DMF一份較完整的DMF文件

1、49b8e1b0eb9ab5d0b9bbb6e98cff8abc.pdf2022/1/9/13:50Table of ContentsSectionPageA.Administrative Information1.Drug Master File Holder .12.Corporate Headquarters.13.Manufacturing Facility.14.Stability Testing Facility.35.Responsible Official or Agent .36.Statement of Commitment.4B.Organization and Pers

2、onnel1.Key Personnel and Their Responsibilities.52.Consultants.103.Contract Laboratories.11C.Buildings and Facilities1.General Design and Construction Features.122.Facility Maintenance .17D.Equipment1.Design and Location.182.Calibration and Maintenance.21E.Physical and Chemical Characteristics1.Intr

3、oduction.222.Description .223.Physical and Chemical Characteristics.244.Structure Elucidation.25F.Manufacture of XX Drug Substance1.Materials Control.452.Isolation and Purification.593.Manufacture of Reference Standard.814.Reprocessing and Reworking.82G.Process Controls1.Quality Control of In-Proces

4、s Materials.832.Analytical Methods for In-Process Materials.8849b8e1b0eb9ab5d0b9bbb6e98cff8abc.pdf2022/1/9/13:50Table of Contents (continued)SectionPageH.Controls of XX Drug Substance 1.Sampling .1132.Release Controls.1143.Controls for Reference Standard .1754.Packaging and Labeling.1775.Lot Numberi

5、ng System .180I.Stability Protocol for XX Drug Substance1. Stability Testing Facility .1812. Stability Protocol.1813. Stability Results.1844. Conclusions .194J.Environmental Assessment.195Appendix I: Literature References .19649b8e1b0eb9ab5d0b9bbb6e98cff8abc.pdf2022/1/9/13:50A.Administrative Informa

6、tion1.Drug Master File HolderYY Technological Development Co. Ltd.YY Tech-Zone,ZZ Hill,Beijing, P.R. China 1000332.Corporate HeadquartersYY Technological Development Co. Ltd.YY Tech-Zone,ZZ Hill,Beijing, P.R. China 100033Contact Person:QiaoYing TaTel: 011-86-000-5321-9583 (office)011-86-000-5321-964

7、3 (receptionist)Fax: 011-86-000-5321-90813.Manufacturing FacilityYY Technological Development Co. Ltd.YY Tech-Zone,ZZ Hill,Beijing, P.R. China 100033Contact Person: QiaoYing TaDirector of QA and QCTel: 011-86-000-5321-9583 (office)011-86-000-5321-9643 (receptionist)Fax: 011-86-000-5321-9081Please re

8、fer to Figure A-1 for a map of the city of Beijing. Directions from Beijing airport to the manufacturing facility are also described below: From BeiJing Airport: Chuncheng East Dongfeng Beijing YY Tech-Zone Xuefu Road North Huancheng YY Technological Development Co., Ltd. 49b8e1b0eb9ab5d0b9bbb6e98cf

9、f8abc.pdf2022/1/9/13:50A.3.Administrative information, Manufacturing Facility (continued) Figure A-1.Map of beijing49b8e1b0eb9ab5d0b9bbb6e98cff8abc.pdf2022/1/9/13:50A.Administrative information (continued)4.Stability Testing FacilityNucro-Technics2000 Ellesmere Road, Unit #16Scarborough, Ontario M1H

10、 2W4CanadaContact person: Charles LeeTel:(416) 438-6727Fax:(416) 438-34635.Responsible Official or AgentAll official correspondence should be directed to the USA agent for YY Technological Development Co., Ltd.:YY Development Co. USA, Inc.Arena Tower I7322 Southwest Freeway, Suite 1888Houston, Texas

11、 77074Contact person: William W. Zuo, Ph.D.General Manager of North American AffairsTel:(713) 777-7088Fax:(713) 777-709149b8e1b0eb9ab5d0b9bbb6e98cff8abc.pdf2022/1/9/13:50A.Administrative information (continued)6.Statement of CommitmentWe certify that this is an accurate submission and all informatio

12、n submitted is true. All specifications presented in this Drug Master File for the bulk drug substance will be met. We will follow the procedures outlined in this Drug Master File and will inform the Food and Drug Administration, and any firm authorized to reference this document, if any changes are

13、 made to its contents.YY Tech Development Co. USA, Inc.William W. Zuo, Ph.D.General Manager of North American Affairs49b8e1b0eb9ab5d0b9bbb6e98cff8abc.pdf2022/1/9/13:50B.Organization and Personnel1.Key Personnel and Their ResponsibilitiesAn organizational chart of the XX manufacturing and control fac

14、ility and the North American marketing and distribution subsidiary of YY Technological Development Co., Ltd., is presented below:Board of DirectorsPresident and CEOQuality Control UnitManufacturing BaseHande USA SubsidiaryQuality Control DepartmentQuality Assurance DepartmentProduction I DepartmentW

15、arehouseA summary description of job functions and responsibilities for the key personnel and departments listed above are provided below:a.President and CEO(1)Legally represents the company in dealing with investors, business partners, clients, regulatory agencies, employees and shareholders.49b8e1

16、b0eb9ab5d0b9bbb6e98cff8abc.pdf2022/1/9/13:50(2)Directly reports to the Board of Directors. Executes all resolutions and completes all tasks assigned by the Board of Directors. Provides strategic leadership in defining the vision and mission of the company. Defines and leads the company to realize it

17、s short term, mid-term and long-term business objectives.49b8e1b0eb9ab5d0b9bbb6e98cff8abc.pdf2022/1/9/13:50B.1.Organization and personnel, Key personnel and their responsibilities (continued)(3)Designs and oversees the management of the companys planning, finance, production, marketing, sales, and p

18、ersonnel departments. Responsible for proposing the companys annual plan, budget, total revenues and reporting losses.b.Quality Control UnitAn organizational chart of the Quality Control Unit is presented below:Organizational Chart of the Quality Control UnitQuality Control UnitQuality Assurance Dep

19、artmentQuality Control DepartmentGMPTrainingSystemDocument ManagementMonitoringTestingQualitySupervisionThe responsibilities of the Quality Control Unit are provided below:49b8e1b0eb9ab5d0b9bbb6e98cff8abc.pdf2022/1/9/13:50(1)Responsible for the companys overall quality control and management, provid

20、ing short-term, middle-term and long-term development objectives on quality and regulation, leading and managing QA, QC and Drug Regulatory Group.(2)Supervise and direct the quality control system, including development, purchasing, warehousing, manufacturing, testing, and distribution.(3)Has author

21、ity for inspecting quality of work of the QA, QC, and relevant departments at any time.49b8e1b0eb9ab5d0b9bbb6e98cff8abc.pdf2022/1/9/13:50B.1.Organization and personnel, Key personnel and their responsibilities (continued)c.Quality Assurance Department(1)Responsible for reviewing, approving, distribu

22、ting, and revising all quality documents. These include manufacturing procedures, SOPs, quality management regulations, and quality specifications (label samples, testing methods, sampling method, recording tables, etc.).(2)Supervising and controlling the quality related to the entire manufacturing

23、process, including development, purchasing, warehousing, buildings and facilities management, equipment management, production management, testing, and marketing.(3)Has the final authority in rejecting or releasing raw materials, auxiliary materials, in-process materials, semiproducts, final product

24、s, labeling, and packaging materials.(4)Reviewing master batch production records (MPRs).(5)Responsible for receiving and responding to customer complaints, proposals, and visits related to product quality.(6)Responsible for investigating and offering suggestions for amendment of all quality deviati

25、ons.(7)Responsible for examining and auditing quality matters related to product, manufacturing process, buildings and facilities, equipment, testing laboratory, contact laboratory, quality assurance system, etc. In addition, responsible for performing periodic self-audits, accepting audits given by

26、 FDA, domestic drug administration or customers, verifying distributors qualification, and analyzing product quality annually.(8)Establishing and implementing cGMP compliance training programs for the employees.(9)Organizing all validations.(10) Responsible for managing quality documents.(11) Knowin

27、g and understanding foreign and domestic policies and regulations related to drug products. Establishing relations to governmental drug administration.(12) Examining and verifying materials for new drug applications (NDA), and guiding the compilation of NDAs.49b8e1b0eb9ab5d0b9bbb6e98cff8abc.pdf2022/

28、1/9/13:50(13) Collecting and distributing technological information about production, quality control, and testing methods.49b8e1b0eb9ab5d0b9bbb6e98cff8abc.pdf2022/1/9/13:50B.1.Organization and personnel, Key personnel and their responsibilities (continued)d.Quality Control Department(1)Responsible

29、for establishing sampling procedures and performing all sampling of raw materials, auxiliary materials, in-process materials, semiproducts, final products, recovered solvents, labeling, and packaging materials.(2)Responsible for establishing testing methods and performing all tests for raw materials

30、, auxiliary materials, in-process materials, semiproducts, final products, recovered solvents.(3)Responsible for monitoring and detecting temperature, moisture, pressure, and air flow in the rooms used for final product manufacture and production site.(4)Establishing reserve samples programs and sta

31、bility study programs.(5)Establishing analytical methods and responsible for their validation.e.Manufacturing Base(1)Responsible for organization and management of the production of XX bulk drug substances according to the cGMP requirements. (2)Providing the production plan and management programs o

32、f the manufacturing base.(3)Responsible for managing and coordinating the daily work of all departments in the manufacturing base.49b8e1b0eb9ab5d0b9bbb6e98cff8abc.pdf2022/1/9/13:50B.1.Organization and personnel, Key personnel and their responsibilities (continued)f.Production I Department(1)Responsi

33、ble for performing column chromatography for separation and isolation of active compounds and packing of XX according to cGMP requirements.(2)Responsible for compiling all SOP and regulations of Production.(3)Responsible for performing site supervision and operation training during production.g.Ware

34、house(1)Responsible for inventory, storage and record keeping of starting materials, packaging material, final product, chemicals and reagents, solvents, as well as auxiliary materials.(2)Responsible for compiling all SOPs and regulations for warehousing.(3)Performs monitoring and training for wareh

35、ouse.h.YY USA Subsidiary49b8e1b0eb9ab5d0b9bbb6e98cff8abc.pdf2022/1/9/13:50(1)Responsible for XX product marketing and distribution in North America and Europe.(2)Responsible for contacting and transmitting information between YY and the Food and Drug Administration.(3)Responsible for contacting and

36、transmitting information between YY and consultants in the USA.49b8e1b0eb9ab5d0b9bbb6e98cff8abc.pdf2022/1/9/13:50B.Organization and personnel (continued)2.ConsultantsBeckloff Associates, Inc., Suite 720, Commerce Plaza II, 7400 West 110th Street, Overland Park, Kansas 66210, USA., has provided guida

37、nce and assistance in the preparation and submission of this Drug Master File.49b8e1b0eb9ab5d0b9bbb6e98cff8abc.pdf2022/1/9/13:50B.Organization and personnel (continued)3.Contract LaboratoriesNucro-Technics has provided analytical support in performing stability testing for XX drug substance.Address:

38、2000 Ellesmere Road, Unit #16Scarborough, Ontario, M1H 2W4, CanadaTel:(416) 438-6727Fax:(416) 438-3463Contact Person:Charles Lee49b8e1b0eb9ab5d0b9bbb6e98cff8abc.pdf2022/1/9/13:50C.Buildings and Facilities1.General Design and Construction FeaturesThe manufacturing plant is located in a 5-story buildi

39、ng whose structure is of reinforced concrete. The plant was designed by the Design Institute of Yunnan Technology and Engineering University and consists of 2 floors (the fourth and fifth floors) which comprise 3,600 square meters of usage area.As detailed in the floor plan drawings, the concentrati

40、on area and the warehouse are located on the fourth floor of the building. This includes an area for reagents and chemicals and the storage rooms for starting material. The fifth floor includes different manufacturing areas including the final product rooms for final product crystallization and pack

41、aging. The QC Laboratory is located in Room 1 and Room 2 on the fourth floor, and Rooms 14 on the fifth floor (for details, see Figures C-1 and C-2). The plant has appropriate distribution, sufficient light and good ventilation. It is divided into common areas and a final product area. The final pro

42、duct area where all manufacturing processes are performed for the semiproduct is located in Area V.Axial-flow fans are installed in areas of the fourth and fifth floors to increase the air exchange and improve the ventilation. Specific ventilation systems are used for the final product area. The air

43、 in the final product area is also taken from the outside but treated by a system of air filters. The air is exhausted without being recycled. Three (3) filtrations have been applied to the in-coming air for the 49b8e1b0eb9ab5d0b9bbb6e98cff8abc.pdf2022/1/9/13:50final product area: the prefilter used

44、 for the air has an efficiency of 33.5%, the secondary filter has an efficiency of 70%, and the HEPA filter has an efficiency of 99.95%. The air is exchanged more than ca. 20 times every hour. The pressure difference is 10 Pa between the final product area and the outside. The temperature and humidi

45、ty are also controlled at the prescribed settings of 1525 C and 50 10% RH for all the rooms in the final product area that are used for crystallization, recrystallization and packaging.Six (6) major manufacturing and processing areas are associated with the production of XX (for details, see Figures

46、 C-1 and C-2, for floor space of each area see Table I). Following is a list of designated areas:49b8e1b0eb9ab5d0b9bbb6e98cff8abc.pdf2022/1/9/13:50C.1.Buildings and facilities, General design and construction features (continued)AreaUseArea IPreparation AreaArea IILarge Column AreaArea IIIRecovery a

47、nd Concentration AreaArea IVMedium Column AreaArea VPurification and Crystallization AreaArea VISolvent Adjusting Area49b8e1b0eb9ab5d0b9bbb6e98cff8abc.pdf2022/1/9/13:50C.1.Buildings and facilities, General design and construction features (continued)廠房平面圖49b8e1b0eb9ab5d0b9bbb6e98cff8abc.pdf2022/1/9/

48、13:501a.Balance Room11.Approved Extract Storage Room1b.Reserve Sample Room12.General Warehouse Area2.QC Office13.Manufacturing Area III:3.Changing RoomRecovery and Concentration4.Changing Room14.Utility Room5.Rest Room15.Office6.Rest Room16.Office7.Service Elevator17.Emergency Exit8.New Product Labo

49、ratory18.Storage Room for Intermediates9.Rejected Extract Storage Room19.Drying Room (Na2SO4)10.Approved Extract Storage Room20.Airing Room (Na2SO4)21.Storage Room For Packaging Materials Figure C-1.Layout of fourth floor.49b8e1b0eb9ab5d0b9bbb6e98cff8abc.pdf2022/1/9/13:50C.1.Buildings and facilities

50、, General design and construction features (continued)廠房平面圖1.Laboratory Area2.Laboratory Area3.Laboratory Area4.Laboratory Area5.Column Washing Room6.Rest Room7.Mixture Drying Area8.Sample Mixing Area9.Column Unpacking Area10.Preparation Room11.Column Packing Room ( For Area IV)12.Column Packing Roo

51、m (For Area II)13.Emergency Exit14.Tool Room and Workshop15.Area for Column Chromatography I (For Area II)16.Area for Column Chromatography II (For Area IV)17.Chromatography Computer Control Room18.Storage Room19.High-Position Tank Area 20.Low-Position Tank Area21.Semiproduct Processing Room22.Solut

52、ion Adjustment Room (For Area V)23.Changing Room For Men24.Air Lock for Material Passage25.Changing Room For Women26.Control Room27.Hallway28.Laundry and Autoclave Room29.Concentration and Recovery Room (For Area V)30.Chromatography Room (For Area V)31.Recrystallization and Drying Room32.Packaging R

53、oom33.Elevator34.Air Lock35.Air Shower36.Storage Room for Tools37.Storage Room for Used Silica GelFigure C-2.Layout of fifth floor.49b8e1b0eb9ab5d0b9bbb6e98cff8abc.pdf2022/1/9/13:50C.1.Buildings and facilities, General design and construction features (continued)Table IFloor Space Utilized by Produc

54、tion of XXFloor NumberArea DescriptionFloor Space (m2)4Warehouse 800 Manufacturing Area III8005Manufacturing Area I 480Manufacturing Area II210Manufacturing Area IV210Manufacturing Area V380Manufacturing Area VI300QC Testing Laboratory (including fourth-floor space)8049b8e1b0eb9ab5d0b9bbb6e98cff8abc

55、.pdf2022/1/9/13:50C.Buildings and facilities (continued)2.Facility MaintenanceThe buildings and the facilities are maintained by qualified personnel in accordance with written and approved Standard Operating Procedures.49b8e1b0eb9ab5d0b9bbb6e98cff8abc.pdf2022/1/9/13:50D.Equipment1.Design and Locatio

56、nThe equipment used in the production and testing of XX is of appropriate design, adequate size, and suitable construction for its intended use. A list of the processing equipment used for the manufacture of XX is presented in Tables II and III.Table IIProduction EquipmentEquipment OriginModel No.Qu

57、antityCapacityApplicationLocationMixers Zhejiang, ChinaHWJ 25 II326 kg/hrMixingArea IRotary Vacuum PumpZhejiang, ChinaZXZ-111 L/SDrying columnsArea IChromatographic ColumnShanghai, China851 m x 0.18 mIsolation and purification of productArea IIVacuum ConcentratorBeijing, China150 LConcentration of e

58、luate and recovery of solventsArea IIIVacuum ConcentratorBeijing, China690 LConcentration and recoveryArea IIIVacuum ConcentratorBeijing, China1150 LConcentration and recoveryArea IIIRound Storage TankBeijing, China11000 LStorage of solutionArea IIICubic Storage TankBeijing, China21350 LStorage of s

59、olutionArea IIIStorage TankBeijing, China1240 LStorage of solutionArea IIIStorage TankBeijing, China4270 LStorage of solutionArea IIIStorage TankBeijing, China1450 LStorage of solutionArea IIIStorage TankBeijing, China5480 LStorage of solutionArea IIIStorage TankBeijing, China2720 LStorage of soluti

60、onArea IIIStorage TankBeijing, China11350 LStorage of solutionArea IIIVacuum PumpBeijing, ChinaSZB-823 KWConcentration and recoveryArea IIIMagnetic PumpZhejiang, ChinaCQF-4051.5 KWConveying of solutionArea IIIWater Heating BoxBeijing, China176 KWHeating of water for concentratorArea IIICentrifugal W