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

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

• Presentation by Ira R. Berry
• International Regulatory Business Consultants,
  L.L.C.
• Maplewood, New Jersey, USA

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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Manufacturing Practice DRAFT GUIDANCE cGMP???????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
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Draft Guidance Aseptic ProcessingI.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Draft Guidance - II.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Draft Guidance III.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Draft Guidance IV.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 ?????

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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??????

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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???

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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
• ?????? ????

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Adjacent Area Class 10,000 or Class
1,000????10,000??1,000?
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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
• ????????,???

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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 ???????

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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 ??

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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
• ?????????????

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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?????

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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
• ??????????

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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 ????

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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
• ???????--??????????

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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
• ?????????????

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Draft Guidance IX. Validation of Aseptic
Processing and Sterilization?????-IX.??????????

• Sterilization and aseptic processing operations
• ?????????
• Aseptic processing media fill (process
  simulation)
• ?????????(????)

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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 ???????

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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
• ?????????????????

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Filter Performance Factors???????

• Material viscosity
• ?????
• pH
• Filter compatibility
• ???????
• Pressures ??
• Flow rates ??

• Maximum filtration time
• ??????
• Temperature ??
• Osmolality ???
• Effects of hydraulic shock?????

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Sterilization Qualification and Validation???????

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

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Change Control Program??????

• Written procedures ????
• Equipment, process, test methods, systems
• ?????????????
• Revalidate ???

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Draft Guidance X. Laboratory Controls
?????-X.?????Environmental Monitoring ????
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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
  ?????????

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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 ?????

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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
• ?????????????????????

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Methods for Monitoring????

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

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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
• ???????

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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
• ??????????????

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Guidance for Industry, Submission Documentation
for Sterilization Process Validation, November
1994

• ???????????????
• 1994?11?

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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
• ????????????????

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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 ??

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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
• ???????????

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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???????

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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
• ??????????????????????

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Terminal Moist Heat Sterilization
Process?????????

• Laboratory controls ?????
• Bacterial endotoxins ?????
• Sterility testing ????

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Terminal Moist Heat Sterilization
Process?????????

• WRITTEN PROCEDURES
• ????

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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 ????????

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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 ????????

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Aseptic Fill Manufacturing Process????????

• Updated in August 2003 Draft Guidance
• ?2003?8??????????

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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
• ???????????

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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

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