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

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

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)

5

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

6

Simple Flowchart

Components

Fermentation Purification

Finish & Fill

7

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

8

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 …)

9

Typical BDT Flow


Panel

ReleaseComponents

toManufacturing

Pass

Fail

FirstManufacturing

Step

ExpandWorking

CellBank

TestPanel

Discard&

Document

Fail

TestPanel

SecondManufacturing

Step

TestPanel

Fail

Pass

Purification

Pass


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

10

... 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?

12

WFI

13

Typical BDT Flow


Panel

ReleaseComponents

toManufacturing

Pass

Fail

FirstManufacturing

Step

ExpandWorking

CellBank

TestPanel

Discard&

Document

Fail

TestPanel

SecondManufacturing

Step

TestPanel

Fail

Pass

Purification

Pass


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

14

15

Tour – master/working cell bank• Typically,

nitrogen Dewar or ultra-low temp freezer

• Inspection issues?

16

Tour –fermentation• Inspection

issues?

17

Typical BDT Flow


Panel

ReleaseComponents

toManufacturing

Pass

Fail

FirstManufacturing

Step

ExpandWorking

CellBank

TestPanel

Discard&

Document

Fail

TestPanel

SecondManufacturing

Step

TestPanel

Fail

Pass

Purification

Pass


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

18

Tour – Purification 1

• Post fermentation– Decrease volume– Remove debris– Concentrate cells

Millipore Corp.

19

Purification – 2

• Crystallization• Centrifugation• Filtration• Ultrafiltration• Separatory

columns– size– ionic – affinity– hydrophobicity

• Inspection issues

20

Purification – 3

• Column chromatography• Issues

21

Purification - 4

• Pre-filtration• Filtration• Sterile

filtration• Inspection

issues

22

Typical BDT Flow


Panel

ReleaseComponents

toManufacturing

Pass

Fail

FirstManufacturing

Step

ExpandWorking

CellBank

TestPanel

Discard&

Document

Fail

TestPanel

SecondManufacturing

Step

TestPanel

Fail

Pass

Purification

Pass


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

23

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…

24

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.

26

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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• 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.

28


• 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.

29


• 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.

30


• 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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• 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.

32


• 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.

33


• 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

36

Clean room

37

Clean room -- access

38

Clean room – easily cleaned

39

Vial washer

40

Stopper washer

41

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

44

“clean” side of sterilizer

45

Filling machine

46

Stoppering machine

47

lyophilization

48

Capping machine

49

Visual inspection

50

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

Documents

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