I.Project name: GMP certification
II.Contents of licensing: GMP certification (for injections, radioactive drugs and biologicals defined by drug regulatory department under the State Council)
"Drug Administration Law", "Regulations for Implementation of the Drug Administration Law," "Good Manufacturing Practice (2010 revised edition) ", and "Provisions for GMP Certification"
Application fees: ￥500 for each enterprise. On-site inspection fees: ￥30,000 for each dosage form (including a production line), Every additional dosage form (including a production line) can be charged ￥3,000. Experts shall be organized for on-site inspection of manufacturers applying for GMP certification of injections, radioactive drugs and biologicals defined by drug regulatory department under the State Council.
Charge basis: "Notice of the National Development and Reform Commission and the Ministry of Finance on the Charging Standards for Drug GMP Certification and Related Issues Notice" (NDRC Price Department"2004" No. 59).
V.Quantity restrictions: No quantity limit for the licensing
VI. List of application documents:
Data number (1) Drug GMP certification application documents
Data number (2) Overall situation of enterprises;
1. Enterprise Information
(1) The name and registered address of the enterprise;
(2) Address and zip code of the enterprise;
(3) Contacts, fax, telephone (including 24-hour contact person and telephone for serious ADRs or recall events).
2. Pharmaceutical production situation
(1) Brief the enterprise’s production activities approved by (food) drug administration departments, including the information of import sub-packaging, export and drug licensed overseas;
(2) Copies of the Business license, drug production license, and related certifying documents issued by overseas institutions, if exports are involved;
(3) All varieties that have obtained approval number (different production sites can be distinguished, and indicate whether the production is perennial, and the annual production output of three consecutive years shall be provided as an attachment);
(4) Whether the production site processes high toxicity, gonadal hormone drugs and other high activity, high allergenicity materials, if any, they should be listed and marked in the annex.
3. The scope of the application for GMP certification
(1) List the production lines, production dosage forms and varieties applying for drug GMP certification, and attach the copies of registration approval documents for relevant products;
(2) (Food) drug administration departments’ latest inspection of the production line (including inspection dates, test results, defects and rectification, together with the relevant GMP Certificate). If the production line has been subject to overseas GMP inspection, and related information shall be provided together.
4. Main changes since the last drug GMP certification
Brief of the changes of key personnel, equipment and facilities, and varieties after previous certification inspection.
Data number (3) Quality management system;
1. Enterprise’s QMS Description
(1) Related management responsibility for QMS, including the responsibilities of senior managers, the person in charge of quality management, quality Authorized Person, and the quality assurance department;
(2) A brief description of the QMS elements, such as the organization, the main procedures, processes and so on.
2. Finished product clearance procedures
General description of the clearance procedures and the person in charge (qualifications, etc.).
3. Supplier management and the situation of commissioned manufacturing and tests
(1) Overview of supplier management requirements, as well as the quality risk management approaches in the evaluation and inspections;
(2) Brief of commissioned production (if any);
(3) Brief of commissioned production (if any).
4. Corporate quality risk management measures
(1) Outline the quality risk management principles of the enterprises;
(2) Scope and focus of the quality risk management activities, as well as the risk identification, evaluation, control, communication and review processes under the quality risk management system.
5. Retrospective analysis of annual product quality
Enterprise’s retrospective analysis of annual product quality and focuses of Inspections. Pharmaceutical production enterprise’s annual, regular, variety-specific product quality summary report and retrospective analysis in written reports. In principle, it should cover a year's time, but do not need to coincide with the calendar year. If the annual production is less than 3 batches, the inspection can be extended until 2-3 batches have been produced, unless there are special requirements of regulatory authorities. Typically, enterprise’s product quality review should be completed within three months after the end of the annual production, but the enterprise should complete the acquisition and aggregation of relevant data right after the end of the daily production, to avoid massive data collection only after the end of the annual production.
Data number (4) Personnel;
1. Includes the organizational chart for quality assurance, production and quality control (including senior managers), as well as the separate organizational chart for each department
2. Qualifications of key personnel and major technical personnel engaged in quality assurance, production and quality control
3. Number of employees in quality assurance, production, quality control, storage and shipment, and other departments
Data number(5) (five) Plant, facilities and equipment;
(1) Brief description of and completion time and service time of the building plants, the types (including the structure and materials for inner and outer surfaces etc.), the area of the venue;
(2) The plant’s general layout diagram, flow chart diagram and layout of the production areas, marked ratio. Cleanliness level of the rooms and the differential pressure of adjacent rooms should be marked, and the production activities carried out in the rooms shall be indicated;
(3) A brief description of the layout of all production lines within the scope of certification application;
(4) a brief description of the warehouses, storage areas, and the special storage conditions;
(5) A brief description of air purification systems: operating principles, design criteria and operating conditions, such as inlet, air temperature, humidity, pressure, ventilation frequency, return air utilization;
(6) A brief description of the water system: operating principles, design criteria and operating conditions and diagrams;
(7) A brief description of other utilities: such as: operating principles, design criteria and operating conditions for compressed air, nitrogen and others.
(1) List the main production and testing instruments and equipment, as well as specific requirements for the equipment: quantity, types, specifications and manufacturer, applicable production lines;
(2) Cleaning and disinfection: brief the methods and verification of the cleaning and disinfection of the surface having direct contact with drugs;
(3) Critical computerized systems related to pharmaceutical production and quality: brief the design, application and validation of computerized systems related to pharmaceutical production and quality.
Data number (6) Document
1. A description of enterprise’s file system
2. A brief description of file drafting, revision, approval, distribution, control and archiving system
Data number (7) Production
1. Description of products
(1) review (brief) of the product;
(2) Process flow diagram of the applied dosage forms and varieties, indicating the main quality control points and projects.
2. Process validation
(1) A brief description of the principles and overall situation of process validation;
(2) Brief of rework, re-processing principles.
3. Materials management and warehousing
(1) Raw materials, packaging materials, semi-finished products and finished products processing, such as sampling, testing, release and storage;
(2) Disposal of substandard materials and products.
Data number (8) Quality control;
Description of all activities conducted in the enterprise’s quality control laboratories, including test standards, methods, validation and so on.
Data number (9) Delivery, complaints and recalls;
(1) Brief description of the necessary controls during product transport, such as temperature/humidity control;
(2) Methods to ensure product traceability.
2. Complaints and Recalls
Brief the Procedures for handling complaints and recalls.
Data number (10) Self-inspection
A brief description of self-Inspection system, highlighting the area selection criteria in planned inspections, implementation of the self-Inspection and rectification processes.
VII. Requirements for application dossier:
(I) General requirements for the dossier:
The first page of the dossier is a list of the application documents, which is arranged in the order specified in the "Provisions for drug GMP certification". The dossier shall be distinguishable with clear markers, and the name and serial number of the dossier shall be indicated. The full set of dossier shall be punched and bound into a book.
2. The dossier shall be printed in A4 size paper, the left margin shall be not less than 3cm, the page number shall be marked on the bottom right corner; the cover shall mark the name of the applying enterprise (Chinese characters not less than font-size junior 4 in Song typeface, English not less than font-size 12), the contents should be complete, clear, and shall not be altered.
3. Two sets of "Application form for drug GMP certification", 1 application electronic documents (suffix. Xml), 1 set of GMP certification application data, the application form should be accurate, complete and legible.
4. The pictures and drawings annexed to the dossier must be clear and legible, should not be copied or color inkjet printed pictures.
5. The applicants should send E-mail, along with the mail or submission of their application dossier, the electronic version of the application form to the following e-mail address: firstname.lastname@example.org, which is dedicated for drug registration.
(II) Specific requirements for application document:
1. Drug GMP certification application documents
The application form is the basic document for GMP certification, and the basis and essentials for Drug Administration department’s approval of the application, and format review of GMP certification application, therefore it must be filled out in an accurate and standardized manner in compliance with the explanatory notes.
(1) Organization code shall be filled as per the "PRC Organization Code Certificate"
(2) Production Category: Fill in “chemical drugs, chemical APIs, TCM patent medicine, herbal extracts, biological products, in vitro diagnostic reagents, radioactive drugs, other Categories (TCM slices, medical excipients, hollow capsules, medical oxygen)”. Chinese patent medicines containing herbal extracts should be noted in parentheses.
(3) Business Type: as per the type in the "business license". Three types of foreign-funded enterprises: Please specify the country of the foreign funded enterprises or Hong Kong, Macao and Taiwan regions.
(4) Scope of Certification: according to the categories of dosage forms, fill in: injections, oral solid dosage, oral liquid preparations, other formulas, APIs, biological products, in vitro diagnostic reagents, radioactive drugs, other categories (TCM slices, medical excipients, hollow capsules, medical oxygen). Penicillins, cephalosporins, hormones, anticancer drugs, contraceptive pills, herbal extraction plant shall be indicated in parentheses; APIs should indicate the names of varieties in parentheses; radioactive drugs, biological products should indicate the names of the varieties and corresponding dosage forms in parentheses.
(5) Scope of Certification: according to the categories of dosage forms, fill in: injections, oral solid dosage, oral liquid preparations, other formulas, APIs, biological products, in vitro diagnostic reagents, radioactive drugs, other categories (TCM slices, medical excipients, hollow capsules, medical oxygen).
(6) Nature of Construction: Fill in new construction (referring to a newly established pharmaceutical manufacturers and new production range), renovation and expansion, relocation.
(7) fixed assets and investment calculation unit: ￥10,000. Production capacity calculation unit: 10,000 bottles/ doses / pieces / tablets / bags, tons, etc.
(8) The contact telephone number should indicate the corresponding long-distance telephone area code.
Note: In the above paragraphs (2)-(5), The production scope shall be specified in a uniform and detailed manner, each production line shall be specifically marked and indicated whether the process involves or not herbal extracts, terminal sterilization or non-terminal sterilization, so as to facilitate future supervision.
2. Drug GMP certification application documents
(1) Copies of "Drug production license" and "business license"; should be in the validity period, the information of the name and address of manufacturers, production sites and legal representatives shall be consistent with the corresponding contents in the "application form for drug GMP certification", and the production scope set forth in the "Drug production license" should cover the certification scope being applied.
(2) The production line, dosage forms and varieties that are subject to the drug GMP Certification, and attached copies of registration approval documents for related products, including the copies of related documents such as rationales and standards, drug approval numbers, new drug certificate, production licenses etc.
(3) Corporate organizational chart, including the organizational chart for quality assurance, production and quality control (including senior managers) departments, as well as the separate organization chart for each department. The names of the departments, mutual relations and department heads shall be specified; the structure shall be integrated and the responsibilities of the departments should be clear cut.
(4) The general layout diagram, flow chart diagram and layout of the production area, requiring clear and complete drawings, clearly marked proportions, cleanliness levels, differential pressure of adjacent rooms, and production activities in the rooms.
Focused description of the production areas, air purification systems and equipment for β-lactam species (such as penicillins, cephalosporins, etc.), contraceptive pills, hormones, anti-cancer agents, radioactive drugs etc., to prevent cross contamination from the angle of design.
Equipment installation layout plan (including changing rooms, toilets, passenger and logistics corridor, airlock, etc., and identify the direction of human flow and logistics, and air cleanliness levels).
(5) Floor plan of air purification system: air, return air, exhausts; shall indicate the position for air inlets and outlets.
(6) Process flow diagram for the dosage forms and varieties being applied, the main process control points and control programs shall be indicated; the actual production process shall be consistent with the approved process.
VIII.Application process diagram:
After the application is filed to the Administrative Acceptance Service Center, and the application dossier submitted is in accordance with the list in VI of this Notice, the format examination shall be conducted by the work staff of the Center in accordance with the "Regulations for GMP Certification". Where the application item is not subject to administrative approval according to law, a decision of non-acceptance shall be notified to the applicant immediately. Where the application item is not within the functions of the administrative authority, a decision of non-acceptance shall be made immediately, and the applicant shall be informed to launch the application to relevant administrative authority. Where in the application dossier, there are errors that can be corrected on the spot, the applicant shall be allowed to make the corrections on the spot. Where the application dossier is incomplete or does not meet the statutory format, the applicant shall be informed of all the supplements and amendments to be made once and for all on the spot or within five days. If the applicant is not informed within the above-mentioned period, the application shall be deemed as accepted from date of receipt of application materials. Where the application dossier is within the functions of the administrative authority, the application materials are complete and comply with the statutory format, or where the applicant has submitted all supplements and amendments in accordance with the requirements of the administrative authority, the application for administrative approval shall be accepted.
CFDA shall perform technical review of the application dossier within 20 working days from the date of acceptance. After technical review, if additional information is needed, CFDA shall notify the applicant in writing. The applicant enterprise should supplement the information within the specified time limit as per the requirements of the Notice, for overdue submission, the application for certification shall be terminated.
(III)Develop on-site inspection program:
After CFDA China Drug Inspection completed the technical review of application dossier, onsite inspection work program should be developed for organization & implementation. The time frame for program development and implementation of on-site inspection is 40 working days.
On-site inspection team leader is responsible for the implementation of the system, the inspection team generally consists of at least three drugs GMP inspectors, who are randomly selected from pharmaceutical GMP inspectors library, and should follow the principle of avoidance. China Drug Inspection should notify the applicant before the on-site inspection. Site inspection time is generally 3-5days, which can be adjusted according to specific circumstances.
The inspection team should deliver the on-site test report, the inspector records and related information to drug certification & inspection institutions within 10 working days after the inspection.
(V)Approval and Certification:
China Drug Inspection shall comprehensively evaluate the on-site inspection report in combination with the enterprise rectification. If necessary, China Drug Inspection shall verify on-site the rectification of the enterprise. Comprehensive evaluation should be completed within 40working days upon receipt of the rectification report, if on-site verification is limited, evaluation time limit shall be extended accordingly.
After China Drug Inspection completed the comprehensive evaluation, the results should be made public, the publicity period is 10 working days. For objections to the publicized results, China Drug Inspection or Drug Administration departments at the same level shall promptly organize investigation and verification. During the investigation, certification shall be suspended.
If there is no objections to the publicized results, or if the objections have been investigated with findings, China Drug Inspection should report the findings to drug administration departments at the same level, who shall perform further examination and approval.
After that, the drug administration departments shall issue "Drug GMP certificate" to GMP-complying applicants; for non-conformity of drug GMP, drug administration departments shall notify the disapproval opinions to the applicant in "opinions for examination and approval of Drug GMP certification". The timeframe for Administrative examination and approval is 20 working days.
X.Commitment time frame:
(I)Technical Review: the timeline for China Drug Inspection technical review of the application dossier is 20 working days.
(II)The development of work program and implementation of on-site inspection: the time frame for China Drug Inspection’s development of work program and implementation of on-site inspection is 40 days.
(III)Comprehensive evaluation: the time frame for China Drug Inspection’s comprehensive evaluation of the on-site inspection report in combination with the corporate rectification verification is 40 working days.
(IV)Results publicity: After China Drug Inspection completed the comprehensive evaluation, the results should be made public, the publicity period is 10 working days.
(V)Administrative examination & approval: the time frame for drug administration department’s administrative examination & approval is 20 working days.
"Drug GMP certificate "shall be valid for 5 years.Drug manufacturers who have obtained the "Drug GMP Certificate" shall reapply for drug GMP certification within 6 months prior to the expiry of the certificate.
XII.Annual inspection or annual review of the license: None
XIII.Authority of Implementation:
Implemented by: CFDA
Accepted at: CFDA Administrative Service Center
XIV.Institutions for inquiries and complaints:
Complaints: CFDA Bureau of Investigation and Enforcement, Department of Legal Affairs
Note: The time frame of this Notice counts on working days, excluding legal holidays