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Biotechnology Derived Therapeutics Manufacturing
Virtual Tour
3-April-2006Pharm523 Survey of Biomedical Regulatory
Affairs
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Objectives
• “see” BDT manufacturing stuff in a flow chart context
• Consider conjunction of manufacturing sequence considerations and cGMPs
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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
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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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Establishment Inspection 2Testing / Laboratory Operations• Analytical Laboratories• Lab Equipment Calibration &
Qualification• Microbiology Quality Control
& SOPs• Stability Testing, Protocol &
Storage Conditions• Sample Accountability &
Tracking • Sampling and Testing for
Acceptance and Rejection of Raw Materials
• Analyst’s Notebooks
• Standards / Reagents / Chemicals / Media
• Analytical Method Validation • Computer System Validation • Method Transfer• OOS Results • Training Protocol for Lab
Personnel• Contract Testing Lab• Stability Program• Records / Reports /
Documentation Control
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Simple Flowchart
Components
Fermentation Purification
Finish & Fill
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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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The Tour
• Start at the loading dock … leave via shipping• Observe incoming components procedures;
quarantine area• “Special” components
– Stuff pumped throughout the facility• Water
– DI– WFI
• Gasses (nitrogen, CO2, argon, etc.)• Acetonitrile (!)
– Biologicals (pancreases insulin; calf serum, caster beans ricin …)
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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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... an aside on “pyrogens”
• 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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15
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
Millipore Corp.
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Purification – 2
• Crystallization• Centrifugation• Filtration• Ultrafiltration• Separatory
columns– size– ionic – affinity– hydrophobicity
• Inspection issues
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Purification – 3
• Column chromatography• Issues
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Purification - 4
• Pre-filtration• Filtration• Sterile
filtration• 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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Bulk sterility test, etc.
• 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
– like Nebuchadnezzar's fiery furnace [dry heat]– saturated steam– chemicals (typically ethylene oxide)– plasma (ultraviolet photons/radicals)– ionizing radiation (electron beam 3-12 MeV, cobalt-60
[gamma])– filtration
• how do you know its done
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oven
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“clean” side of sterilizer
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Filling machine
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Stoppering machine
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lyophilization
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Capping machine
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Visual inspection
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Finishing the tour
• Packaging & labeling• Final inspection• Laboratory
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Lingering Issues
• Environmental monitoring• Laboratory inspection• Adverse event reporting; triage
Process Flow for Penicillin Production – after Cooney
P-1 / V-101Blending / Storage Medium P-4 / ST-101
Heat Sterilization
P-2 / V-102Blending / Storage Glucose
P-3 / MX-101Mixing
P-5 / G-101Gas Compression
P-6 / AF-101Air Filtration
P-7 / V-103Fermentation
P-8 / AF-102Air Filtration
P-20 / RVF-101Removal Biomass
P-21 / HX-101Cooling
P-22 / MX-102Acidification
P-23 / CX-101Centrifugal Extraction
P-25 / V-104Re-ectraction + Crystallization
P-26 / BCF-101Basket Centrifugation
P-29 / MX-103Adding Fresh Butyl Acetate
P-31 / FBDR-101Fluid Bed Drying
P-32 / V-105Storage Penicillin Sodium Salt
S-101
S-102
S-103
S-104
S-105
S-107
S-108
S-109
S-113 S-114
S-115
S-116
S-117
S-150 S-151
S-152
S-154
S-155
S-156
S-157
S-161
S-162
S-163
S-164
S-165
S-166S-167
S-173
S-174
S-175
S-176
S-177
S-178
S-106
S-110
S-111 S-112
P-27 / CSP-101Component Splitting
S-168
S-172
S-153P-9 / V-106Storage
S-118S-119
P-24 / MX-104Neutralization
S-158
S-159
S-160
P-28 / MX-105Neutralization
S-169
S-170
S-171
Process Flow for a MAB – after Cooney
Inoculum Prep
P-1 / TFR-101
T-Flask (225 mL)
P-2 / RBR-101
Roller Bottle (2.2 L)
P-5 / SBR1
First Seed Bioreactor (1000 L)
P-6 / V-102
Media Prep
P-7 / DE-101
Sterile Filtration
P-11 / V-104
Media Prep
P-12 / DE-102
Sterile Filtration
P-10 / SBR2
Second Seed Bioreactor (5000 L)
P-20 / PBR1
Production Bioreactor (20000 L)
P-21 / V-106
Media Prep
P-22 / DE-103
Sterile Filtration
S-101
S-102
S-103
S-111
S-112 S-113
S-115
S-114
S-119
S-130S-121
S-122S-123
S-125
S-124
S-129
S-149
S-140
S-141 S-142
S-144
S-143
S-120
P-30 / V-101
Surge Tank
S-148
P-33 / V-103
Storage
P-34 / UF-101
Concentration
S-155
S-156
S-157
P-35 / V-105
Virus InactivationP-36 / DE-104
Polishing FIlter
P-37 / V-107
Storage
S-158
S-159
P-40 / C-101
Prot-A Chromatography
P-42 / V-108
Prot-A Pool Tank
P-38 / DF-102
Diafiltration
S-160
S-162
PrA-Equil
PrA-Wash
PrA-Eluat
PrA-Reg
S-181
S-164
S-163
S-161
S-165
S-169
P-41 / DE-105
Polishing FIlter
S-180
S-183
S-182
P-50 / C-102
IEX Chromatography
S-184
P-52 / V-109
IEX Pool Tank
IEX-Equil
IEX-Wash
IEX-WFI
IEX-Eluat
IEX-Strip
S-190
S-194
P-60 / C-103
HIC Chromatography
P-62 / DE-106
Dead-End Filtration
P-70 / V-110
HIC Pool Tank P-71 / DF-103
Diafiltration
P-72 / DE-107
Final Polishing Filtration
P-73 / DCS-101
Freeze in Plastic Bags
S-195
HIC-Equil
HIC-Wash
HIC-Eluat
HIC-Reg
S-200
S-205
S-204
S-210
S-211S-212
S-213
S-215
S-217
S-216
Final Product
IEX-Rinse
P-31 / DS-101
Centrifugation
P-32 / DE-108
Polishing Fitler
S-150
S-152
S-151
S-154
S-153
P-3 / BBS-101
Bag Bioreactor (20 L)
S-104
S-105
S-107
Bioreaction
Primary Recovery
Protein-A
IEX Chrom HIC Chrom
Final Filtration
P-4 / BBS-102
Bag Bioreactor (100 L)
S-106
S-108 S-110
S-109
S-214
P-39 / MX-101
Mixing
S-166
S-167
S-168
P-51 / MX-102
MixingP-61 / MX-103
Mixing
S-191
S-192
S-193
S-201
S-202
S-203
P-9 / AF-101
Air Filtration
P-8 / G-101
Gas Compression
S-116
S-117
S-118
P-13 / G-102
Gas Compression
P-14 / AF-102
Air Filtration
S-126
S-127
S-128
P-24 / AF-103
Air Filtration
P-23 / G-103
Gas Compression
S-145
S-146
S-147 54
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
55