1 Biotechnology Derived Therapeutics Manufacturing Virtual Tour 3-April-2006 Pharm523 Survey of Biomedical Regulatory Affairs 2 Objectives • “see” BDT manufacturing stuff in a flow chart context • Consider conjunction of manufacturing sequence considerations and cGMPs 3 Citations • FDA IOM Chapter 5 – Establishment Inspections www.fda.gov/ora/inspect_ref/iom/ChapterText/540.html#SUB540 • Thanks to – James Young, Berlex – Steve Steinman, Steinman Associates 4 Model: Establishment Inspection • Description of Facility • Equipment • Training Program • Component & Materials Control • Reprocessing / Reworking • Adverse Event Reports • Water Systems • Computer Systems • Packaging & Labeling • Scale-Up Procedures • QA / QC Systems • Contracting Services/Vendors • Product Reviews / Discrepancy / Failure Evaluation and Reporting Systems • Testing/Laboratory Operations See chapter headings in 21CFR211)
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6523 BDT Inspection Tour - University of Washingtoncourses.washington.edu/pharm523/documents/6523 BDT...• B) The validation records for the performance of the HVAC system filters
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1
Biotechnology Derived Therapeutics Manufacturing
Virtual Tour
3-April-2006Pharm523 Survey of Biomedical Regulatory
Affairs
2
Objectives
• “see” BDT manufacturing stuff in a flow chart context
• Consider conjunction of manufacturing sequence considerations and cGMPs
• a substance, as a thermostable bacterial toxin, that produces a rise in temperature in a human or animal– largely from family Enterobacteriaceae– objectionable by itself – marker – “whereby” clause in the Act
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Water
• WFI– Distillation or
reverse osmosis
– Feed?– Distribution?– What’s a
batch?– Sampling?– Specifications?
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WFI
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Typical BDT Flow
Supplier ReceiveComponents Quarantine Test
Panel
ReleaseComponents
toManufacturing
Pass
Fail
FirstManufacturing
Step
ExpandWorking
CellBank
TestPanel
Discard&
Document
Fail
TestPanel
SecondManufacturing
Step
TestPanel
Fail
Pass
Purification
Pass
TestPanel Reprocess Test
PanelFail
Bulk
Sterile Fill&
Lyophilize
TestPanel
Package&
Label
RA/QARelease
TestPanel
Pass
Pass
Pass
FinishedGoods
Inventory
Pass
Pass
Pass
TestPanel Pass
Fail
Fail
Fail
Fail
Fail
Fail
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Tour – master/working cell bank• Typically,
nitrogen Dewar or ultra-low temp freezer
• Inspection issues?
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Tour –fermentation• Inspection
issues?
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Typical BDT Flow
Supplier ReceiveComponents Quarantine Test
Panel
ReleaseComponents
toManufacturing
Pass
Fail
FirstManufacturing
Step
ExpandWorking
CellBank
TestPanel
Discard&
Document
Fail
TestPanel
SecondManufacturing
Step
TestPanel
Fail
Pass
Purification
Pass
TestPanel Reprocess Test
PanelFail
Bulk
Sterile Fill&
Lyophilize
TestPanel
Package&
Label
RA/QARelease
TestPanel
Pass
Pass
Pass
FinishedGoods
Inventory
Pass
Pass
Pass
TestPanel Pass
Fail
Fail
Fail
Fail
Fail
Fail
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Tour – Purification 1
• Post fermentation– Decrease volume– Remove debris– Concentrate cells
• 21CFR610.12(a) The test. Bulk material shall be tested separately from final container material and material from each final container shall be tested in individual test vessels as follows…
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Finish & fill
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Finish & fill – a 483 aside …
• A) The quality control unit did not assure adequate validation of the HVAC system which supplies air to aseptic fill lines and did not detect that existing validation records do not document the operating conditions or equipment configurations used during validation.
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Finish & fill – aside 2
• The quality control unit did not conduct a thorough investigation of the drop in the air flow to the HEPA filters over aseptic fill line 1 between 4/2/99 and 8/25/99.
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Finish & fill – aside 3
• The quality control unit did not assure that adequate systems and controls were in place to monitor the functioning of and to detect malfunctions of the air handling systems used to control and assure aseptic conditions in aseptic manufacturing areas.
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Finish & fill – aside 4
• The quality control unit did not sign / approve Procedure 00887 (Airflow Velocity Measurements of HEPA Filter), which describes the air velocity measurements in the aseptic fill area, and did not detect that this procedure lacks air velocity specifications.
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Finish & fill – aside 5
• The quality control unit did not detect that two different air flow velocity specification values were used on 1999 Pressure Drop Reports for Line 9.
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Finish & fill – aside 6
• The quality control unit did not review HEPA Bank test report findings for up to two months after the tests were performed and specifications / procedures had not been established to evaluate these test results.
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Finish & fill – aside 7
• The quality control unit did not assure that all areas used for aseptic manufacturing and processing operations are appropriately controlled and classified for their intended use.
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Finish & fill – aside 8
• The quality control unit did not assure that adequate controls were in place to assure that re-sterilized storage tank “vent” filters were appropriate for their intended use.
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Finish & fill – aside 9
• The quality control unit did not investigate, evaluate, and resolve all critical defects or discrepancies (in the number of contaminated vials found) during Sterile Process Simulation 634-08.
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Finish & fill – aside 10• Failure to provide adequate air handling systems for aseptic
processing, as required by 21 CFR 211.46. For example:• A) There were no established specifications for air velocity at the HEPA
filters which supply air to the aseptic fill lines.• B) The validation records for the performance of the HVAC system
filters which supply air to aseptic filling lines 1, 8 and 9 did not document the system operating conditions during validation.
• C) There was no system in place to detect and/or report malfunctions of the air handling systems used to control aseptic conditions.
• D) The air flow supplied to the HEPA filters over aseptic filling line 1 dropped significantly sometime between 4/2/99 and 8/25/99; but, the drop was not detected and corrected at the time of occurrence.
• E) The primary barriers used on aseptic fill line 8 were altered. Written procedures describing how such a change is to occur were not available and there is no assurance that the change did not affect the adequacy of the air handling system to the line.
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Finish & fill – zoo configuration
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Clean room
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Clean room -- access
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Clean room – easily cleaned
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Vial washer
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Stopper washer
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Scrambler vial washer oven
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sterilization rant
• what is – product vs. container/closure• how do you know– sterility assurance level• how do you do it ... and what you get