Provisions for Post-marketing Changes of Drugs (Interim)

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  • Time of issue:2019-07-31 19:36
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(Summary description)Article 1 [Objective] These Provisions are formulated for the purpose of further regulating post-marketing changes of drugs and strengthening administrative responsibilities of drug marketing authori

Provisions for Post-marketing Changes of Drugs (Interim)

(Summary description)Article 1 [Objective] These Provisions are formulated for the purpose of further regulating post-marketing changes of drugs and strengthening administrative responsibilities of drug marketing authori

  • Categories:National policy
  • Author:
  • Origin:
  • Time of issue:2019-07-31 19:36
  • Views:
Information

  Chapter I  General Provisions

  Article 1  [Objective] These Provisions are formulated for the purpose of further regulating post-marketing changes of drugs and strengthening administrative responsibilities of drug marketing authorization holders (hereinafter referred to as" holders") on post-marketing changes of drugs in accordance with Drug Administration Law, Vaccine Administration Law, Provisions for Drug Registration (Order No. 27 of the State Food and Drug Administration) and Provisions for Supervision of Drug Manufacturing (Order No. 28 of the State Food and Drug Administration).

 

  Article 2  [Scope of Application] Post-marketing changes of drugs in these provisions refer to changes of items specified in the holder's drug manufacturing certificate, changes of items and contents in the drug marketing approval proof document and its attachments, as well as changes listed in the guidelines for changes. Post-marketing changes of drugs consist of changes of manufacturing supervision and changes of registration.

 

  Article 3 [Principles of Encouraging Changes and Improvement] Holders shall take the initiative to carry out post-marketing study of drugs, so as to realize full life-cycle management of post-marketed drugs. Holders are encouraged to use new manufacturing technology, new methods, new equipment and new scientific and technological achievements, so that the production process can be improved and optimized continuously, the quality of drugs be further increased and well controlled, and the safety and effectiveness of drugs be upgraded.

 

  Post-marketing changes of drugs shall not affect or bring potential risk to the the safety, effectiveness and quality control of drugs.

 

  Article 4  [Obligations of Holders and Principles of Classification Management] As the responsibility subject for the management of post-marketing changes of drugs, holders shall establish the control system for post-marketing changes of drugs in accordance with laws and regulations, Good Manufacturing Practice and other relevant requirements; holders shall formulate and implement classification principles of internal changes, procedures and standards of risk management in accordance with relevant technical instructions and guidelines of International Conference on Harmonization (ICH), and determine the category of change management after adequate research and verification regarding the characteristics of the products.

 

  Article 5  [Change Classification Management] Changes are of three categories: major changes, medium changes and minor changes, the management of which are implemented or reported after being approved and filed in accordance with relevant requirements of Provisions for Drug Registration. Holders are responsible for the authenticity, accuracy and integrity of the submitted materials.

 

  Article 6 [Responsibilities for Change Management] The National Medical Products Administration (NMPA) is responsible for formulation of regulations and relevant technical guidelines for post-marketing change management of drugs, and shall guide holders to conduct study on post-marketing changes of drugs; NMPA is responsible for major change management of post-marketing drug registration and medium and minor change management of overseas manufactured drugs, and shall organize and implement the supervision and management of post-marketing changes of drugs in accordance with the law.

 

  Provincial drug regulatory departments are responsible for approving, filing, reporting and other management of post-marketing drug changes within their administrative regions, and shall organize and implement the supervision and management of post-marketing changes of drugs under the rule of law.

  Chapter II Conditions of Changes

  Section 1 Classification of Changes

  Article 7 [Management of Changes of Manufacturing Supervision Items] Changes of manufacturing supervision items include changes of approval and registration items specified in the drug manufacturing certificate. The specific change management is conducted according to relevant requirements of Provisions for Supervision of Drug Manufacturing.

 

  Article 8 [Management of Changes of Registration Items] Changes of registration items include the change of the holder, change of technical contents and corresponding management information specified in drug approval proof document and its attachments, as well as changes listed in the guidelines for changes.

 

  Procedures and materials for the changes of registration items shall meet the requirements of change items and application dossiers of marketed drugs, as well as the requirements of relevant technical guidelines.

 

  Section II  Changes of Drug Marketing Authorization Holders

 

  Article 9  [Application for Changes of Registration Items] Changes of holder’s name and manufacturing sites, house number and name of the contract manufacturer should be filed at provincial drug regulatory departments regarding related management information of drug approval document, after the changes of corresponding items for drug manufacturing certificate are finished. Application for changes of overseas manufactured drugs should be submitted to Center for Drug Evaluation of NMPA (hereinafter referred to as CDE) for filing.

 

  Article 10  [Application for Changes of Holders] In case of application for changes of the holder, the transferee shall acquire the drug manufacturing certificate in accordance with the corresponding scope of manufacturing before submit supplementary application, for which technical review is not needed, to CDE for registration.

 

  CDE shall make the decision concerning the change application within the specified time limit, and send a copy to the provincial drug regulatory department where the transferor and the transferee are located. Procedures, time limit and relevant requirements shall be in accordance with the attachments of these Provisions.

 

  The newer holder shall have a manufacturing quality control system that meets the requirements of Good Manufacturing Practice, and the drug is not allowed to enter the market until the inspection is passed.

 

  Article 11  [Criteria for Changes of Holders] After the change of the holder is approved by CDE, the previous drug registration certificate will be revoked and a new one be issued, meanwhile related information concerning the holder or manufacturer shall be rectified in production process, specification, insert packages and labels, or comments shall be made in the approval conclusion. The approval number and the date of expiry of the certificate remain unchanged.

 

  Article 12 [Management After Changes of Holders] The manufacturing site, drug formulation, production process and specification of the drug should be consistent with those of the original drug despite of the change of the holder.

 

  Holders who are subject to change shall conduct adequate study and verification, and implement or report the change as required after being approved and filed, so as to ensure that drugs with the same quality as the original drugs can be produced on a long-term and stable basis.

 

  Article 13  [Changes of Marketing Authorization Holders of Overseas Manufactured Drugs] If the marketing authorization holder of overseas manufactured drugs is still located abroad after the change, supplementary application should be submitted to CDE by the new holder after the approval by relevant national or regional drug regulatory departments overseas is achieved.

 

  Section III Management of Changes of Manufacturing Sites

 

  Article 14  [Definition of changes of manufacturing sites] Changes of manufacturing sites refer to changes of address, location and manufacturers (including self-owned manufacturing sites and contract manufacturing sites) specified in the holder’s drug manufacturing certificate and drug approval proof document, including newly-built, rebuilt and expanded factories and production lines at the original sites or relocated sites.

 

  Article 15  [Approval of Changes of Manufacturing Sites] Holders to conduct changes of manufacturing sites shall submit an application to  provincial drug regulatory department, and perform the procedures in accordance with the requirements specified in the Provisions for Drug Supervision of Manufacturing and the attachment of these Provisions.

 

  Article 16  [Management of Drugs After Changes of Manufacturing Sites] After the change of drug manufacturing site, the drug formulation, production process and technology and specification should be consistent with those of the original drug, so as to ensure that drugs with the same quality as the original drugs can be produced on a long-term and stable basis. In case of any change, research shall be carried out and the change be implemented or reported after being approved and filed as per these Provisions.

 

  For the changes of manufacturers, including the change of contract manufacturers, the addition of contract manufacturers, the change from  self-manufacturing by the holder to contract manufacturing, and the change from contract manufacturing to self-manufacturing by the holder, supplementary application should be submitted to CDE after the change of manufacturing certificate is completed as required and research is finished according to relevant technical guidelines. CDE shall carry out technical review within the specified time limit, and conduct on-site verification and take samples for inspection as required.

 

  Article 17 [Localized Manufacturing of Overseas Manufactured Drugs] For overseas manufactured drugs to be locally manufactured, holders shall submit supplementary application for change of the manufacturer to CDE upon completion of verification at domestic manufacturing site in accordance with the requirements of technical guidelines. CDE shall carry out technical review within the specified time limit, and conducts on-site verification and take samples for inspection as required.

 

  Section IV Changes of Registration Items for Other Drugs

 

  Article 18  [Changes of Drug Production Process] Concerning changes of manufacturing process such as key production equipment, source and types of important APIs, excipients and packaging materials, technical parameters of key production steps, holders shall fully evaluate the risk of the change upon safety, effectiveness and quality control of the drug, and carry out adequate study and verification in accordance with relevant technical guidelines and Good Manufacturing Practice, determine the management category of the change, and implement or report the change after being approved and filed.

 

  Article 19 [Specification, package inserts and labels] The management of changes of drug specification, package inserts and labels should be carried out in accordance with relevant regulations and technical requirements.

 

  Chapter III Adjustments to the Categories of Change Management

 

  Article 20 [Determination of Category of Change Management] Holders shall determine the categories of change management according to relevant regulations, if it is specified in laws and regulations, or clearly required by technical guidelines.

 

  For categories of change management that are not specified in laws, regulations or technical guidelines, holders shall determine the category in accordance with technical guidelines and on the basis of classification principles for internal changes, procedures and standards of risk management, as well as product characteristics and verification results.

 

  Article 21  [Communication and Determination of Change Management Category] For holders failing to determine the change management category, implementation should be carried out as required after consensus is achieved from communication between the holder and provincial drug regulatory department on the basis of adequate study and verification; if consensus cannot be achieved, the provincial drug regulatory department shall turn to CDE for assistance in determining the change management category, and CDE shall reply within 30 days.

 

  For overseas manufactured drugs of which the change management category can not be determined, communication with CDE is recommended on the basis of adequate study and verification, and it shall be carried out according to relevant communication procedures for drug registration.

 

  Article 22  [Adjustments to Change Management Category] Holders may adjust the change management category as per the changes in management and manufacturing technology, and conduct implementation or reporting pursuant to the adjusted change management category after being approved and filed.

 

  Downgrading the change management category specified in the technical guidelines should only be implemented after consensus is achieved from communication with drug regulatory departments. If the major change management category is to be downgraded, provincial drug regulatory departments shall turn to CDE for assistant in determining the management category, and CDE shall reply within 30 days.

 

  Article 23 [Integration of New and Former Systems] Prior to the implementation of revised Drug Administration Law and Provisions for Drug Registration, for changes that have been proved not affecting drug quality by study and verification carried out by holders or manufacturers in accordance with relevant regulations of change management of the previous production process and technical requirements, or process changes that have been approved and re-registered, re-application pursuant to new change management regulations and technical requirements is not needed (not  deemed as illegal despite of the new change management regulations and technical requirements.) New changes will be performed in accordance with current change management regulations and technical requirements, and will be included in the categorical files.

 

  Article 24 [Principles of Change Management of APIs] For technical changes of APIs that are marked as “A” on the joint review and approval platform or has passed the joint review and approval together with the drug preparation, registrant of APIs shall determine the change category according to current regulations of drug registration administration, technical guidelines and these Provisions, and implement or report the change after being approved and filed. Related information should be updated on the registration platform in a timely manner.

 

  After implementation of the change, the registrant of APIs shall notify relevant holders of the change in time. Upon being informed, holders shall carry out timely evaluation and study on the impact of the change on the quality of the drug products, and submit supplementary application, file or report the change as per relevant regulations.

 

  Chapter IV Procedures, Requirements, Supervision of Changes

 

  Article 25  [Application for Major Changes] For major change, holders shall submit supplementary application to CDE, and research materials should also be submitted in accordance with relevant regulations and technical guidelines for change. Implementation is only allowed after the change is approved. The specific working time limit should be consistent with the Provisions for Drug Registration.

 

  Article 26 [Filing of Medium Changes] Medium changes should be filed at CDE or provincial drug regulatory departments by holders. Filing related information should be publicized by the filing department within 5 days from the date of filing completed.

 

  On the basis of risk characteristics of changes and credit profiles of enterprises, the filing department shall carry out timely review on the filing, strengthen post-event supervision and administration, and conduct examination and inspection when necessary.

 

  The provincial drug regulatory department may establish its own procedures and requirements for filing management of changes of drug registration and administration in accordance with local government's requirements for filing review.

 

  Article 27 [Minor changes] Minor changes should be managed by holders according to requirements of change management, and should be described in the annual report.

 

  Article 28  [Changes Received] When supplementary application and filing received by provincial drug regulatory departments and CDE are considered to be inconsistent with their administrative functions, a written document with the official seal will be issued to clarify the reasons of rejection and to inform the applicant that application should be submitted to corresponding departments.

 

  Article 29  [Information Sharing and Annual Reports] Information approvals and filings of post-marketing changes of drugs should be included in the drug variety archive by drug regulatory departments in time; holders shall summarize and analyze all the drug changes throughout the year in the annual reports.

 

  Article 30 [Management of Changes of Supervision] Provincial drug regulatory department where the holder and contract manufacturer are located shall strengthen supervision of post-marketing changes of drugs. Major changes specified in laws, regulations and guidelines or determined by holders should be implemented according to relevant requirements after approval. Major changes of downgrading change management categories upon consensus achieved from communication with drug regulatory departments should be filed or reported according to the categories of change management in the consensus. Changes for filing and reporting management specified in laws, regulations and guidelines or determined by holders should be filed or reported according to relevant regulations.

 

  Article 31 [Changes Punished] When drug regulatory departments find that the results of study and verification concerning the change can not provide sufficient evidence for more scientific, rational and risk-controllable performance, or the change management category is inappropriate, the holders shall make rectification and drug regulatory departments shall conduct risk evaluation on post marketed drugs and take corresponding risk control measures.

 

  Changes made during the production process without being approved or filed, or not reported accordingly are subject to the Drug Administration Law.

 

  Chapter V Supplementary Provisions

 

  Article 32 [Exception] Change management of toxic drugs for medical use, narcotics, psychological drugs, radioactive drugs, pharmaceutical precursor chemicals, vaccines, biological products are subject to specific regulations, if any.

 

  Article 33  [Principles of Early Application Handling] Supplementary application and filing of post-marketing changes of drugs received before the implementation of these Provisions are subject to the previous procedures and requirements, or the applicant may withdraw the original application and submit supplementary application, put for filing or report in accordance with these Provisions.

 

  Article 34 [Implementation Date] These Provisions shall come into force as of the date of issuance. As of the date when the Provisions goes into effect, Announcement on Issues Concerning Administration Regulations of Registration of Drug Technology Transfer (Order No. 518 of the State Food and Drug Administration [2009]),  Notice on Implementation of Drug Technology Transfer Under Revised Good Manufacturing Practice (Order No. 38 of the State Food and Drug Administration [2013]) shall be annulled therefrom.

 

  Annexe: Management Requirements for Change of Holders

  Annexe

  Management Requirements for Change of Holders

 

Conditions of Changes

Procedures of Application and Approval or follow-up work

Working time limit

(Working day)

Requirements for application dossiers

1. Changes of drug registration items such as holders’ names

Submit the application for filing to the provincial drug regulatory department where the holder is located or CDE

In accordance with relevant regulations

1. Drug Manufacturing Certificate Changed

2. Other materials required for filing by provincial drug regulatory departments

2. Changes of marketing authorization holders

Supplementary application for registration, when technical review is not needed,  should be submitted to CDE by the transferee.

Time limit for registration, review and approval: 20 days

1. A copy of drug registration certificate to be transferred;

2. Drug manufacturing certificate and business license of the transferee;

3. Documents of the transferee that meet relevant requirements of Good Manufacturing Practice

4. Notarized transfer contract by both parties (confidential contents should be hidden)

5. For changes of overseas subjects, approval proof document by relevant national or regional drug regulatory departments should be submitted;

6. Other materials specified in the requirements for supplementary application

3. After change of holders completed

(1) Drug manufacturing sites unchanged

GMP compliance inspection

In accordance with relevant regulations

——

(2) Change of drug manufacturing sites (including the change of manufacturing sites of contract manufacturers, change of drug manufacturers excluded)

After the change of drug manufacturing certificate completed and GMP compliance inspection passed, changes concerning other registration items should also be implemented or reported after being approved and filed in accordance with the change management category.

In accordance with relevant regulations

Research materials required by relevant technical guidelines

(3) Change of drug manufacturers

After the change of drug manufacturing certificate, supplementary application should be submitted to CDE by holders and implemented upon approval.

 

 

4. Change of drug manufacturing sites by holders

Change of drug manufacturing sites (including the change of manufacturing sites of contract manufacturers, change of drug manufacturers excluded)

After the change of drug manufacturing certificate completed and GMP compliance inspection passed, changes concerning other registration items should also be implemented or reported after being approved and filed in accordance with the change management category.

In accordance with relevant regulations

Research materials required by relevant technical guidelines

 

Change of drug manufacturers

After the change of drug manufacturing certificate, supplementary application should be submitted to CDE by holders and implemented upon approval.

In accordance with relevant regulations

Research materials required by relevant technical guidelines

 

 

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