval drug studies. They are encouraged to continuously improve and optimize the production process with new technologies, methods, equipment and scientific and technological achievements. This will ultimately improve drug safety, efficacy, and quality control.
MAHs will also need to establish a post-approval changes control system in accordance with the laws and regulations on drug supervision, the Good Manufacturing Practice for Drugs and other relevant regulations. They will be expected to formulate and implement the principles for their internal classification of changes, working procedures and risk management requirements in accordance with NMPA and ICH's relevant technical guidelines. Additionally, they will have to manage the classification of changes after sufficient study, evaluation and necessary verification in combination with product characteristics.
Redefining the scope of post-approval changes
There are also new regulations on changes to administrative items for registration and supervision items for production. Changes to administrative items for registration includes the technical content and corresponding management information. Changes to management requirements must now comply with drug registration regulations and their accompanying technical guidelines. Changes to production supervision items includes the licensed and registered items specified in the drug manufacturing license. The management requirements for changes will now have to follow regulations for drug registration, manufacturing supervision and the relevant provisions of the Good Manufacturing Practice for Drugs.
New post-approval classifications
Based on legal requirements and the impact on drug safety, effectiveness, and quality control, post-approval changes have been divided into three classifications. They comprise: review and approval, notification, and reporting. These changes will be now be implemented or reported after approval and filing.
Who the new regulations affect
Changes for overseas MAHs
When applying for changes, overseas MAHs will now have to ensure that the manufacturing site, formulation, manufacturing process and drug specifications are consistent with those of the original drug. Upon approval, the MAH will then have to conduct sufficient study, evaluation and verification before implement or reporting these changes.
Changes between overseas MAHs will now have to be submitted in a supplementary application to the CDE.
When relocating a manufacturing site from overseas to China, the domestic applicant must submit an application consisting of relevant CMCs, non-clinical and clinical data (if applicable) and the drug's original registration application dossiers. Those meeting the requirements may apply to become a reference drug product.
The CDE must now be notified of any name changes of MAHs, manufacturers, or manufacturing sites.
Changes for manufacturing sites
According to these new regulations, any change in address, new construction, or expansion of an existing site is a manufacturing site change. The manufacturing site's information must be specified in the drug manufacturing license and the MAH's drug approval documentation. This regulation applies to sites owned by MAHs as well as sites owned by contract manufacturing organizations (CMO).
MAHs must ensure that the drug's formulation, production process, and quality standards are consistent with those of the original drug. Any changes to a drug's formulation, manufacturing process, and specifications require sufficient study, evaluation, and necessary verification. The MAH must then implement or report the changes upon notification of approval.
Any MAHs still operating outside of China must conduct a study and evaluation in accordance with the relevant technical guidelines and submit a supplementary application of notification to the CDE.
Changes to other drug registration items
MAHs must now evaluate the degree of risk that any changes in the production process may pose to the drug’s safety, efficacy and quality control. They will be required to evaluate, implement and report the changes after approval and notification.
Any changes to package inserts and labels must be made in accordance with the relevant regulations and technical requirements.
Any changes made to an API that has been reviewed and approved will have to be specified, implemented and reported after approval and notification. The API registrant must also notify all relevant MAHs before the implementing the changes. MAHs must in turn evaluate any affects the changes may have on the quality of pharmaceutical preparations and submit a supplementary application, notification or report.
New change management classifications
Where specified by laws, regulations or technical guidelines, MAHs shall generally determine change management classifications. However, if no such specifications exist, MAHs must determine change management classifications based on sufficient evaluation and study. If necessary, MAHs can apply for a classification with the CDE.
MAHs may adjust change management classifications according to changes in management and production technology. They may implement or report the changes as upon approval and notification as well.
If change management classifications of overseas drugs are lowered, MAHs must implement them after communicating with the CDE and reaching an agreement based on sufficient study, evaluation, and necessary verification.
New procedures and requirements
MAHs shall submit a supplementary application for review and approval changes to the CDE along with the relevant study data. MAHs must also implement these changes within six months from the date of approval. Matters involving drug safety-related changes are an exception and will be subject to the implementation date specified in the supplementary application approval letter.
MAHs must report changes in accordance with the relevant requirements, which will be indicated in the annual report.
To continuously improve drug quality and manage life-cycle risks, MAHs will receive guidance and support in handling post-approval changes when applying new drug technologies, methods, facilities, etc.
Certain hurdles nevertheless remain in place. For instance, overseas MAHs still may not contract China-based CMO(s). Likewise, China-based MAHs may not contract ovearseas CMO(s). So, for some products licensed in to China or licensed out to countries overseas, deciding where to locate MAHs and manufacturing sites remains a difficult, albeit important, business decision.