Questions and answers on the related review of drug packaging materials and excipients

Questions and answers on the related review of drug packaging materials and excipients

2016-11-12 Dandelion

Source: China Medical News

 

1. The auxiliary materials are produced in the United States and have not been registered in China. How should they be operated? What materials should be submitted? How long will it take to get the approval?

Answer: In accordance with the provisions of Article 2 of the Announcement of the General Administration on Matters Related to the Review and Approval of Drug Package Materials and Pharmaceutical Accessories (hereinafter referred to as the "Announcement") (No. 134 of 2016), when applying for drug registration, the drug package materials and pharmaceutical accessories shall be subject to related review and approval. In other words, the State Administration will no longer accept the declaration of pharmaceutical excipients separately. Only when the drugs using the pharmaceutical excipients are registered, the review and approval shall be carried out according to the scope of pharmaceutical excipients subject to related review specified in the "Announcement". For pharmaceutical excipients used in domestic listed or unlisted preparations without approval documents or approval numbers, the provisions of Article 3 of the "Announcement" shall be followed, for pharmaceutical excipients that meet the application requirements, the data shall be filled in according to the "Requirements for Application Data of Drug Package Materials and Pharmaceutical Excipients" issued by the General Administration, and the application shall be made according to the procedures for review and approval of drug package materials, pharmaceutical excipients and drugs in the "Announcement" (for trial implementation). After the application for drug production is approved, the related declared pharmaceutical excipients will no longer be issued approval documents, but will be given an approval number by the Drug Examination Center of the General Administration.

 

2. During the transition period of the implementation of related review and approval, when applying for new pharmaceutical preparations, the drug packaging materials and pharmaceutical excipients that have obtained the registration certificate are used. If all materials are prepared according to DMF data requirements, can the review be given priority?

Answer: In the current implementation of the drug packaging materials pharmaceutical excipients and drug related review and approval management system, has not yet stipulated the pharmaceutical excipients for DMF data filing related management requirements, so the current national drug regulatory agencies do not separately accept the pharmaceutical excipients DMF application data. The "Announcement" has been officially issued and implemented by the State Administration on August 10, 2016. After the implementation of the "Announcement", if the pharmaceutical excipients used by drugs currently on the market have obtained the approval number, when used in other similar preparations, if they are within the scope of the pharmaceutical excipients subject to joint review and evaluation specified in the "Announcement", In particular, the excipients for high-risk preparations and the pharmaceutical excipients that the State Administration specifically requires supervision according to needs still need to be reviewed; if it is not within the scope of the pharmaceutical excipients for the implementation of the associated review specified in the "Announcement", there is no need for the associated review. (The expert answering the questions in this issue is Hong Xiaoxu, deputy director of the Business Integration Department of the State Pharmacopoeia Commission)

 

3. How to declare the replacement of drug packaging materials (suppliers) and the addition of alternative drug packaging materials (suppliers) for registered drugs? How to review?

Answer: Article 5 of the General Administration's Announcement on Matters Related to Review and Approval of Drug Packaging Materials and Drug-Related Excipients (No. 134 of 2016) specifies that applications for drug clinical trials or production of drugs shall be submitted in accordance with the requirements of the Announcement. For changes (replacement or addition of alternatives) to drugs already on the market, a supplementary application for drugs shall be submitted in accordance with the requirements of the measures for the administration of drug registration, and whether the supplementary application is applicable to the scope of the published related review announcement shall be subject to official interpretation. For specific change declaration requirements, we can refer to the "Technical Guidelines for Research on Changes of Listed Chemicals" issued by CDE to carry out research and verification work on different situations of changes of Class I, II and III of drug packaging materials, and compare the classification of high-risk drug packaging materials and non-high-risk drug packaging materials in Annex 1 of the related review announcement, and comprehensively consider the risk level and change classification requirements of enterprises to change drug packaging materials. In general, changes to the packaging materials and containers of the drug product should have a beneficial effect on the quality and stability of the product, or at least not reduce its protective effect, and there should be no adverse interaction between the drug and packaging materials and the container.

 

4. After the import registration certificate of the original imported packaging materials expires, what documents does the original user use to support the continued use? Is it enough for the packaging material production enterprise to file and declare the materials?

A: If the validity period of the registration certificate for imported packaging materials described in this question has expired, please refer to the provisions of Article 5 of the General Administration's Announcement on Matters Related to Review and Approval of Pharmaceutical Packaging Materials and Drugs (No. 134 of 2016). The registration certificate for drug packaging materials expires before December 31, 2017, and the validity period extends to December 31, 2017. After December 31, 2017, it can also continue to be used in the original drug. If the original drug submits its drug renewal registration before December 31, 2017, the expired drug packaging material registration certificate can be used as a supporting document; If the original drug submits its drug renewal registration after December 31, 2017, the drug packaging material can continue to be used according to the announcement, but there will be no supporting documents for the packaging material available at that time. It is suggested that drug packaging material manufacturers consider submitting related review data of packaging material varieties with expired validity during the transitional period of December 31, 2017 given by the announcement. (This issue is answered by experts from China Pharmaceutical Packaging Association)

 

5. How can the associated review of drug packaging materials and drugs be consistent in time?

Answer: in accordance with the provisions of the announcement and the associated review procedure, when the drug packaging materials are applied for in connection with the drug clinical trial or production application, the drug packaging material manufacturer shall fill in the application form of drug packaging materials according to the information such as the applicant, drug name and acceptance number of the associated drug registration application, and truthfully submit the application materials to the local provincial food and drug supervision and administration department. When the drug registration applicant submits the drug registration application, the relevant information of all related drug packaging materials should be indicated in the "source of drug packaging materials" item in the drug registration application form. In terms of procedure and time, it is necessary for the drug registration applicant to submit the application first, and after obtaining the acceptance number, the drug packaging material production enterprise shall submit the information with this acceptance number. Because the materials are submitted separately and may be submitted in different provincial bureaus, the potential impact is that drug registration applicants will be more worried about whether the time and quality of materials submitted by raw and auxiliary materials suppliers will affect the drug registration application, so they will be more inclined to choose drug packaging materials manufacturers with better credit, better service quality and better product quality, and may involve the time limit and quality requirements for submitting materials in the agreement between the two parties. In terms of technical requirements, the specific "Application Data Requirements" will be announced later. Drug registration applicants will select drug packaging materials and put forward relevant requirements according to the requirements of risk level. At the same time, drug packaging materials enterprises are required to submit relevant information and materials according to regulations.

 

In addition, the data involved (including drugs, drug packaging materials, raw materials, etc.) will not start the review until the drug review center summarizes them, and the specific review procedures within the drug review center have not yet been made public, so it is not clear in the specific circulation and information transmission of the application data.

 

6. When the situation of drug packaging materials changes, the drug packaging materials manufacturers intentionally conceal the changes, and the drug quality problems can only be discovered. Is there a good way to solve this problem?

Answer: The Announcement clearly stipulates the responsibilities and obligations of drug packaging materials manufacturers and drug registration applicants, that is, when drug packaging materials and pharmaceutical excipients change prescriptions, processes, quality standards and other changes that affect product quality, their manufacturers Should take the initiative to carry out corresponding assessments, notify drug manufacturers in a timely manner, and submit relevant materials to the food and drug supervision and administration department as required. The applicant for drug registration shall ensure that the drug packaging materials used meet the medicinal requirements, timely grasp the changes of the drug packaging materials, study and evaluate the impact of the changes, and submit the corresponding supplementary application to the food and drug supervision and administration department in accordance with the measures for the administration of drug registration and other relevant provisions. In order to avoid the impact of supplier problems on drug quality, on the one hand, drug manufacturers will be more inclined to choose drug packaging material manufacturers with better credit, better service quality and better product quality; on the one hand, they will establish information communication between the two parties. A mechanism to ensure timely access to change information; in addition, the requirements for the change of drug packaging materials will be put forward in the agreement between the two parties. (The answer expert for this issue is Han Peng, Vice President and Academic Director of Yihong Business College of Shenyang Pharmaceutical University)

 

7, the production management of pharmaceutical packaging materials enterprises with what standards to regulate and supervise, there will be specific guidelines?

Answer: The standardized management of the daily production of pharmaceutical packaging materials manufacturers is the fundamental guarantee for the quality, stability and reliability of pharmaceutical packaging materials. The implementation of the review and approval system for drug packaging materials, pharmaceutical excipients and drugs will further strengthen the main responsibility of drug manufacturers. Pharmaceutical manufacturers should strengthen the audit of drug packaging suppliers, ensure product quality and reduce potential risks through the control of the whole production process. At present, China's drug administration has not yet issued a mandatory drug packaging material production management practices (GMP) technical requirements. At present, there is a situation of "emphasis on inspection and light management; emphasis on results and light process" in the selection and quality of drug packaging materials, which ignores the impact of the production process of drug packaging materials on product quality to a certain extent. Because there are many types of drug packaging materials used in drugs, different raw materials, large differences in production methods, and a completely unified model of drug packaging material production management specifications are difficult to adapt to the needs of different types of drug packaging material production, therefore, corresponding production management specifications should be formulated for different types of drug packaging materials, such as GMP requirements for glass and rubber. In line with the principle of steady progress and gradual standardization, at present, the State Pharmacopoeia Commission has begun to consider guiding relevant industry associations to formulate GMP requirements for different types of pharmaceutical packaging materials. Initially, it will be issued in the form of a technical guide for the GMP industry, which will be used as a reference technical requirement for the daily audit of pharmaceutical packaging production and preparation enterprises. After a period of implementation and supplement and improvement, after the technical requirements are mature, the relevant GMP technical requirements for pharmaceutical packaging materials can be issued through official release or approval, as a mandatory implementation of technical requirements.

 

8. If the registration certificate of drug packaging materials and pharmaceutical excipients expires at the time of registration application, should the drug packaging materials and pharmaceutical excipients enterprises submit related review materials?

Answer: According to Article 5 of the "Announcement of the General Administration on Matters Related to the Review and Approval of Drug Package Materials and Pharmaceutical Accessories" (hereinafter referred to as the "Announcement"): "Approved drug package materials and pharmaceutical accessories, their approval documents Continue to be valid during the validity period. After the expiration of the validity period, it can continue to be used in the original drug. If it is used for drug clinical trials or production applications for other drugs, the relevant information shall be submitted in accordance with the requirements of this announcement". In other words, after the expiration of the validity period of the approval documents for drug packaging materials, there is no need to re-register or submit related declaration materials before December 31, 2017, and it can still be used in the original preparation. After January 1, 2018, if it is used for registration declaration of other drugs, relevant information shall be submitted. (The expert answering the questions in this issue is Hong Xiaoxu, deputy director of the Business Integration Department of the State Pharmacopoeia Commission)

 

9. When the pharmaceutical packaging materials change the prescription, process, quality standard, source of raw materials and other changes that affect the product quality, how should the pharmaceutical companies that use the pharmaceutical packaging materials declare? How to review?

Answer: According to the announcement, the food and drug supervision and administration departments at all levels will no longer separately accept applications for registration of drug packaging materials and pharmaceutical excipients, and will no longer separately issue relevant registration approval documents. At present, the change channels of pharmaceutical excipients and pharmaceutical packaging materials are not clear, and the guidelines for the change of pharmaceutical excipients and pharmaceutical packaging materials will be specially formulated in the future. If the original use of the preparation product is affected, the preparation enterprise can apply for the supplementary application according to the registration management method.

 

10, drug packaging materials enterprises to produce new products, whether it is necessary to register a new drug through the pharmaceutical enterprises to file and obtain the record number?

Answer: According to the announcement, new auxiliary materials or new packaging materials shall be declared in association with preparation products according to the principle of "re-reporting when used", I .e. the declaration materials shall be submitted according to the acceptance number of preparation products. Therefore, it is necessary to participate in the early development of formulation products as soon as possible.

 

After the import registration certificate expires, what documents will the original user use to support the continued use of the original imported packaging materials? Does the packaging material manufacturer need to file and declare the materials?

 

According to the announcement, the certified excipients will no longer be re-registered, and the validity period will be extended to December 31, 2017, and will not be affected when used in the original preparation products; after January 1, 2018, if used in other preparations When the product is required to be declared in association with the preparation product in accordance with the new application data requirements. (The answer expert for this issue is Han Peng, Vice President and Academic Director of Yihong Business College of Shenyang Pharmaceutical University)

 

11, has accepted clinical and clinical approval of biological products preparations, the use of non-registration certificate excipients, the need for related review when reporting

Answer: According to Article 3 of the Announcement of the General Administration on Matters Related to the Review and Approval of Drug Package Materials and Pharmaceutical Accessories, starting from the date of this Announcement, drug package materials and pharmaceutical accessories shall be subject to the application for drug registration and review and approval according to the procedures. The Requirements for the Application Data of Drug Package Materials and Pharmaceutical Accessories shall be published separately. Food and drug supervision and administration departments at all levels will no longer separately accept applications for registration of drug packaging materials and pharmaceutical excipients, and will no longer separately issue relevant registration approval documents. Biological products enterprises in the use of new products without registration certificate accessories, must be in accordance with the provisions of the associated review, submit the review data.

 

12. After January 1, 2018, the drug will be re-registered. The original drug packaging materials and auxiliary materials still used do not involve the required changes. Do they need related review?

Answer: According to Article 5 of the announcement of the General Administration on matters related to the review and approval of pharmaceutical packaging materials and pharmaceutical excipients, the approved pharmaceutical packaging materials and pharmaceutical excipients shall continue to be valid during the validity period. After the expiration of the validity period, it can continue to be used in the original drug. If it is used for drug clinical trials or production applications of other drugs, relevant materials shall be submitted in accordance with the requirements of this announcement.

 

Drug packaging materials and pharmaceutical excipients whose approval documents expire before December 31, 2017 (inclusive) shall be valid until December 31, 2017. Starting from January 1, 2018, when applying for drug clinical trials or production of other drugs, relevant materials shall be submitted in accordance with the requirements of this announcement.

 

Other medicinal excipients that meet the medicinal requirements historically used in the marketed drugs may continue to be used in the original drugs. However, when applying for clinical trials or production of drugs used for other drugs, the relevant information shall be submitted in accordance with the requirements of this announcement.

If the original packaging materials and auxiliary materials are still used and do not involve changes in requirements, the filing materials shall be supplemented to obtain a new filing number. (The answer expert for this issue is Professor Tu Jiusheng of China Pharmaceutical University)

 

13. When new customers buy old preparations, how to deal with the drug packaging materials without registration certificate? When the drug production enterprise is associated with the review, should they declare their own materials or use the same variety data declared by the drug packaging materials enterprise in other drug companies?

Answer: Article 5 of the announcement of the State Food and Drug Administration on matters related to the review and approval of pharmaceutical packaging materials and pharmaceutical excipients clearly stipulates that the approved pharmaceutical packaging materials and pharmaceutical excipients shall be approved within the validity period. continue to be valid. After the expiration of the validity period, it can continue to be used in the original drug. If it is used for drug clinical trials or production applications of other drugs, relevant materials shall be submitted in accordance with the requirements of this announcement. Include data on association studies and additional data on drug packaging materials.

 

If a new customer purchases a preparation and the drug package used for the preparation does not have a registration certificate, the related review shall be conducted again in accordance with the relevant regulations. In the related review, the data declared by the packaging materials that have been filed (there should be the authorization letter of the packaging materials enterprise and comply with relevant laws and regulations) can be used, and supplementary materials should be supplemented if necessary after review.

 

14. Do you need to communicate with the preparation enterprises to determine the varieties before carrying out the compatibility test of drug packaging materials?

Answer: Pharmaceutical packaging materials enterprises should assist preparation enterprises to carry out compatibility tests. According to the provisions of Article 3 of the announcement of the General Administration on matters related to the review and approval of drug packaging materials and pharmaceutical excipients, from the date of the announcement, drug packaging materials and pharmaceutical excipients shall be reported and reviewed and approved in accordance with procedures related to drug registration applications, and the Requirements for Application Materials for Drug packaging materials and pharmaceutical excipients shall be published separately. Food and drug supervision and administration departments at all levels will no longer separately accept applications for registration of drug packaging materials and pharmaceutical excipients, and will no longer separately issue relevant registration approval documents.

 

After the implementation of the related review, the preparation enterprise is the main body of quality responsibility, and the applicability and compatibility of drug packaging materials should be studied in the whole research and development stage. (The answer expert for this issue is Professor Tu Jiusheng of China Pharmaceutical University)

 

15. If the registration certificate of pharmaceutical packaging materials and accessories is still valid after January 1, 2018, can it replace the approval number or acceptance number?

Answer: According to Article 5 of the Announcement of the General Administration on Matters Related to the Review and Approval of Pharmaceutical Encapsulating Materials and Drug-related Materials, the approval documents for approved pharmaceutical packaging materials and pharmaceutical excipients will continue to be valid during the validity period. After the expiration of the validity period, it can continue to be used in the original drug. If it is used for drug clinical trials or production applications of other drugs, relevant materials shall be submitted in accordance with the requirements of this announcement.

　

Drug packaging materials and pharmaceutical excipients whose approval documents expire before December 31, 2017 (inclusive) shall be valid until December 31, 2017. Starting from January 1, 2018, when applying for drug clinical trials or production of other drugs, relevant materials shall be submitted in accordance with the requirements of this announcement.

 

Other medicinal excipients that meet the medicinal requirements historically used in the marketed drugs may continue to be used in the original drugs. However, when applying for clinical trials or production of drugs used for other drugs, the relevant information shall be submitted in accordance with the requirements of this announcement.

 

The registration certificate of pharmaceutical packaging materials and accessories in the above problems is still valid after January 1, 2018, and is still effectively used in the original products; for new products, relevant materials shall be submitted in accordance with the requirements of the announcement.

 

16. Is there any risk classification for pharmaceutical packaging materials and accessories, and how to change different risk levels?

Answer: according to Article 4 of the announcement of the General Administration on matters related to the review and approval of pharmaceutical packaging materials and pharmaceutical excipients, when pharmaceutical packaging materials and pharmaceutical excipients change prescriptions, processes, quality standards and other changes that affect product quality, their production enterprises should take the initiative to carry out corresponding evaluation, timely notify the drug production enterprises, and submit relevant materials to the food and drug supervision and administration department as required. The relevant requirements for the change of drug packaging materials and pharmaceutical excipients shall be separately formulated by the State Food and Drug Administration.

 

The risk level of pharmaceutical packaging materials and accessories is mainly divided into channels. Any change of pharmaceutical packaging materials and accessories enterprises should communicate with the production enterprises in a timely manner. Pharmaceutical production enterprises should conduct self-assessment according to the risk degree affecting product quality and apply for changes to high-risk changes. (The answer expert for this issue is Professor Tu Jiusheng of China Pharmaceutical University)

 

17. There is a drug whose registration certificate expires in June 2017, and the packaging materials it uses are still within the validity period. Do you need to file and resubmit the information if you re-register the packaging materials? Can the submitted information follow the information of the original registration certificate of the packaging materials?

Answer: According to Article 5 of the Announcement of the General Administration on Matters Related to the Review and Approval of Drug Package Materials and Drug Related Materials, the approval documents for approved drug package materials and pharmaceutical excipients will continue to be valid during the validity period. After the expiration of the validity period, it can continue to be used in the original drug. If it is used for drug clinical trials or production applications of other drugs, relevant materials shall be submitted in accordance with the requirements of this announcement.

 

Drug packaging materials and pharmaceutical excipients whose approval documents expire before December 31, 2017 (inclusive) shall be valid until December 31, 2017. Starting from January 1, 2018, when applying for drug clinical trials or production of other drugs, relevant materials shall be submitted in accordance with the requirements of this announcement.

 

Other medicinal excipients that meet the medicinal requirements historically used in the marketed drugs may continue to be used in the original drugs. However, when applying for clinical trials or production of drugs used for other drugs, the relevant information shall be submitted in accordance with the requirements of this announcement.

 

18. If the manufacturing enterprise submits the application for drug registration, will the drug packaging materials and auxiliary materials used still submit the information within the validity period?

Answer: According to the announcement on matters related to the review and approval of drug packaging materials and drugs, the drug packaging materials and excipients used in the drug registration application can be directly used within the validity period of December 31, 2017 (inclusive). (The answer expert for this issue is Professor Tu Jiusheng of China Pharmaceutical University)