Reflections on the change management of pharmaceutical excipients and pharmaceutical packaging materials under the related review policy

Summary 

OBJECTIVE: To provide reference for the implementation of the change management system for pharmaceutical excipients and pharmaceutical packaging materials under China's related review and approval poli.

Methods: The management policies of pharmaceutical excipients and pharmaceutical packaging materials in China, the United States, the European Union and Japan were briefly introduced, and the management system for the change of pharmaceutical excipients and pharmaceutical packaging materials was studied and sorted o.

RESULTS AND CONCLUSION: Under the linked review and approval system, drug preparation registration applicants need to pay more attention to the influence of pharmaceutical excipients and pharmaceutical packaging materials on the quality of preparations, and should scientifically and reasonably incorporate pharmaceutical excipients and pharmaceutical packaging materials into the full life cycle of dru.

Key words: related review; pharmaceutical excipients; pharmaceutical packaging materials; change management; drug quality 

CLC number :R954Document identification code: A 

1 my country's drug related review and approval system 

Before the reform of the drug-related review and approval system, APIs, pharmaceutical excipients, and packaging materials and containers that come into direct contact with drugs (hereinafter referred to as "pharmaceutical packaging materials") were all administrative licensing matters, and were managed through registration approval procedur.
After APIs, pharmaceutical excipients, and pharmaceutical packaging materials have obtained approval numbers through independent registration and review, preparation companies purchase APIs, pharmaceutical excipients, and pharmaceutical packaging materials produced by companies with registration certificat.
In 2010 and 2011, the former State Food and Drug Administration publicly solicited opinions twice on the "Medical Raw Materials and Excipients Filing Management System (Draft for Comment)" [1-2], which opened China's filing management of APIs and pharmaceutical excipien.
explorati.
In August 2015, the State Council issued the “Opinions of the State Council on Reforming the Review and Approval System for Drugs and Medical Devices” (Guo Fa [2015] .
44)[3] for the first time, it was proposed to implement the joint review of drugs, pharmaceutical packaging materials and pharmaceutical excipien.
The requirements for the reform of the approval system have been changed from "separate approval of pharmaceutical packaging materials and pharmaceutical excipients" to "reviewed and approved together with the approval of drug registration application.
In order to implement the relevant requirements of the State Council, in August 2016, the former State Food and Drug Administration issued the "Announcement of the General Administration on the Related Review and Approval of Pharmaceutical Packaging Materials, Medicinal Excipients and Drugs" (2016 .
134) [4] , in accordance with the principle of risk management, when examining and approving drug registration applications, the associated review and approval of pharmaceutical packaging materials and pharmaceutical excipients has officially opened the prelude to the reform of the associated review system for pharmaceutical excipients, pharmaceutical packaging materials and pharmaceutical preparations in Chi.
This reform not only shortens the original review time for pharmaceutical excipients and pharmaceutical packaging materials, and then reviews drug preparation applications, but also simplifies the relevant review process, saves government management resources, and strengthens preparatio.
The main responsibility of the applica.
On September 29, 2017, the State Council issued the "Decision of the State Council on Cancelling a Batch of Administrative Licensing Items" (Guo Fa [2017] .
46)[5], which listed a total of 40 items in the catalogue of administrative licensing items cancelled by the State Counc.
The 14th and 15th items in the list of administrative licensing matters are the approval of registration (registration of new pharmaceutical excipients and imported pharmaceutical excipients) and approval of packaging materials and containers in direct contact with dru.

On October 8, 2017, the General Office of the Central Committee of the Communist Party of China and the General Office of the State Council jointly issued the "Opinions on Deepening the Reform of the Review and Approval System and Encouraging the Innovation of Medicines and Medical Devices" (Tingzi [2017] .

42) [
Excipients and pharmaceutical packaging materials will be reviewed and approved together when examining and approving drug registration applications, and API approval numbers will no longer be issu.

Announcement for relevant enterprises to choo.

The drug marketing authorization holder is responsible for the quality of the APIs, pharmaceutical excipients and packaging materials used in the production of the preparatio.

On November 30, 2017, the former State Food and Drug Administration issued the "Announcement of the General Administration on Adjusting the Review and Approval Items of APIs, Pharmaceutical Excipients and Pharmaceutical Packaging Materials" (2017 .

146) [7], clarified that Registration and management of APIs, pharmaceutical excipients and pharmaceutical packaging materia.

Relevant enterprises or units can submit the registration materials of APIs, pharmaceutical excipients and pharmaceutical packaging materials through the registration platform according to the requirements of the announcement, and obtain the registration numbers of APIs, pharmaceutical excipients and pharmaceutical packaging materia.

comme.

Pharmaceutical excipients and pharmaceutical packaging materials adopt the linked review mode, that is, in the application stage of drug clinical trials, the pharmaceutical excipients and pharmaceutical packaging materials that have not been used in domestic and overseas marketed preparations should be related to the application or submitted by the drug registration applicant in accordance with 201 Announcement .

155 [8] of 2008 requires the submission of all research materials; for other pharmaceutical excipients and pharmaceutical packaging materials, the applicant for drug registration shall at least provide information on the manufacturers of relevant pharmaceutical packaging materials and pharmaceutical excipients in the drug registration application materials , product basic information, quality standards and inspection reports and other related materia.

If the related application or all the research materials are not submitted in the drug clinical trial application stage, the relevant pharmaceutical packaging materials and pharmaceutical excipient manufacturers should make the related declaration in the drug marketing application stage, or the drug registration applicant shall submit the related application in accordance with the 2016 Article 15 Notice .

requires the submission of all research materia.

The announcement emphasizes that the drug is regarded as a whole consisting of APIs, pharmaceutical packaging materials and pharmaceutical excipients, and the elements of historical review and approval are unified on a common platform to provide a more scientific and effective drug review for my count.

Metho.

On July 16, 2019, the State Drug Administration issued the "Announcement on Further Improving the Related Matters of Drug-related Review, Approval and Supervision" (2019 .

56) [9], which was officially implemented on August 1 , the announcement further clarified the management method of APIs, updated the registration data requirements of pharmaceutical excipients and pharmaceutical packaging materials, classified the registration data of pharmaceutical excipients and pharmaceutical packaging materials from the perspective of preparation risk, and announced the registration-exempt dru.

Use the catalogue of excipients (2019 edition) to clarify the basic requirements for annual reports and post-market supervisi.

 The implementation of the new system adjusts the isolated and decentralized management mode of pharmaceutical excipients and pharmaceutical packaging materials in the past to a new unified management mode with preparation quality as the core, and improves the technical requirements for pharmaceutical excipients and pharmaceutical packaging materia.

Improving the quality of medicines in China will help to realize the governance concept of "the strictest supervisio.

However, when the pharmaceutical excipients and pharmaceutical packaging materials are changed, how the applicant (or registrant) should conduct risk assessment, what research should be carried out after the change, and what research verification data needs to be provided, e.

are not yet cle.

2 Change management of foreign pharmaceutical excipients and pharmaceutical packaging materials1 Change management of pharmaceutical excipients and pharmaceutical packaging materials in the United States Considering the protection of intellectual property rights, the US Food and Drug Administration (FDA) Pharmaceutical excipients and pharmaceutical packaging materials adopt the management mode of Drug Master File (DMF) [10.

A DMF is a set of documents submitted to the FDA that can be used to provide confidential details about equipment, processes, or items used in the manufacture, processing, packaging, and storage of pharmaceuticals for human us.

Drug master files are divided into the following types:Class I DMF: manufacturing facility or site, technicians and operating procedure.

However, since January 12, 2000, Type I DMF has not been used;Class II DMF: APIs, API intermediates, materials or drugs used in the preparation of APIs and their intermediates; Class III DMF: packaging materials; Class IV DMF: excipients, colorants, flavors, flavors or Materials used in the preparation above;Class V DMF: Other FDA-approved reference informati.

 Before the manufacturers of pharmaceutical excipients and packaging materials submit DMF information to the FDA, they need to apply to the FDA for an initial DMF numb.

After the DMF data has passed the administrative review (Administrative Review), the DMF number status is activated (Active) before it can be authorized to be cited in the New Drug Application (NDA), Abbreviated New Drug Application (ANDA) ), biological product marketing authorization application (Biologics License Application, BLA) and other application materia.

The FDA will only conduct a technical review (Technical Review) of the DMF data after the preparation applicant cites the activated DMF, and will not conduct a technical review of the activated DMF alo.

 When the pharmaceutical excipients and pharmaceutical packaging materials are changed, it is necessary to evaluate the impact of the changes on the drug [11-1
The FDA's management ideas for changes in excipients and packaging materials are consistent with the overall change management ide.

Based on the impact of changes on the effectiveness and safety of drugs, changes are divided into three categories: minor changes, moderate changes and major chang.

Minor changes can be notified to the regulator through the annual repo.

Moderate changes are divided into supplemental requests that need to be implemented immediately and supplemental requests that are implemented after 30 da.

Significant changes require FDA approval of the supplemental application before the changes can be implement.

FDA will review changes in pharmaceutical excipients and packaging materials at the same time as the review of supplemental applications for preparatio.

To sum up, due to the complexity of the changes, the impact of the same change on different drugs may also be differe.

Therefore, the FDA will give the applicant the initiative to evaluate the impact of the change and whether to declare it, and requires the applicant to complete the corresponding research and verification work according to the evaluati.

2 EU's change management of pharmaceutical excipients and pharmaceutical packaging materialsIn the EU, the Active Substance Master File (ASMF) system, which is similar to the US DMF system, is only applicable to APIs [1
The regulatory mode of pharmaceutical excipients and pharmaceutical packaging materials is different from that of the F.

Among them, pharmaceutical excipients with existing Pharmacopoeia standards in the European Union can adopt the European Pharmacopoeia Adaptability Certification Program (Certificate of Suitability to the Monographs of the European Pharmacopoeia, CE.

There is also an option to be submitted together with the preparation as part of the preparation dossi.

CEP certification[15] means that for excipients that have been included in the European Pharmacopoeia, applicants can submit information to the European Directorate for the Quality of Medicines & HealthCare (EDQM), and obtain a CEP certificate after the review is pass.

It is independent of the marketing application of the drug and can be changed separate.

The CEP certificate indicates that the pharmaceutical excipients meet the European Pharmacopoeia standards and are able to control all impurities and contaminants that may be introduced in this production process rou.

If the pharmaceutical excipients used in the declared drug have obtained the CEP certificate, the marketing authorization application can directly use the certificate, and there is no need to evaluate the quality of the pharmaceutical excipien.

 For pharmaceutical packaging materials and new pharmaceutical excipients outside the European Pharmacopoeia, the EU does not have a separate approval route, but is declared together with the preparation as part of the preparation application da.

For the required information, please refer to the excipient guide in the drug marketing authorization application materials [1
The EU divides post-marketing product changes into four categories, namely, minor changes in category IA, minor changes in category IB, major changes in category II, and emergency safety restrictio.

Compared with the FDA's change management, the EU regulations have carried out a more detailed analysis and classification of the specific circumstances of the change of excipients and packaging materials, and introduced the information and requirements needed to support the change one by one [1
Category IA minor changes do not require prior approval before implementation, and only need to be notified to the competent authority or the European Medicines Agency (EMA) after implementati.

Minor changes in category IB need to be notified by the marketing authorisation holder to the competent authority or EMA before implementation, and can be implemented after 30 days if the competent authority or EMA does not issue an objecti.

Category II major changes require prior approval from the competent authority or EMA before they can be implement.

Emergency safety restrictions apply primarily to immediate changes to drug labe.

Either the applicant or the regulatory body (competent authority or EMA) can initiate an emergency safety restriction on a medicinal product, which is deemed to be accepted if it is initiated by the applicant and no objection is received within 24 hou.

An official change request for emergency security restrictions can be submitted within 15 days of initiati.

3 Change management of pharmaceutical excipients and pharmaceutical packaging materials inJapan The Japanese Master File System (MF) [18] began with the revision of Japan's Pharmaceutical Affairs Law in April 2005 [1
OEMs can register by submitting data on production methods, specifications and inspection metho.

The Pharmaceuticals and Medical Devices Agency (PMDA) of Japan does not individually review and approve the registered da.

This part of the registration data will only be reviewed when the drug that uses the registration data is review.

The contents that can be registered in MF include: APIs and intermediates; pharmaceutical raw materials (pharmaceutical materials used in special dosage forms, which play a special pharmaceutical role, such as sustained release); Mixed materials; medical device materials; containers/packaging materia.

MF registration is a non-mandatory voluntary a.

On the one hand, PMDA only conducts a formal examination of the submitted MF registration application, and can issue an MF registration certificate if it meets the requiremen.

When reviewing the drug marketing authorization application citing the MF, the reviewer will refer to the relevant MF according to the copy of the MF registration certificate submitted by the listing applicant and the agreement with the MF registrant, and conduct scientific review; on the other hand , if the detailed information on the production and quality control of the prescribed pharmaceutical raw materials and excipients can be provided in the drug marketing authorization application, the pharmaceutical raw materials and other materials can also be exempted from MF registrati.

MF registration can be regarded as a system for the protection of intellectual property rights, and it is not necessary to adopt it if it does not involve intellectual property issu.

In terms of change management, if there is a small change in the MF registration information, the MF registrant only needs to communicate with the relevant drug marketing authorization holder in advance, and then the drug marketing authorization holder submits a "Minor Change Notification" to PM.

If there is a major change in the MF registration information, the drug marketing authorization holder must submit a "Partial Change Approval Application", and only after the drug change application is approved, the MF change application will be By review [2
3 Thoughts on the change of pharmaceutical excipients and pharmaceutical packaging materials inChina 1 Change In 2005, the former State Food and Drug Administration successively issued the "Letter on Printing and Distributing the Requirements for the Registration of Pharmaceutical Excipients" (Food and Drug Administration Note Letter [2005] .

61) [21] and "On Pharmaceutical Packaging Materials, Imported Drug.

"Notice on the Application and Acceptance of Registration Application for Sub-Packaging" (Food and Drug Administration Note Letter [2005] .

83), which stipulates the materials that need to be submitted to change the standards, prescriptions, production processes, and production sites of pharmaceutical excipients and pharmaceutical packaging materia.

It is stipulated in Annex 4 of the 2007 version of the "Administrative Measures for Drug Registration" [22] that, to change the excipients and pharmaceutical packaging materials that have been prescribed for medicinal use in drug prescriptions, the provincial, autonomous region, and municipal drug administration departments shall submit examination opinions and submit them to the sta.

The Food and Drug Administration shall approve and notify the applicant at the same ti.

Changes to the packaging materials or containers (except injections, ophthalmic preparations, aerosols, powder aerosols, and sprays) that come into direct contact with drugs shall be approved by the provincial food and drug administration and submitted to the State Food and Drug Administration for recordati.

The "Relevant Regulations on Strengthening the Supervision and Administration of Pharmaceutical Excipients" issued in 2012 (Guo Shi Jian Office [2012] .

212) [23] requires that supplementary applications for changing the types of pharmaceutical excipients should conduct corresponding research, submit research materials and supply The commercial audit results shall be reported to the State Drug Administration for approval before u.

Due to regional differences in review scales, there are quality differences between pharmaceutical excipients and pharmaceutical packaging materials, and the separate review and approval of the two and the final drug may lead to a disconnection of the entire quality control syste.

Due to the inability to clarify the main responsibility of drug quality problems, the quality problems caused by pharmaceutical packaging materials can only be paid by drug manufacturers in the e.

This approval model increases the cost of new drug applications and brings difficulties to supervisi.

2 Since the implementation of the related review policy, the management of changes inpharmaceutical excipients and pharmaceutical packaging materials in China has changed from the original separate registration declaration to the registration on the platform according to the technical requirements of the registration materials, and the registration number is obtain.

The drug preparation registration application is associated with the registered original and auxiliary packagi.

When the drug preparation is approved, it means that its associated pharmaceutical excipients and pharmaceutical packaging materials have passed the technical review, and the registration platform is marked as "A"; it has not passed the technical revi.

or those that have not yet been associated with the formulation registration are identified as ".

The related review and approval policy requires that the registrant should take the initiative to carry out research when the pharmaceutical excipients and pharmaceutical packaging materials are changed, promptly notify the relevant pharmaceutical preparation manufacturers (drug marketing authorization holders), and update the registration information in a timely manner, which should be reflected in the annual repo.

The pharmaceutical preparation manufacturer (drug marketing license holder) should promptly evaluate or study the impact of the corresponding changes on the quality of the pharmaceutical preparation after receiving the above notificati.

If the quality of the pharmaceutical preparation is affected, a supplementary application should be submitt.

At the technical level, if the pharmaceutical excipients or pharmaceutical packaging materials of the marketed drug preparations are changed, or the pharmaceutical excipients or pharmaceutical packaging materials used are technically changed, the drug marketing authorization holder shall comply with the "Research on Pharmaceutical Changes of Listed Chemical Drug.

Technical Guiding Principles (Trial)"[24], "Technical Guiding Principles for Pharmacy Change Research of Listed Chinese Medicines (Trial)"[25], and "Technical Guiding Principles for Pharmacy Change Research of Listed Biological Products (Trial)"[26] Research, and implement in accordance with the relevant regulations of the current drug registration manageme.

 In addition, the International Association of Pharmaceutical Excipients (China) and the China Pharmaceutical Packaging Association have also released a draft for comments on the technical guidelines for the research on changes in pharmaceutical excipients [27] and a technical guide for the research on changes in pharmaceutical packaging materials [2
Based on the principle of risk assessment, the packaging material registrant conducts corresponding research on various changes that occur in the production process, and evaluates the research resul.

At the same time, the guidelines also pointed out that the change research carried out by the manufacturers of pharmaceutical excipients and pharmaceutical packaging materials cannot replace the research and assessment of the impact of the change on the quality of the drug by the drug marketing authorization hold.

Drug marketing authorization holders shall comprehensively evaluate and verify the impact of changes on drug safety, efficacy and quality controllability in accordance with relevant technical guidelin.

 3 Management thinkingon the change of pharmaceutical excipients and pharmaceutical packaging materials used in marketed preparations in the future The change management procedures and requirements for pharmaceutical excipients and pharmaceutical packaging materials are different, but they are all promoting innovation from the perspective of intellectual property protection and saving resources required for registration review and daily supervisi.

The level of detail of the information required for the modified preparation mainly depends on whether it can support the stable and controllable quality, safety and effectiveness of the preparation in the life cyc.

The related review system of pharmaceutical excipients and pharmaceutical packaging materials in China is still in its infan.

The national drug regulatory authorities are also continuously introducing regulations and technical requirements for changes in the sources, quality standards, and prescription processes of pharmaceutical excipients and pharmaceutical packaging materials related to the associated review syst.

Combined with the fact that the current related review system for pharmaceutical excipients and pharmaceutical packaging materials is still in the early stage, the following two methods can be considered for the management of changes in pharmaceutical excipients and pharmaceutical packaging materials used in marketed preparations in the future:one is to compact the drug marketing license Responsibility of the holder, the initiative of changing the risk assessment and declaration is given to the marketing authorization holder of the related preparation, and the marketing authorization holder of the related preparation will judge the impact of the change of the pharmaceutical excipients and pharmaceutical packaging materials on the dr.

 The second is to carry out classification and post-marketing change management in combination with the registration categories of pharmaceutical excipients or pharmaceutical packaging materia.

The State Drug Administration has updated the registration data requirements for pharmaceutical excipients and pharmaceutical packaging materials in Announcement .

56 [9], adding classification descriptions, and based on the past use history of pharmaceutical excipients and pharmaceutical packaging materials, as well as routes of administration and risks Factors differentiate the categories of registration da.

Combining product registration categories for classified post-marketing change management can also be used as a management method or as a transition management method before the full implementation of ModeMajor changes that occur after the listing of Class 1 high-risk pharmaceutical excipients/Class 1 high-risk pharmaceutical packaging materials require the marketing authorization holder of the related preparation to submit a supplementary application, and the implementation can only be implemented after the related review is pass.

 For changes in other types of pharmaceutical excipients and pharmaceutical packaging materials, the drug marketing authorization holder is required to evaluate or study the impact of the corresponding changes on the quality of the drug preparation in a timely manner, and submit a proposal to the corresponding department in accordance with the current drug registration management regulatio.

Supplemental application, filing or repo.

To sum up, the initiative to evaluate the impact of changes in the pharmaceutical excipients and pharmaceutical packaging materials on the preparation and whether to declare it is given to the drug marketing authorization holder, which is in line with the "pharmaceutical preparation registration applicant or drug marketing authorization hold.

The concept of taking primary responsibility for drug quality” is also an international common practi.

However, in view of the fact that China's current related review system for pharmaceutical excipients and pharmaceutical packaging materials is still in its infancy, pharmaceutical excipients and pharmaceutical packaging materials companies are small and scattered, lack of quality awareness, and uneven capabiliti.

For actual situations such as the risk assessment of changes in pharmaceutical excipients and pharmaceutical packaging materials and the lack of experience in auditing the supplier's quality management system, holders still need to issue technical guidelines for evaluating the impact and risks of changes in pharmaceutical excipients and pharmaceutical packaging materials themselves on drugs Or a path to realize a multi-dimensional drug quality assurance system of government supervision, industry self-discipline, and enterprise self-consciousne.

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