gmpcasestudytrainingnov13rev3-090330153728-phpapp02
TRANSCRIPT
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Chet French
Manager, Global SafetyAmylin Pharmaceuticals, Inc.November 2007
Lessons Learned: cGMP Case
Studies
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cGMP Case Studies Training SessionAgenda
Agenda:
Introduction
Case #1: IV Bottle Contamination (Abbott Laboratories)
Case #2: Hemodialysis Filters (Baxter Pharmaceuticals)
Case #3:Albuterol Inhalers (Schering Plough)
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21 CFR Parts 210/211cGMPs
Subparts:A General Provisions
B Organization and Personnel
C Buildings and Facilities
D EquipmentE Control of Components and Drug Product Containers and Closures
F Production and Process Controls
G Packaging and Labeling Controls
H Holding and Distribution
I Laboratory Controls
J Records and Reports
K Returned and Salvaged Drug Products
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cGMPsRaising the Bar
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Regulations: Goodor Bad?
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Regulations: Goodor Bad?Medical Mistakes
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Regulations: A Goodor Bad?Medical Mistakes
5% of people admitted to hospitals incur an iatrogenicinfection
3.3% incur Adverse Event
56% of Adverse Events are attributable to mistakes.
Medical mistakes kill 44,000 - 98,000 people annually in U.S.
Yourchance of being killed by mistake = 1:500 !
Source: National Institute of Medicine Nov 2000
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IV Bottle Contamination Case
CASE #1
IV Bottle Contamination
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IV Bottle Contamination CaseBackground
October 1970March 1, 1971
150 bacteremias caused byEnterobacter Cloacae
8 U.S. hospitals
Commonality ObservedAll used fluids and IV systems manufactured by Abbott Laboratories
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IV Bottle Contamination CaseBackground
Enterobacter Cloacae
Gram-Negative Organism
A relatively common ICU bug
Opportunistic pathogen among the vulnerable (i.e.infants and the elderly)
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Abbott LaboratoriesCompany Background 1970
A Diversified Company:
Consumer Goods (Selsun, Murine, Similac) 1960s
Hospital Products (Monitors, IV Equipment, Drug Testing).
Cyclamate = 30% of Revenue
Largest Supplier of IV Fluid in U.S.
45% Marketshare
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IV Bottle Contamination CaseIV-Associated Septicemias 1970-1971
0
2
4
6
8
1 3 5 7 9 11 13 15 17 19 21 23
Hospital A
Hospital B
Hospital C
Week of Onset
9/26/70
3/13/71
1/23/71
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IV Bottle Contamination CaseAbbott LaboratoriesIV Bottle - New Cap Design 1970
ElastomerLiner
Old Design
Metal Slip Disc
Glue
Plastic Disc
New Design
Metal Slip Disc
Red Rubber Disc
Gilsonite
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IV Bottle Contamination CaseContamination Intrusion
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IV Bottle Contamination CaseOutcome
Contaminated Bottles linked to:
>434 Infections
49 Deaths
Abbott forced to recall 3.5 million bottles of IV fluid
IV Sales Decrease 84% ($17.9 million to $3 million)
Abbott redesigns IV bottle seals
Litigation Ensues
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IV Bottle Contamination CaseInvestigation Findings and Recommendations
Abbott Laboratories:
Facility Cleanup
Screw Cap Inadequate
Spun off IV Business
Hospital Procedures:
~24 hr Changeout
Minimize IV Integrity Breach
Avoid Disrupting Contents
Never Replace Cap
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IV Bottle Contamination CaseApplicable cGMPs
211.110 Sampling and testing of in-process materials anddrug products.
(c) In-process materials shall be tested for identity, strength,quality, andpurityas appropriate, and approved or rejected by
the quality control unit, during the production process, e.g. atcommencement or completion of significant phases or afterstorage for long periods.
211.113 Control of microbiological contamination
(b) Appropriate written procedures, designed topreventobjectionable microorganismsin drug products purporting to besterile, shall be established and followed.
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IV Bottle Contamination CaseSummary
What went wrong?
What can we learn?
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CASE #2
Hemodialysis Filters
Hemodialysis Filter Case
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Hemodialysis Filter CaseTimeline
August 2001
Dialysis Patient Deaths - Spain
Cardiac Arrest; 15 min7 hrs
21- 35 age range
Gas bubbles in blood
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Hemodialysis Filter CaseCommonality Observed
Althane A, AF, AX dialysis filters
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Baxter PharmaceuticalsBackground Information - 2001
Large hospital supply/medical product company
45,000 employees
Mfg & Sales in 110 countries
$ 6.9 Billion in annual revenue
OEM Manufacturer
Renal products ~20% of revenue
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Hemodialysis Filter CaseTimeline (cont.)
Aug-Sept 2001
Baxter investigation exonerates filters
Voluntary LimitedRecall by Baxter
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Hemodialysis Filter CaseTimeline (cont.)
Oct 2001
Croatia 23 Deaths
Independent investigation exonerates filters
JMS/Nikkoso Initiate Recall
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Hemodialysis Filter CaseTimeline (cont.)
Oct-Nov 2001
Deaths in Texas & Nebraska
Worldwide Recall
Investigation finds root cause
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HemodialysisFilter CaseManufacturing Process
PASS
Filter IntegrityQC Test
FAIL
QC
F
AIL
Filter Integrity RetestWith PF-5070
H2O
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PF- 5070Chemical Properties
An Industrial Solvent
Cooling/heat transfer/cleaning solution for electronic equipment
Virtually non-toxic
Fast evaporating
160 L = fatal dose*
*Journ al of the American Society of Nephrology Study 2005
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Dialysis Filter CaseOutcome
Complete Recall of Althane filters
85 Confirmed Deaths
2 plants idled/closedRonneby Sweden
Miami Lakes, FLA
500 layoffs
$150 million allocated to date for damages
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Hemodialysis Filter CaseSummary
What went wrong?
What can we learn?
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Provent i l Asthma Inhaler Case
CASE #3
ProventilAsthma Inhaler Case
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Schering-PloughCompany Background
$9.8 Billion Annual Sales
Areas of Focus:
Allergy & Respiratory
Anti-Infection
Cancer
Cardiovascular
Consumer Division:
Dr. Scholl's , Coppertone , Bain de Soleil
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Schering-PloughProventil Asthma Inhaler Deaths 1998-2000
0
1
2
3
4
5
Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4
Number of Deaths
1998 1999 2000
Recall 1 Recall 2
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Schering-PloughAAC AuditFindings -- Kenilworth, NJ Plant
Personnel:
Inordinately high turnover
Employee Lack of experience/knowledge
Lack of Accountability
Systems:
No Culture of Quality Evident
No in-process Testing for Active Ingredient
Outmoded Equipment
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Schering-PloughPublic Citizens Health Research GroupLetters
March 1, 2001
Urges Investigation Regarding Asthma Inhalers KnowinglyShipped w/o Active Ingredient
August 9, 2001
Alleges Criminal Intent
August 15, 2001
Schering-Plough Rebuttal: Every inhaler involved in a patients
claim of injury that has been tested by the company has beenshown to date to contain active ingredient.
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Provent i l Asthma Inhaler CaseOutcome
Consent Decree $500 MillionFine
Stock Plummets -- >$10 Billion Market Value Lost
Reduced Earnings ExpectationsDelayed Product Approval
CEO, COO Resign
$50 Million Equipment/Facilities Investment
3 years Climb to Compliance
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Provent i l Asthma Inhaler CaseFDA Compliance Inspectional Outcomes
FDA 483 Form
EstablishmentInspection Report
Warning Letter
Consent Decree
NOIR
Regulatory Action
ContinuedOperation
NoRegulatory
Ac
tion
Criminal Charges
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Provent i l Asthma Inhaler CaseApplicable cGMPs
211.22 Responsibilities of Quality Control Unit
(a) There shall be a quality control unit that shall have theresponsibility and authority to approveor rejectall components,drug product containers, closures, in process materials,
packaging material, labeling, and drug products, and the authority
to review production records to assure that no errors haveoccurred.
211.110 Sampling and Testing of In-Process Materials andDrug Products
(c) In-process materials shall be tested for identity, strength,quality, andpurityas appropriate, and approved or rejected bythe quality control unit.
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How Could This Happen?
Inertia
Group Anonym i ty
Legacy EffectsBureaucracy
Corpo rate Arrogance
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What About Amylin?
What controls do we have in place that would preventthe following?
Bacterial contamination in our product?
An apparent innocuous change in raw materialsadversely impacting patient safety?
Product produced/shipped without active
ingredient?
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Why Follow cGMPs?
Protects the patient
Protects the company
Protects our jobs
Its the law!
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Some Final Thoughts
We are empowered with an awesome responsibility --the work we do has the power to healor injurepatients.
cGMP compliance is our assurance that the work isperformed the right way, each and every time.
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Q & A
Questions/Comments
?