Comments on the Implementation Regulations of the Drug Administration Law (Draft for Comments) on Drug Production Article by Article

Staff Writer | Alang

From | Dandelion (oury.

On May 9, the State Food and Drug Administration issued the "Regulations on the Implementation of the Drug Administration Law of the People's Republic of China (Draft for Comments)" (hereinafter referred to as the "Draft for Comments") to solicit public commen.

Yesterday, the author interpreted the first 51 articles < Comments one by one | Regulations for the Implementation of the Drug Administration Law (Draft for Comments) >

Now continue to share and interpret Chapter 4 of the "Implementation Regulations of the Drug Administration Law": Drug Production (Articles 52-6

Chapter 4 Pharmaceutical Production

Article 52 [Production License] To engage in drug production activities, the applicant shall apply to the drug regulatory department of the people's government of the province, autonomous region, or municipality directly under the Central Government for a production license, and shall, in accordance with the provisions of the drug regulatory department of the State Council, submit its compliance with Article 1 of the Drug Administration L.

[Interpretation] This article concerns the application for drug production license, licensing conditions, inspection and approv.

The type of production license (classification code): A, B, C, D licen.

Article 42 of the "Drug Administration Law" stipulates the licensing conditions: the need for personnel, workshops and facilities, QA, QC, equipment and systems,e.

(1) There are pharmacy technicians, engineering technicians and corresponding skilled workers who have been qualified according to law;

(2) It has workshops, facilities and sanitary environment suitable for drug production;

(3) Having institutions, personnel and necessary instruments and equipment capable of conducting quality management and quality inspection of the drugs produced;

(4) It has rules and regulations to ensure the quality of drugs, and meets the requirements of the drug production quality management standards formulated by the drug regulatory department of the State Council in accordance with this L.

3, A, B, C, D production license application conditions are differe.

The establishment of vaccine enterprises must comply with industrial polici.

Article 53 [Items stated in the production license] The items stated in the drug production license are divided into licensing items and registration ite.

[Interpretation] Increasing the production address, production scope, e.

Change of licensing items: refers to the change of production address and the change of production sco.

Change of registered items: refers to the change of the enterprise name, unified social credit code, domicile (business place), legal representative, person in charge of the enterprise, person in charge of production, person in charge of quality, person in charge of quality,e.

Changes in licensing items often require the provincial bureau to arrange on-site inspections or even sampling inspections; generally, there is no need to arrange on-site inspections for changes to registered items, and they can often be approved after being submitted online through the provincial bureau’s exclusive platfo.

Article 54 [Production License Period] The drug production license is valid for 5 yea.

[Interpretation] Article 19 of the "Measures for the Supervision and Administration of Drug Production" has expired, and if it is necessary to continue to produce drugs, it shall apply to the original license-issuing authority for re-issuing the drug production license six months before the expiration of the validity peri.

Generally, the licenses of the provincial bureaus will expire in a centralized mann.

For example, on June 16, 2020, Guangdong Province issued a notice on the renewal of the "Drug Production License" in 2020: According to the "Drug Administration Law of the People's Republic of China", "Drug Production License" Production Supervision and Administration Measures (Order .

28 of the State Administration for Market Regulation) and other requirements, in order to do a good job in the renewal of the "Drug Production License" in 2020, all enterprises need to log in to the "Enterprise-exclusive webpage" of the Guangdong Provincial Bureau's online service platform to conduct online To declare, for those who have not received GMP inspection since July 1, 2018, have received administrative penalties within 5 years, and other situations that require on-site verification, on-site inspections need to be initiated before recertificati.

In the event that the license will not be renewed, it will be cancelled when the validity period expires and the application has not been received, and the new license will be downloaded from the provincial bureau’s service platform system by itse.

Article 55 [Personnel Management Requirements] Holders of drug marketing licenses and drug production enterprises shall appoint the person in charge of the enterprise, the person in charge of production management, the person in charge of production management, Personnel in key positions such as the person in charge of quality management and the quality authorized pers.

Key personnel such as the person in charge of the enterprise, the person in charge of production, the person in charge of quality and the person authorized for quality shall be full-time personnel of the enterpri.

The quality authorized person is mainly responsible for drug release, ensuring that the production and inspection of each batch of released products comply with relevant regulations and drug registration management requiremen.

The quality authorized person shall perform their duties independently, and shall not be released without the signed consent of the quality authorized pers.

[Interpretation] In drug production, people are the first eleme.

 

Drug manufacturing enterprises refer to the units that have obtained the A certificate, the C certificate entrusted, and the D certificate raw materia.

The drug marketing authorization holder refers to the unit including the A certificate, but more refers to the unit after the R&D institution has obtained the B certifica.

At present, there are more than 1,600 units with B certificates in China, and the number is still increasi.

Usually obtaining a B certificate requires sufficient personn.

For example, Jiangsu has at least 12 people or more for enterprises that have obtained a B certifica.

In the "Measures for the Supervision and Administration of Drug Production", it is mentioned that the legal representative, the person in charge of the enterprise, the person in charge of production management (hereinafter referred to as the person in charge of production), the person in charge of quality management, and the quality authorized person are the key "five members" of the enterprise, 2021 From December 1, 2009, the "Quality Management Practice for Pharmacovigilance" was officially implement.

The drug marketing license holder also needs to add a "sixth member" in charge of pharmacovigilance, and the requirement is a full-time pers.

For example, during the B certificate inspection, it is necessary to provide These key personnel's employment contracts, enterprise appointment certificates, salary certificates, e.

, the "Drug Administration Law" and "Vaccine Administration Law" also stipulate that these key personnel are the main body responsible for the enterpri.

 

The quality authorized person should perform their responsibilities independent.

For example, for a B certificate enterprise, the quality authorized person of the entrusted production plant is responsible for entrusting the product to leave the factory, and the quality authorized person of the B certificate holder is responsible for entrusting the product to be released into the mark.

Article 56 [Production Management Requirements] To engage in drug production activities, a quality management system covering the entire process of drug production shall be established to ensure that drug production activities continue to comply with drug production quality management practices and relevant regulatio.

The data and records of drug production and inspection shall be true, complete and traceab.

[Interpretation] Emphasizes that the production management system must be established, in line with GMP and data authenticity specificatio.

 

Article 43 of the Drug Administration Law: Those engaged in drug production activities shall abide by the drug production quality management standards, establish and improve the drug production quality management system, and ensure that the entire process of drug production continues to comply with legal requiremen.

The legal representative and principal person in charge of a pharmaceutical production enterprise shall be fully responsible for the pharmaceutical production activities of the enterpri.

Article 25 of the "Vaccine Management Law": The vaccine marketing license holder shall establish a complete production quality management system, continuously strengthen the management of deviations, and use information technology to truthfully record all the data formed during the production and inspection process to ensure that the production is comple.

The process continues to comply with statutory requiremen.

 

Article 26 of the "Measures for the Supervision and Administration of Drug Production": To engage in drug production activities, one should abide by the drug production quality management standards, establish and improve a drug production quality management system, cover all factors affecting drug quality, and ensure that the entire process of drug production continues to comply with statutory regulations reque.

Article 57 [Material Management Requirements] When engaging in drug production activities, suppliers shall review raw materials, auxiliary materials, packaging materials and containers that directly contact drugs, e.

, and establish specific operating procedures to ensure that the purchased and used raw materials, auxiliary materials, The packaging materials and containers that come into direct contact with drugs meet the requirements for medicinal use, and comply with the quality management standards formulated by the drug regulatory department of the State Council and related requirements such as related review and approv.

【Interpretation】 Material management, first of all, it depends on whether the preparation is developed and whether it is related to the raw materials, auxiliary materials, and inner packaging materia.

Once bound, it will not change easi.

If you add a material supplier, you must first check whether the original, auxiliary, and package are A-status materia.

If they are I-status, they cannot be us.

Next, the change of new material suppliers must be initiated, and research work can be carried out according to the guidelines for post-marketing changes of drugs, whether it is small test or pilot test, and if it is basically feasible, audit of material suppliers to evaluate whether to carry out product process verification or Stability inspection, the quality of the product after the change should not be lower than before the change, and finally determine whether to submit a CDE supplementary application or provincial bureau filing or annual report according to the degree of risk and quality impa.

Article 58 [Holder's management of entrusted production] In the case of entrusted production of drugs, the drug marketing license holder shall perform the obligations of raw and auxiliary material supplier review, product annual report, change management review and product listing release, e.

, supervise the entrusted The parties perform their obligations under the agreement to ensure that the production process continues to comply with legal requiremen.

The entrusted party shall organize production in accordance with the pharmaceutical production quality management standards, and strictly implement the quality agreeme.

The entrusted party shall not entrust production aga.

[Interpretation] This clause mainly refers to the entrusted production of B-certificate MAH currently carried out by Ruhuoru.

Both the holder and the entrusted factory must establish their own quality management syste.

The holder must keep an eye on the choice of CMO or CDMO, and carry out B certificate application, technology transfer, site change, e.

The entrusted factory mainly abides by GMP And there is an entrusted production system and the holder is well connect.

The rights and responsibilities of both parties are mainly stipulated in detail through the entrustment agreement and the quality agreeme.

The state stipulates that the entrusted party shall not entrust production aga.

  

Article 59 [Overseas Production Requirements] If the drug production site is overseas, its production activities shall comply with the relevant requirements of laws, regulations, rules, standards and nor.

  

[Interpretation] The state allows overseas holding and overseas production, but it needs an agency with an overseas owner in Chi.

As a daily communication, the domestic agency needs to assume the obligations and responsibilities of the owner, and requires MAH to have quality management, Three capabilities of risk prevention and control and liability compensati.

The state will organize experts to conduct on-site inspections or unannounced inspections at overseas production plan.

At present, there is no way for cross-border holding in Chi.

If there is no liberalization of overseas holding and domestic production, or domestic holding and overseas production, this is related to excessive risks and insufficient supervisi.

 

 Article 60 [Marketing of large-scale drugs before registration] For commercial-scale batches of drugs whose quality standards and production processes are consistent with the registration certificate, the production process conforms to the drug production quality management standard, and after obtaining the drug registration certificate, it meets the requirements for product relea.

If required, it can be marketed and sold; the holder of the drug marketing license shall strengthen its production and sales management and risk manageme.

  

[Interpretation] This clause should be the biggest highlight of the implementation regulation.

This opening is very lar.

Basically, the commercial batch of process verification approvals for new foreign products before the launch can be marketed after approval, so as to save R&D costs and avoid resourc.

Waste, should be prais.

This will bring two real dividends to the enterprise: First, the dynamic batch can be listed for sale from the previous verification, which is expanded to the pre-market verification bat.

The enterprise obtains the approval document and passes the license and GMP compliance inspecti.

Second, after obtaining the production license, commercial batch products can be produced and put into production in advan.

After obtaining the approval and GMP approval, these products produced in advance can also be listed, which greatly shortens the listing and sales of new products of the enterpri.

ti.

Of course, these two dividends still need the correct interpretation of the drug regulatory department to confi.

  

Article 61 [Vaccine Entrusted Production] In any of the following situations, and the current production capacity of the vaccine marketing license holder cannot meet the demand, upon approval by the drug regulatory department of the State Council, the production may be entrusted to a qualified vaccine production enterprise:  

(1) When the competent department of industry and information technology of the State Council proposes the need for reserve;  

( 2) The competent health department of the State Council proposes that it is urgently needed for disease prevention and control;  

(3) Polyvalent multivalent vaccines that really need to be produced by entrustme.

  Entrusted vaccine manufacturers shall abide by the Drug Administration Law, the Vaccine Administration Law and relevant state regulations to ensure the quality of vaccin.

  

[Interpretation] Article 22 of the "Vaccine Administration Law": The holder of a vaccine marketing license shall have the vaccine production capacity; if the production capacity exceeds the vaccine production capacity and it is necessary to entrust the production, it shall be approved by the drug regulatory department of the State Counc.

Those who accept entrusted production shall abide by the provisions of this Law and relevant state regulations to ensure the quality of vaccin.

Vaccines are used to inoculate healthy people, especially children, and are the most strictly controlled drugs by the sta.

At present, domestic new crown vaccines can be approved with conditions upon the approval of the State Council Special Office, and can also be produced by the holder upon approval by the National Bureau to meet the needs of sudden public security inciden.

  

Article 62 [Vaccine Production Requirements] Vaccine marketing license holders shall use information technology to truthfully record all data formed during production and inspection to ensure that the entire production process continues to meet statutory requiremen.

For manual operation steps that cannot be used to collect data online, the data formed in the process should be entered into the relevant information system in a timely manner or converted into electronic data to ensure the authenticity, integrity and traceability of the relevant da.

  

[Interpretation] Vaccines are the most strictly regulated of all dru.

As early as November 11, 2020, the National Bureau required vaccine holders to implement annual reports, while other drugs were released on April 12, 202 Report Management Regulations, and the annual report can be completed before August 3  Vaccine informatization requirements are also the highe.

For vaccine production enterprises, the National Bureau revised and implemented the GMP "Biological Products" appendix in July 2020, which clearly stipulated that "if enterprises use an information system that collects data in real time to record data, due to the need for a certain period of information construction, they should be in 202 Meet the relevant requirements before July ", "Vaccine manufacturers should use information technology to truthfully record all data formed during production and inspection to ensure that the entire production process continues to meet legal requiremen.

For manual operations (including manual operations, observation and Recording, e.

) steps, the data formed in this process should be entered into the relevant information system in time or converted into electronic data to ensure the authenticity, integrity and traceability of the relevant da.

Vaccine companies are all using computerized systems such as MES electronic batch records and LIMS to meet the regulatory requirements of regulatio.

Vaccine production companies will face the "July 2022 Informatization Exa.

Article 63 [Administration of Chinese Medicinal Materials] The Chinese medicinal materials used for pharmaceutical production shall conform to the national pharmaceutical standards or the local standards for medicinal materials formulated by the pharmaceutical supervision and administration department of the people's government of the province, autonomous region, or municipality directly under the Central Government in accordance with the l.

  The state encourages the development of standardized planting and breeding of traditional Chinese medicinal materials, promotes the implementation of quality management standards for the production of traditional Chinese medicinal materials in an orderly manner, and gradually realizes the standardized and intensive development of key Chinese medicinal materia.

  Manufacturers of Chinese herbal decoction pieces and holders of marketing licenses for proprietary Chinese medicines shall strictly implement the supplier audit responsibilities, strengthen the authenticity identification, inspection and acceptance of purchased Chinese herbal medicines, and ensure the quality of purchased Chinese herbal medicin.

  

[Interpretation] On March 17 this year, the State Food and Drug Administration, the Ministry of Agriculture and Rural Affairs, the National Forestry and Grass Administration, and the State Administration of Traditional Chinese Medicine jointly issued the announcement on the "Quality Management Practice for Chinese Medicinal Materials" (.

22 of 2022) (referred to as the new version of Chinese medicin.

Material GAP), the full text has 14 chapters and 144 articl.

Compared with the 10 chapters and 57 articles of the trial version of Chinese herbal medicine GAP, 4 chapters and 87 articles have been added, and the content has been greatly revis.

Whether the standardized planting of Chinese herbal medicines is good or bad, and whether it can achieve the same refined management as GMP for medicines, let us wait and s.

  China stipulates that the raw materials of Chinese patent medicines can only be Chinese herbal piec.

At present, most of the Chinese herbal medicines are of poor quali.

The announcements of unqualified quality sampling often "top the list" and "dominat.

Excessive pesticide residues in Chinese herbal medicines are also a historical problem of headac.

Only when the industry is self-disciplined and promotes the industrialization, standardization and high quality of decoction pieces, can Chinese herbal medicines, Chinese medicine decoction pieces, and Chinese patent medicines have a bright futu.

  

Article 64 [Processing of Chinese Medicinal Materials in Origin] The origin processing of Chinese medicinal materials shall not adversely affect the quality of Chinese medicinal materia.

The drug regulatory departments of the people's governments of provinces, autonomous regions, and municipalities directly under the Central Government shall formulate management requirements and technical guidelines for the processing of traditional Chinese medicinal materials in the place of origin based on the distribution of local Chinese medicinal materials resources, natural environment conditions, the history of traditional planting and breeding, and the characteristics of authentic medicinal materia.

  

[Interpretation] Harvesting and processing of traditional Chinese medicinal materials are the key links that affect the safety, efficacy and stability of traditional Chinese medicinal materia.

The origin processing of Chinese medicinal materials (cleaning and removing impurities, scraping the skin and extracting the heart, cutting while fresh, drying in the sun, grading, classification, e.

), the processed medicinal materials at the origin can not only ensure the quality of the medicinal materials, but also prevent Rotten and rotten, easy to store and transpo.

The advantages of origin processing are: first, fresh processing can reduce the loss of active ingredients; second, it can greatly reduce labor costs; third, purification and selection at the origin can reduce logistics cos.

It is recommended that the state formulate the management requirements and technical guidelines for the processing of traditional Chinese medicinal materials as soon as possible, formulate the standardization and standardization of the working process, and build a perfect circulation and traceability system for authentic medicinal materials, so that the processing of traditional Chinese medicinal materials can achieve sound developme.

  

Article 65 [Packaging Labels of Chinese Herbal Medicines] Chinese herbal medicines used for pharmaceutical production shall have packaging labe.

The content of the label should include the name of the medicinal material, the source of the medicinal material, the place of origin (marked to the county-level administrative region), the date of harvest, the date of packaging, the implementation standard, the shelf life, the storage conditions, the supplier, e.

, and a quality certification mark should be attach.

  

[Interpretation] Article 48 of the Drug Administration Law: Chinese herbal medicines should be packaged for shipme.

On each package, the product name, place of origin, date, and supplier should be indicated, and a mark of qualified quality should be attach.

The standardized management of Chinese herbal medicines is to ensure that the material basis of subsequent Chinese herbal decoction pieces, Chinese herbal formula granules, and Chinese patent medicines is reliable and guarante.

Article 66 [Production Management of Decoction Pieces of Traditional Chinese Medicine] Manufacturers of decoction pieces of traditional Chinese medicine shall establish a quality management, risk prevention and control and traceability system for decoction pieces of traditional Chinese medicine, and implement whole-process management of the preparation and sale of decoction pieces of traditional Chinese medici.

  Manufacturers of Chinese herbal decoction pieces shall not entrust the production, nor shall they purchase Chinese herbal decoction pieces in separate packages or sell them after changing the packagi.

  

[Interpretation] Emphasizes the standardized management of Chinese herbal decoction piec.

In recent years, several countries have made high-profile efforts to promote the Chinese medicine industry and encourage the development of the Chinese herbal medicine industry, attracting the enthusiastic participation of various proprietary Chinese medicines, pharmaceutical companies, and health platform compani.

However, there are many problems in the Chinese herbal medicine industry, and it is necessary to improve quality management, strengthen risk prevention and control and establish a traceability syst.

In April of this year, Chinese herbal decoction pieces also abide by the "Regulations on the Administration of Drug Annual Reports" like chemical drugs, and can be required to complete the annual report before August 3 Considering the risks, it is stipulated that the production enterprises of Chinese herbal decoction pieces shall not entrust the production, and shall not make fraudulent purchases of Chinese herbal decoction pieces in separate packaging or after changing the packaging, so as to purify the atmosphere of the indust.

  

Article 67 [Packaging and Labeling of Chinese Herbal Pieces] Chinese Herbal Pieces shall have standardized packaging and labels, and the packaging materials that directly contact Chinese Herbal Pieces shall meet the requirements for medicinal u.

The contents of the label of Chinese herbal decoction pieces include the name of the product, the source of the medicinal material, the specification, the origin of the medicinal material (marked to the county-level administrative region), the manufacturer, the batch number of the product, the production date, the shelf life, the implementation standard, and the storage conditions, e.

, and a quality qualification mark is attach.

  

[Interpretation] In April this year, a document on the labeling of Chinese herbal decoction pieces was posted on the Internet, involving major changes in the content and requirements of the labeling of Chinese herbal decoction piec.

The key contents are: for traditional medicinal and edible products, it should be clearly distinguished on its label; the words in the label must not have the phenomenon of falling off or not sticking firmly; it must not be modified or supplemented by pasting, cutting, altering, e.

, and the label must not be Use handwriting; the labels of Chinese herbal medicines produced and sold in ethnic autonomous areas can use the ethnic characters commonly used in the region at the same time, and the content should be based on the Chinese characters, and the font size should not be larger than the corresponding Chinese characters; Chinese herbal medicines for medical toxic drugs, narcotic drugs, and psychotropic dru.

, special logo; if the main function exceeds the standard range, it will be punished as counterfeit medici.

It should be said that this document will further standardize the labeling of decoction pieces; however, it is recommended to make appropriate adjustments to lower the standard in consideration of the actual situation of the indust.

Article 68 [Management of TCM Formula Granules] An enterprise producing TCM formula granules shall have the complete production capacity of processing, extracting, concentrating, drying, and granulating TCM decoction pieces, and process TCM decoction pieces for the production of TCM formula granules by themselv.

  Manufacturers of traditional Chinese medicine formula granules shall fulfill the main responsibility and related obligations of the whole life cycle of medicines, implement whole-process management of production, follow the relevant requirements of the Good Manufacturing Practice for Medicines, establish a traceability system, and have risk management capabiliti.

  

[Interpretation] "Announcement of the State Food and Drug Administration, State Administration of Traditional Chinese Medicine, National Health Commission and National Medical Insurance Bureau on Ending the Pilot Work of Traditional Chinese Medicine Formula Granules" (.

22 of 2021) issued on February 10, 2021, since March 1994 Since Guangdong Yifang Pharmaceutical was identified by the Science and Technology Department of the State Administration of Traditional Chinese Medicine as a "pilot unit for the research and development of traditional Chinese medicine formula granules", the pilot program of traditional Chinese medicine formula granules has reached 27 yea.

From November 1, 2021, the pilot program of traditional Chinese medicine formula granules in China will be completely complet.

All qualified traditional Chinese medicine enterprises can produce traditional Chinese medicine formula granules only by filing, and no longer need to apply for approv.

The traditional Chinese medicine formula granules implement the filing system, unify the standards and expand the sales scope, which can provide a guarantee for the safety of patients' medicati.

  Traditional Chinese medicine formula granules also implement the whole process and drug life cycle management, and also have the ability to build a quality system, establish a traceability system and control ris.

 

Article 69 [Sectional production management] For innovative drugs with special requirements for production technology, facilities and equipment, or drugs that are urgently needed in clinical practice, they may be produced in stages with the approval of the drug regulatory department under the State Counc.

  Where the production process of a drug involves multiple production locations, the holder of the drug marketing authorization shall establish a unified quality assurance system covering the entire process of drug production and all production locations to ensure that the drug production process continues to comply with statutory requiremen.

  

[Interpretation] Our country has not released staged production, let alone staged production commissioned by M.

For example, staged production of biological product stock solutions and preparations is not allow.

The EU is relatively op.

As long as MAH is willing to take responsibility, it can be just a “skin bag” compa.

For example, intermediates can be entrusted to one company, raw materials can be entrusted to another company, preparations can be placed abroad, and imported into China in sub-packages, as well as entrusted storage, transportation, e.

Sales, pharmacovigilance, e.

can be commission.

Of course, this clause shows that the state has not completely "blocked" the staged producti.

Special innovative drugs, or drugs in urgent clinical need, can be produced in stages with the approval of the National Bure.

For example, some time ago, the new crown vaccine country also released the original solution and preparati.

Fragmented delegati.

It is required that segmented production involves multiple manufacturers, multiple production locations, multiple workshops, and multiple production lines, and the MAH quality system should be extended to ensure compliance and product quality contr.