Objectives. Citations. Model: Establishment Inspection

Transcription

1 Objectives Biotechnology Derived Therapeutics Virtual Tour 3-April-2006 Pharm523 Survey of Biomedical Regulatory Affairs see BDT manufacturing stuff in a flow chart context Consider conjunction of manufacturing sequence considerations and cgmps 1 2 Citations Model: Establishment Inspection FDA IOM Chapter 5 Establishment Inspections Thanks to James Young, Berlex Steve Steinman, Steinman Associates 3 Description of Facility Equipment Training Program Component Materials Control Reprocessing / Reworking Adverse Event Reports Water Systems See chapter headings in 21CFR211) Computer Systems Packaging Labeling Scale-Up Procedures QA / QC Systems Contracting Services/Vendors Product Reviews / Discrepancy / ure Evaluation and Reporting Systems ing/laboratory Operations 4

2 Establishment Inspection 2 ing / Laboratory Operations Simple Flowchart Analytical Laboratories Lab Equipment Calibration Qualification Microbiology Quality Control SOPs Stability ing, Protocol Storage Conditions Sample Accountability Tracking Sampling and ing 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 ing Lab Stability Program Records / Reports / Documentation Control Fermentation Purification Finish Fill 5 6 Supplier Receive Quarantine to The Tour Typical BDT Flow Expand Working Cell Bank First Second Purification Bulk Sterile Fill Lyophilize Reprocess Discard Document Finished Goods Inventory 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, CO 2, argon, etc.) Acetonitrile (!) Biologicals (pancreases insulin; calf serum, caster beans ricin ) Package Label RA/QA 7 8

3 Supplier Receive Expand Working Cell Bank Quarantine to... an aside on pyrogens Typical BDT Flow First Second Purification Bulk Reprocess Discard Document Finished Goods Inventory 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 Sterile Fill Lyophilize Package Label RA/QA 9 10 Water WFI WFI Distillation or reverse osmosis Feed? Distribution? What s a batch? Sampling? Specifications? 11 12

4 Supplier Receive Quarantine to Expand Working Cell Bank Typical BDT Flow First Second Purification Reprocess Discard Document Finished Goods Inventory Bulk Sterile Fill Lyophilize Package Label RA/QA Tour master/working cell bank Typically, nitrogen Dewar or ultra-low temp freezer Inspection issues? Tour fermentation Inspection issues? 15 16

5 Supplier Receive Quarantine to Tour Purification 1 Expand Working Cell Bank Typical BDT Flow First Second Purification Bulk Sterile Fill Lyophilize Reprocess Discard Document Finished Goods Inventory Post fermentation Decrease volume Remove debris Concentrate cells Package Label RA/QA 17 Millipore Corp. 18 Purification 2 Crystallization Centrifugation Filtration Ultrafiltration Separatory columns size ionic affinity hydrophobicity Inspection issues Purification 3 Column chromatography Issues 19 20

6 Purification - 4 Supplier Receive Expand Working Cell Bank Quarantine to Pre-filtration Filtration Sterile filtration Inspection issues Typical BDT Flow First Second Purification Bulk Reprocess Discard Document Finished Goods Inventory Sterile Fill Lyophilize 21 Package Label RA/QA 22 Bulk sterility test, etc. Finish fill 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 23 24

7 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. 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/ 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. Finish fill aside 4 The quality control unit did not sign / approve Procedure (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

8 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. 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 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. 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

9 Finish fill aside 9 Finish fill aside 10 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 ure to provide adequate air handling systems for aseptic processing, as required by 21 CFR 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. 34 Finish fill zoo configuration Clean room 35 36

10 Clean room -- access Clean room easily cleaned Vial washer Stopper washer 39 40

11 sterilization rant Scrambler vial washer oven 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 oven clean side of sterilizer 43 44

12 Filling machine Stoppering machine lyophilization Capping machine 47 48

13 Visual inspection Finishing the tour Packaging labeling Final inspection Laboratory Lingering Issues Environmental monitoring Laboratory inspection Adverse event reporting; triage Process Flow for Penicillin Production after Cooney S-101 S-105 S-117 S-102 P-8 / AF-102 S-103 S-116 Air Filtration S-104 S-106 P-1 / V-101 Blending / Storage Medium S-111 P-4 / ST-101 S-112 S-150 S-151 P-3 / MX-101 Heat Sterilization Mixing S-107 S-109 S-110 S-118 P-20 / RVF-101 S-152 S-119 P-21 / HX-101 S-108 Removal Biomass Cooling P-7 / V-103 S-115 P-2 / V-102 Fermentation P-9 / V-106 S-153 Storage Blending / Storage Glucose S-113 P-6 / AF-101 S-114 Air Filtration S-164 S-161 S-155 P-22 / MX-102 P-5 / G-101 S-158 Acidification S-154 Gas Compression S-160 P-23 / CX-101 S-167 S-176 S-166 S-163 Centrifugal Extraction S-174 P-24 / MX-104 Neutralization S-159 S-157 S-165 P-25 / V-104 S-162 Re-ectraction + Crystallization S-175 P-26 / BCF-101 S-156 P-31 / FBDR-101 S-168 S-173 Basket Centrifugation S-177 Fluid Bed Drying S-172 P-29 / MX-103 Adding Fresh Butyl Acetate 51 P-32 / V-105 Storage Penicillin Sodium Salt S-178 P-27 / CSP-101 Component Splitting S-169 S-170 P-28 / MX-105 Neutralization S-171

14 Process Flow for a MAB after Cooney S-101 S-111 Inoculum Prep P-1 / TFR-101 T-Flask (225 ml) S-112 S-113 S-116 S-122 S-105 S-126 S-121 P-6 / V-102 Media Prep P-11 / V-104 Media Prep S-127 P-13 / G-102 Gas Compression S-140 S-141 S-142 S-145 P-3 / BBS-101 Bag Bioreactor (20 L) P-8 / G-101 Gas Compression P-21 / V-106 Media Prep P-23 / G-103 Gas Compression S-117 S-146 S-102 P-2 / RBR-101 S-104 Roller Bottle (2.2 L) S-108 S-110 S-107 P-7 / DE-101 Sterile Filtration S-106 S-123 P-12 / DE-102 Sterile Filtration P-22 / DE-103 Sterile Filtration S-103 S-114 S-115 P-9 / AF-101 Air Filtration P-14 / AF-102 Air Filtration S-124 S-125 Bioreaction P-24 / AF-103 Air Filtration S-128 S-144 P-4 / BBS-102 Bag Bioreactor (100 L) P-5 / SBR1 First Seed Bioreactor (1000 L) S-118 S-119 S-148 S-143 S-120 S-130 P-10 / SBR2 Second Seed Bioreactor (5000 L) S-149 S-109 S-129 P-30 / V-101 Surge Tank P-37 / V-107 Storage IEX-Equil IEX-Wash IEX-WFI IEX-Eluat IEX-Strip IEX-Rinse S-150 P-31 / DS-101 Centrifugation S-164 S-163 S-169 P-50 / C-102 IEX Chromatography S-192 S-190 P-38 / DF-102 Diafiltration S-165 P-52 / V-109 IEX Pool Tank P-33 / V-103 Storage S-158 S-155 PrA-Equil PrA-Wash PrA-Eluat PrA-Reg P-34 / UF-101 Concentration S-157 P-40 / C-101 Prot-A Chromatography S-156 S-180 S-181 S-159 P-35 / V-105 Virus Inactivation P-41 / DE-105 Polishing FIlter HIC-Equil S-194 HIC-Wash IEX Chrom HIC-Eluat HIC Chrom S-210 Primary Recovery S-151 S-152 S-191 S-211 P-32 / DE-108 Polishing Fitler S-168 P-51 / MX-102 Mixing S-153 S-154 P-39 / MX-101 Mixing S-193 S-166 S-195 S-212 S-167 HIC-Reg P-60 / C-103 HIC Chromatography S-203 Final Filtration S-216 P-61 / MX-103 Mixing Protein-A S-200 S-201 S-182 S-183 P-62 / DE-106 Dead-End Filtration S-160 S-205 S-202 P-36 / DE-104 Polishing FIlter P-42 / V-108 Prot-A Pool Tank S-204 S-162 S-184 S-161 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 / ure Evaluation and Reporting Systems ing/laboratory Operations Final Product P-70 / V-110 P-72 / DE-107 P-73 / DCS-101 P-20 / PBR1 HIC Pool Tank P-71 / DF-103 S-147 S-215 Final Polishing Filtration Freeze in Plastic Bags S-214 Diafiltration Production Bioreactor (20000 L) 54 S-213 S