NMPA Registration of Pharmaceuticals, Packaging and Ingredients

Drugs

The SAMR (State Administration for Market Regulation) and NMPA (National Medical Products Administration) - former CFDA (China Food and Drug Administration) - oversee the management and registration of drugs (pharmaceuticals), pharmaceutical products, medical devices, in-vitro diagnostics and cosmetics.

Cisema works with pharmaceutical companies large and small for China marketing approvals, drug master filing (DMF), China good manufacturing practice (GMP) gap analysis, CMC consulting and other quality and regulatory services.

 In China, drugs are divided into: 

1. chemical drugs, 

2. TCM (Traditional Chinese Medicine), and

3. biological products for classified management. 

Chemical drugs and biologics are the primary categories for which we support importing manufacturers. The demand for DMF of active pharmaceutical ingredients (API), packaging and excipients is also fast increasing. If you would like to learn in detail about our services relating to these topics or receive ongoing updates and education content, please request our brochure or contact a Cisema expert.

Approval categories and processes for chemical drugs, biologics and DMF are presented in brief below, followed by some sample of recent customer projects. 

Pre-market Registration: In view of the special characteristics of pharmaceutical products (including API, excipients and packaging), foreign manufacturer shall appoint a professional domestic registration agent for drug registration in compliance with Chinese regulations.

Post Market Surveillance: According to Drug Administration Law of the People's Republic of China (2019 version), China implements system of drug market license holder management, which to manage drug safety, effectiveness and quality of drug development and production, which is called full life cycle management of drug. If the license holder is a foreign manufacturer, the foreign manufacturer shall appoint a domestic legal agent for fulfillment of legal obligations and responsibilities related to the license (product).

Applicants who want to appoint a Chinese distributor as NMPA Legal Agent should be aware of the risks involved. Unfortunately, if your distributor is either lack of general knowledge of regulations and standard policies or not fully transparent to you, you may lose your independence regarding product import, preventing you from changing distributors. Your options when choosing the NMPA Legal Agent is explained in more detail in our brochure.

➤ Are you a pharmaceutical manufacturer and need support with the supplementary dossier and second NMPA evaluation?

➤ Are you a pharmaceutical packaging or ingredients manufacturer and require assistance attaining your DMF?

➤ Would you like to know how much time and costs you should expect for the China NMPA registration?

➤ Wondering how many test samples you need to provide to Chinese laboratories?

➤ Are you unsure who to appoint as your NMPA Legal Agent and want to protect your independence?

➤ Are you unsure if your ingredients are China compliant?

➤ Do you have any concerns about revealing the exact manufacturing method and ingredients of your pharmaceutical product as part of the registration?

➤ Do you worry about miscommunication with NMPA because of culture and language differences?

➤ Are you afraid of failing the Chinese tests?

➤ Wondering which application documents you have to submit?

➤ Advice on applicable legislation and regulations.

➤ Determining whether your products need NMPA approval.

➤ Analysis of ingredients for compliance with Chinese regulations.

➤ Legal representation in China as NMPA Legal Agent for registration and regulatory affairs and protecting your independence.

➤ Application for China NMPA registration.

➤ Provision of complete document checklist and templates, including advice on the correct completion.

➤ Translations and notarizations.

➤ Provision of comprehensive test sample list.

➤ Close follow up of your sample tests in China.

➤ Communication and coordination between you and the Chinese authorities in technical and cultural terms.

➤ Provide response proposal of technical reviews by CDE.

➤ Assist site inspection initiated by CDE & CFDI.

➤ Follow-up support during the NMPA application of pharmaceuticals containing API or Drug. 

Chemical Drugs

The registration of chemical drugs is divided into three categories: innovative new chemical drugs, improved new chemical drugs, and generic drugs. The second classification criterion is whether and where the drug is marketed. The chemical drug registration includes therefore the following five classes in total:

Innovative new chemical drug that is not marketed both domestically and abroad It refers to drug that contains new compound with clear structure and pharmacologic effects and demonstrates clear clinical values. 

Improved new chemical drug that is not marketed both domestically and abroad It refers to drug which has improved the structure, dosage form, prescription process, route of administration, and indications, etc. of the known active ingredients, and demonstrates obvious clinical advantages over the original drug varieties. 

Generic drug produced by Chinese applicants domestically by imitating the original drug which has been marketed overseas but not marketed in China. It should be consistent with the originator in terms of quality and therapeutic effect. 

Generic drug produced by Chinese applicants domestically by imitating the original drug which has been marketed in China. It should be consistent with the originator in terms of quality and therapeutic effect. 

Drug marketed overseas

5.1 Original and improved drug having been marketed overseas (Improved drugs should have obvious clinical advantages).

5.2 Generic drug having been marketed abroad.

 

Chinese Pharmacopoeia & Standards

Drug quality standards are divided into statutory standards and corporate standards. The statutory standards are further divided into national pharmacopoeia, industry standards and local standards. The drug production should conform to the national pharmacopoeia; the production of drugs that have not been enrolled in the national pharmacopoeia should be in line with the industry standards; for those that have not been included both in the pharmacopoeia and the industry standards, the local standards need to be followed. The drugs, for which there are no statutory standards or which cannot meet the statutory standards, are not allowed to be produced, sold, and used in China.

The “Chinese Pharmacopoeia” provides the legal technical standards for supervising and managing the quality of drugs in China, and so to ensure the efficacy, safety, and quality controllability of drugs. The development of the “Chinese Pharmacopoeia” evolved together with the new China; from 1950 to 1980, three editions of the Pharmacopoeia were issued in China; since 1980, the Chinese Pharmacopoeia was amended every five years. The current version is the 2020 edition. As China became one of the ICH member countries (The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use), this revised 2020 edition, which used the experience of the international advanced drug standards as an invaluable source of reference and integrated the content of the drug standards implemented in other countries, is regarded as the "most rigorous standards" to date.

According to the regulations of the NMPA, if an overseas-manufactured drug has been enrolled in the “Chinese Pharmacopoeia”, it must meet its standards. However, in the technical review phase of the drug registration process, the regulatory requirements are much higher than the standards of the “Chinese Pharmacopoeia”, i.e., the regulatory requirements have integrated with the pharmacopoeia standards of many other countries in which the drug is also included; they are thus called the "most stringent review standards" in the world.

If you need to apply for marketing registration of a drug in China, you are welcome to contact Cisema for technical consultation. Cisema is proficient in confirming whether the overseas quality standards for abroad-produced drugs are consistent with the Chinese standards & requirements in the phase of technical review. In addition, after receiving the order and the necessary technical documents from customers, Cisema will report defects in their applications files in time; before the submission for registration, Cisema will provide a risk assessment to the clients in the first instance.

Registration of Foreign-produced Chemical Drugs in Class 1 & 2

The drugs in class 1 and 2 are innovative and modified new chemical drugs that have not been marketed both inside and outside China; for foreign-produced drugs which belong to these two classes, there are two main paths for the registration.

#1 Separate clinical trials in China: The first path is conducting separate clinical trials in China to support the marketing of the product. Before conducting a drug clinical trial in China, an IND-application (Investigational New Drug) is required. Within 60 days after the date of acceptance of such application, if the applicant does not receive any negative comments from the CDE, the clinical trial can be conducted in accordance with the submitted protocol, i.e., the applicant doesn’t have to wait for the approval letter from the NMPA (approval by default) thanks to an important recent law change. 

#2 Involving China in global clinical trials: The second path is involving China in the global development plan of the product at the very beginning or joining the MRCT (The Multi-Regional Clinical Trials). After the clinical trials are completed, the clinical data obtained from the MRCT can be used to support the NDA (New Drug Application) in China. However, in this case, it could also happen that a pharmacokinetic study that includes the Chinese population is required to be added.

In general, although the NMPA & CDE have promulgated many relevant measures and provisions, considering the special nature of drugs, the concrete regulatory situation of the registration needs to be analyzed according to the specific type of drugs.

Registration of Foreign-produced Chemical Drugs in Class 5 (5.1 & 5.2)

The class 5 (5.1/5.2) refers to the chemical drugs that have already been marketed outside China. For overseas-manufactured drugs that belong to this class, there are many regulations and guidelines available for reference.

In an effort to increase the availability of pharmaceutical treatments in China, the NMPA released, in July 2018, guidelines to allow pharmaceutical drugs that have already undergone clinical trials in other countries to enter the Chinese market without undergoing domestic clinical trials. In October 2020, the CDE issued the “Clinical Technical Requirements for Drugs Marketed Abroad but not Marketed Domestically”. Based on the overseas clinical data and on the urgency level of the domestic clinical demand, this regulatory document divides the drugs listed overseas but unlisted in China into three classes: 

A. Exemption from domestic clinical trials; 

B. Conducting necessary bridging trial and necessary exploratory and confirmatory clinical trials in line with the requirements for new drugs; 

C. Not approving clinical trials in China.

In all cases, Cisema can provide you advisory services on a case-by-case basis.

Biologics

Biological products are preparations that use microorganisms, cells, animal or human-derived tissues, and body fluids as starting materials and are produced by biological techniques for the prevention, treatment, or diagnosis of human diseases. In order to standardize the registration and management of biological products, they are divided into preventive biological products, therapeutic biological products, and in-vitro diagnostic reagents managed as biological products. In addition, the registration procedure is further classified according to innovative biological products, improved biological products, and marketed biological products (including Biosimilars).

Class 1: Innovative vaccine

Class 2: Improved vaccine

Class 3: Vaccines already marketed within or outside China

Class 1: Innovative biological product

Class 2: Improved biological product

Class 3: Biological product already marketed within or outside China

Class 1: Innovative in-vitro diagnostic reagent

Class 2: In-vitro diagnostic reagent already marketed within or outside China

 

 

According to the definition in China’s "Provisions of Drug Registration", applications for drug registration include the applications for drug clinical trials, for drug marketing authorization, for re-registration, and other supplementary applications which comply with the legal procedures and related requirements.

Depending on the registration strategy, the existing clinical data derived from sources outside China may not be sufficient to directly support the registration application for marketing authorization here. In this case, it is necessary to first apply to the CDE for permission to conduct clinical trials in China, and the process is as follows:

When the CDE permits the drug clinical trial, the applicant can carry it out according to the submitted protocol. According to the regulatory requirements for clinical trials, the trial period should be at least 1 year. For innovative new drugs, when significant problems are encountered during the clinical trial, Cisema can organize the communication between the client, investigators, and professional technical institutions such as the CDE.

Contact Cisema for more detail or ask about our whitepaper.

Drug Master File (DMF) for Active Pharmaceutical Ingredients (API), Packaging and Excipients

As part of the registration of pharmaceuticals, manufacturers may submit the DMF (Drug Master File) number of the active pharmaceutical ingredient (API), pharmaceutical packaging and ingredients (together, AEP). Cisema can support the applicant during the preparation of the supplementary dossier and the second NMPA technical evaluation. We can help provide the required technical documents or test data in this supplementary phase.

The DMF consists of confidential and detailed information on the production and quality control of AEP, which are submitted to NMPA and filed in their database. The data from the DMF will later be accessed by the NMPA as part of the approval of an end product, a drug.

With the help of a DMF number, the manufacturer of AEP - the supplier - can avoid passing confidential information on to the drug manufacturer.

China DMF compared with US and EU DMF

The China DMF process has some similarities with US and EU DMF systems, but also some noticeable differences. Here is a brief comparison. 

Comparison-of-China-US-and-EU-DMF-types-1.png

As part of the registration of pharmaceuticals, manufacturers may submit the DMF (Drug Master File) number of the active pharmaceutical ingredient (API), pharmaceutical packaging and ingredients (together, AEP). Cisema can support the applicant during the preparation of the supplementary dossier and the second NMPA technical evaluation. We can help provide the required technical documents or test data in this supplementary phase.

The DMF consists of confidential and detailed information on the production and quality control of AEP, which are submitted to NMPA and filed in their database. The data from the DMF will later be accessed by the NMPA as part of the approval of an end product, a drug.

With the help of a DMF number, the manufacturer of AEP - the supplier - can avoid passing confidential information on to the drug manufacturer.

China DMF compared with US and EU DMF

The China DMF process has some similarities with US and EU DMF systems, but also some noticeable differences. Here is a brief comparison. 

Only a few excipients are exempted from filing a DMF. They are listed on the exemption list - such as some flavours, fragrances, colourings, or pH regulators.

An NMPA Legal Agent must be authorized in order to submit the China DMF. 

Once obtained, various information – such as DMF number, product name, company name, company address, import status, packaging specifications, product specification, update date and NMPA review status – can be found in the NMPA database at http://www.cde.org.cn/.

China DMF Status “I” 

After submission of the DMF, NMPA formally verifies that all required information has been submitted. Within two weeks, the status in the database will be set to "I". This status illustrates the progress of the technical review. "I" (inactive) indicates that the Completeness Assessment has been finished and that the application dossier is now ready to be reviewed by the evaluator, but that the technical review has not yet been completed with the drug.

AEP can undergo a bundle technical review together with the approval of the drug. This prevents unnecessary burden on the NMPA, improves the efficiency of the technical review and accelerates the process for the market approval of new drugs.

APIs can additionally undergo an independent technical review. APIs now require payment of an official application fee together with the submission. An additional requirement for APIs is that they have to undergo registration tests in China.

China DMF Status “A”

If the DMF application satisfies all requirements, the status on the database is then set to "A" (Active). "A" indicates that the AEP is approved for use in finished drugs or API is approved for Independent listing.

Contact us for more information or ask about our China DMF whitepaper.

SAMPLE CUSTOMER JOURNEYS

Gene cell therapy manufacturer

We advised an international manufacturer of advanced delivery systems in the field of gene cell therapy (GCT), wherein the principle of action of the product is highly advanced. Cisema has supported and advised the customer about relevant and appropriate GCT field regulations in China, a burgeoning area of interest both in China and abroad. Cisema supports on regulatory communications and dossier preparations for approval submissions. We also support the customer on the research and experiment pathway of investigator-initiated trials (IIT) in China.

Swiss pharmaceutical manufacturer

Cisema, as the China legal agent of a Swiss pharmaceutical manufacturer, assists in the filing of reference preparations for the manufacturer’s advanced sodium salt pharmaceutical product. We also conduct detailed gap analyses of the product in accordance with the technical requirements for improved new drugs in category 5.1 of chemical drugs.

US manufacturer of therapeutics targeting gastrointestinal diseases

We worked with a US therapeutics company bringing innovative medicines to patients with high unmet needs in gastrointestinal diseases, to seek required clinical trial application (CTA) and marketing approvals (MA) in China. As the manufacturers China legal agent, Cisema is responsible for organizing and reviewing the application dossier of the drug in accordance with the technical requirements of NMPA and submitting the clinical trial application of the drug to NMPA. 

Japanese manufacturer of transdermal patch drugs

Cisema supported a Japanese manufacturer of transdermal patch drugs to conduct a gap analysis between the pharmaceutical and clinical parts of its transdermal patch products that have been marketed in Japan in accordance with the requirements of NMPA regulations and combined with our own experience. After an in-depth discussion, the two parties reached an agreement on the next step of the customer's experimental plan.

European manufacturer of vaginal suppository products

Cisema conducted a gap analysis for an European manufacturer of vaginal suppository products. The vaginal suppository product is recognized as a medical device for sale in Europe, but according to the classification and regulatory requirements of NMPA, this product is defined as a chemical drug. We conducted in-depth analysis of the classification pathways and worked with the customer to formulate a Chinese approval pathway according to relevant Chinese regulations and policies.

Korean traditional Chinese medicine manufacturer

We supported a Korean manufacturer of Traditional Chinese Medicine renewed its registration certificate issued by NMPA. Pain points we worked through with the customer included targeted interpretation of the Review Conclusion on the product renewal certificate to formulate the next research plan, and assist the manufacturer to complete the work stipulated in the Review Conclusion before the next renewal registration.

German Tradition Herbal Medicinal Products (THMP)

Cisema prepared a feasibility study report about a Tradition Herbal Medicinal Products (THMP) in China. We gave conclusions and recommendations about whether the products can be registered and sold in China, and advised about the correct registration category for these products.

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