cGMP for Sterile Drug Products and APIs ?????????cGMP - PowerPoint PPT Presentation

Loading...

PPT – cGMP for Sterile Drug Products and APIs ?????????cGMP PowerPoint presentation | free to view - id: 417110-Mzk0M



Loading


The Adobe Flash plugin is needed to view this content

Get the plugin now

View by Category
About This Presentation
Title:

cGMP for Sterile Drug Products and APIs ?????????cGMP

Description:

... Current Good Manufacturing Practice, August 2003 Guidance for Industry, Submission Documentation for Sterilization Process Validation, ... – PowerPoint PPT presentation

Number of Views:83
Avg rating:3.0/5.0
Slides: 48
Provided by: westyxCom
Category:

less

Write a Comment
User Comments (0)
Transcript and Presenter's Notes

Title: cGMP for Sterile Drug Products and APIs ?????????cGMP


1
cGMP for Sterile Drug Products and
APIs?????????cGMP
  • Presentation by Ira R. Berry
  • International Regulatory Business Consultants,
    L.L.C.
  • Maplewood, New Jersey, USA

2
Guidance for Industry Sterile Drug Products
Produced by Aseptic Processing Current Good
Manufacturing Practice DRAFT GUIDANCE cGMP???????
??????????(???) Office of Regulatory Affairs
(ORA) August 2003 Pharmaceutical
cGMPs \\CDS029\REGAFF\!guidanc\J 874dft.doc
08/12/03
3
Draft Guidance Aseptic ProcessingI. Introductio
n??????(???)??
  • Use with 1994 guidance ??1994???
  • Covers facility design, equipment suitability,
    process validation, quality control
  • ?????????????????????????

4
Draft Guidance - II. Background?????-II.??
  • Aseptic processing ????
  • Terminal sterilization ????

5
Draft Guidance III. Scope?????- III. ??
  • Finished drug products ??
  • Upstream bulk processing steps
  • ??????????
  • Terminal sterilization not covered
  • ???????

6
Draft Guidance IV. Buildings and
Facilities?????- IV. ?????
  • Separate and controlled areas ??????
  • Microbiological and particle standards
  • ??????????
  • Evaluate under static and dynamic conditions
  • ???????????

7
Critical Area Class 100????100?
  • Sterilized drug product, containers, closures
    exposed to environment maintain sterility
  • ????????????????????
  • Design air handling system ???????
  • Personnel practices and procedures
  • ?????????
  • Personnel flow ??
  • Monitor daily ?????

8
Air Handling System ????
  • HEPA filtered and laminar flow
  • (HEPA?????)
  • Retain NLT 99.97 particulates gt 0.3 micron
  • Leak test introduce upstream challenge
    installation, every 6 months dioctylphthalate
    (DOP) and polyalphaolefin (PAO) aerosols
  • ????--???????
  • ???????????a???????????
  • Monitor face velocity??????

9
Air Handling System ????
  • Carry particles from closing area????????
  • Unidirectional air flow ???
  • Constant flow ??
  • Conduct air pattern analysis??????
  • HEPA(HIGH EFFCIENCY PARTICULATE AIR )
  • HEPA(?????????)?????????????,?0.3?????????????
    ??99.97???

10
Supporting Clean Area Class 100,000???????10000
0?
  • Non-sterile components, products, materials,
    equipment, containers and closures - prepared,
    stored or transferred
  • ??????????????????????--????????
  • Minimize particle contamination
  • ?????????
  • Control microbiological content bioburden
  • ?????? ????

11
Adjacent Area Class 10,000 or Class
1,000????10,000??1,000?
12
Air and Compressed Gas Filtersand Membrane
Filters???????????????
  • Free from oil and water ????
  • Microbiological and particle quality
    environment air
  • ????????????
  • Prevent backflow ????
  • Integrity test installation, after use
  • ????????,???

13
Design Factors????
  • Personnel flow and number of people ?????
  • Material flow and number of transfers
  • ???????
  • Equipment layout ????
  • Equipment design curtains, plastic shields,
    double door sterilizers
  • ????-?????????????
  • Minimize movement ???????

14
Design Factors (continued)
  • Minimize manual activities ?????????
  • Product transfers under appropriate conditions
  • ???????????
  • Airlocks and interlocking doors ????????
  • Written procedures for personnel and materials
  • ??????????
  • Change control ????
  • Air handling shutdown ????
  • Construction ??

15
Cleanroom Design?????
  • Facilitate cleaning and sanitizing ????????
  • Seamless and rounded floor-wall junctions
  • ????????????
  • Floors, walls, ceilings smooth, hard surfaces
  • ????????--???????
  • Ceilings and HEPA filter banks prevent
    contamination ????HEPA????????
  • No unused equipment, fixtures or materials
  • ?????????????

16
Processing Equipment Design???????
  • Sanitary fittings and valves ???????
  • No drains ????
  • Ease of sterilization ????
  • Facilitate aseptic setup ??????
  • No flat surfaces or ledges ??????
  • Should not interfere with airflow?????

17
Draft Guidance V. Personnel
Procedures?????-V.?????
  • Use sterile instruments to contact sterile
    materials ????????????
  • Move slowly and deliberately ?????????
  • Avoid the unidirectional airflow path ???????
  • Do not compromise product sterility
  • ??????????
  • Follow proper gown control ?????????
  • Laboratory personnel use aseptic technique
    ?????--??????
  • Personnel monitoring and training program
  • ??????????

18
Draft Guidance VI. Components, Containers,
Closures?????-VI.??????????
  • Characterize microbial content ??????
  • Establish acceptance limits based on bioburden
  • ?????????????
  • Sterilization methods ????
  • Filtration membrane or cartridge ??-????
  • Steam ??
  • Dry heat ??
  • Ethylene oxide ????

19
Draft Guidance VII. Endotoxin
Control?????-VII. ?????
  • Control bioburden prevent endotoxin load
  • Clean, dry, store equipment properly
  • ??????--???????
  • ?????????????
  • Dry heat endotoxin inactivation on equipment
    surfaces ?????????????
  • Validate cleaning procedures remove endotoxins
    from equipment surfaces
  • ???????--??????????

20
Draft Guidance VIII. Time Limitations?????-VIII
. ????
  • Establish limits for each processing phase
  • ?????????????
  • Assess bioburden and endotoxin load at each stage
  • ?????????????????????
  • Replace filters after each product lot
  • ?????????????

21
Draft Guidance IX. Validation of Aseptic
Processing and Sterilization?????-IX.??????????
  • Sterilization and aseptic processing operations
  • ?????????
  • Aseptic processing media fill (process
    simulation)
  • ?????????(????)

22
Aseptic Processing Validation Runs?????????
  • Design worst-case media fill program mimic
    commercial production conditions
  • ????????????--????????
  • Three consecutive runs for initial qualification
  • ???????3?????
  • Routine semi-annual requalification ?????????
  • 5,000 to 10,000 units 5000?10000?????
  • Bracket vial sizes and fill volumes worst case
    line speed ?????????????-???????
  • Actual manufacturing conditions ???????

23
Aseptic Processing Validation Controls?????????
  • Microbiological growth medium ???
  • Positive controls with lt100 CFU challenge ????
  • Incubation time 14 days minimum, 20-35 ?
  • 20-35?????14??
  • Investigate any contaminated unit ?????????
  • Microbiological challenges to filters
    ????????????
  • Determine bioburden of unsterilized bulk
    solutions
  • ?????????????????

24
Filter Performance Factors???????
  • Material viscosity
  • ?????
  • pH
  • Filter compatibility
  • ???????
  • Pressures ??
  • Flow rates ??
  • Maximum filtration time
  • ??????
  • Temperature ??
  • Osmolality ???
  • Effects of hydraulic shock?????

25
Sterilization Qualification and Validation???????
  • Qualification empty chamber ??-??
  • Validation loaded chamber/configuration
  • ??-??/??
  • Equipment and instrument calibration
  • ????????

26
Change Control Program??????
  • Written procedures ????
  • Equipment, process, test methods, systems
  • ?????????????
  • Revalidate ???

27
Draft Guidance X. Laboratory Controls
?????-X.?????Environmental Monitoring ????
28
Product Development Activities??????
  • Microbial limits and bioburden ????????
  • Raw materials, packaging components, product
  • ??????????
  • Endotoxin limits ?????
  • Antimicrobial effectiveness for preservatives
  • ????????
  • Container-closure integrity ????????
  • Bacterial challenge testing for sterilizing
    filters
  • ?????????????
  • Process validation ????
  • Aseptic or terminal sterilization process
    ?????????

29
Environmental Monitoring Program??????
  • Written procedures ????
  • All production shifts ?????
  • Air ??
  • Floors, walls ?????
  • Equipment surfaces ????
  • Sample locations, timing, frequency
  • ??????????
  • Sample points of contamination risk ?????????
  • Track data trends ?????

30
Microbiological Levels and Reporting????????
  • Establish microbiological monitoring levels
  • ?????????
  • Alert levels ????
  • Action levels ????
  • Issue environmental trend reports
  • ????????
  • Assess suitability, efficacy, limitations of
    sanitization agents and procedures
  • ?????????????????????

31
Methods for Monitoring????
  • Surface monitoring ????
  • Active air monitoring ???????
  • Passive air monitoring ??????
  • Characterize recovered microorganisms ??????????
  • Minimize bioburden, eg, prefiltration
    ????????,????
  • Monitor air particles ??????

32
Draft Guidance XI. Sterility Testing?????-XI.??
??
  • Identify organisms in positive results
  • ???????????
  • Review trends in laboratory results
  • ??????????
  • Monitor and trend production area environment
  • ????????????
  • Trend daily monitoring of personnel?????????
  • Trend product bioburden ?????????
  • Review batch and production control records
  • ??????????
  • Trend manufacturing history
  • ???????

33
Draft Guidance XII. Batch Record Review
Process Control Documentation?????-XII.
??????-??????
  • Establish daily process and environmental
    controls
  • ????????????
  • Review all batch records and data for batch
    release
  • ??????????????

34
Guidance for Industry, Submission Documentation
for Sterilization Process Validation, November
1994
  • ???????????????
  • 1994?11?

35
Introduction to the Guidance?????
  • Submission of information and data????????
  • Relates to sterilization processes???????
  • Aseptic processing ????
  • Terminal sterilization ????
  • Evaluate process by series of protocols and
    scientific experiments
  • ????????????????

36
Terminal Moist Heat Sterilization
Process?????????
  • Describe the product and process ???????
  • Drug product, container-closure system
  • ?????????
  • Sterilization process ????
  • Autoclave process and cycle, loading patterns
  • ???????????????
  • Controls to monitor production ???????
  • Requalification requirement ??????
  • Reprocessing ??

37
Terminal Moist Heat Sterilization
Process?????????
  • Thermal qualification of the cycle???????
  • Heat distribution and penetration ???????
  • Thermal monitors ????
  • Thermal input for minimum and maximum loads
  • ????????????
  • Master batch record based on validation studies
  • ???????????

38
Terminal Moist Heat Sterilization
Process?????????
  • Microbiological efficacy of the sterilization
    cycle
  • ????????????
  • Sterility assurance of 10-6 or better????10-6
  • Identify and characterize bioburden
    organisms??????
  • Bioburden specifications????????
  • Biological indicator identification, resistance,
    stability?????????,???,???
  • Microbiological challenge studies???????

39
Terminal Moist Heat Sterilization
Process?????????
  • Container-closure integrity ????????
  • Simulate processing stress ????
  • Demonstrate integrity following maximum exposure
  • ???????????
  • Evaluate each of multiple sterility barriers
  • ???????????
  • Specify sensitivity of the integrity
    test???????????
  • Demonstrate microbial integrity over the product
    shelf life
  • ??????????????????????

40
Terminal Moist Heat Sterilization
Process?????????
  • Laboratory controls ?????
  • Bacterial endotoxins ?????
  • Sterility testing ????

41
Terminal Moist Heat Sterilization
Process?????????
  • WRITTEN PROCEDURES
  • ????

42
Ethylene Oxide Sterilization Process????????
  • Describe the sterilizer ??????
  • Cycle parameters ????
  • Prehumidification, gas concentration ?? ,?????
  • Vacuum and gas pressure cycles ???????
  • Exposure time, temperature, humidity
  • ???????????
  • Degassing and aeration ?????
  • Determination of residuals ??????
  • Microbiological testing methods ???????
  • Stability ???
  • Packaging ??
  • Container-closure integrity ????????

43
Radiation Sterilization Process??????
  • Describe the facility and process ????????
  • Radiation source ???
  • Method of exposure ?????
  • Type and location of dosimeters to monitor
  • ?????????????
  • Describe product packaging ???????
  • Multiple dose mapping studies ???? ??
  • Microbiological methods and controls ????????
  • Stability ???
  • Packaging ??
  • Container-closure integrity ????????

44
Aseptic Fill Manufacturing Process????????
  • Updated in August 2003 Draft Guidance
  • ?2003?8??????????

45
Microbiological Control and Quality Stability
Considerations????????-?????
  • Container-closure integrity ????????
  • Microbial barrier ???
  • Shelf life ????
  • Sensitivity of the integrity test ?????????
  • Preservative effectiveness ??????
  • Beginning and end of stability period
  • ???????????
  • Microbial challenge and chemical assays
    ??????????
  • Pyrogen or endotoxin testing ????????
  • Beginning and end of stability period
  • ???????????

46
References ????
  • U.S. FDA GUIDANCES
  • Draft Guidance for Industry, Sterile Drug
    Products Produced by Aseptic Processing - Current
    Good Manufacturing Practice, August 2003
  • Guidance for Industry, Submission Documentation
    for Sterilization Process Validation, November
    1994

47
(No Transcript)
About PowerShow.com