Chet FrenchManager, Global SafetyAmylin Pharmaceuticals, Inc. November 2007
Lessons Learned: cGMP Case Studies
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)
21 CFR Parts 210/211cGMPs
Subparts:
A General Provisions
B Organization and Personnel
C Buildings and Facilities
D Equipment
E 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
cGMPsRaising the “Bar of Expectations”
Tragedies
Technology
Evolution
The Bar of Expectations
cGMPs“Raising the Bar”
Regulations: Good or Bad?
Regulations: Good or Bad? Medical Mistakes
Regulations: A Good or Bad? Medical Mistakes
5% of people admitted to hospitals incur an iatrogenic infection
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.
Your chance of being killed by mistake = 1:500 !
Source: National Institute of Medicine Nov 2000
IV Bottle Contamination Case
CASE #1IV Bottle Contamination
IV Bottle Contamination CaseBackground
October 1970 – March 1, 1971
150 bacteremias caused by Enterobacter Cloacae
8 U.S. hospitals
Commonality Observed – All used fluids and IV systems manufactured by Abbott Laboratories
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)
Abbott LaboratoriesCompany Background 1970
A Diversified Company:Consumer Goods (Selsun®, Murine®, Similac®) 1960’sHospital Products (Monitors, IV Equipment, Drug Testing).
Cyclamate = 30% of Revenue Largest Supplier of IV Fluid in U.S.
45% Marketshare
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 AHospital BHospital C
Week of Onset
9/26
/70
3/13
/71
1/23
/71
IV Bottle Contamination CaseAbbott Laboratories IV Bottle - New Cap Design 1970
Abbott Laboratories
USP5% Dextrose Saline
IV Bottle Contamination Case Abbott Laboratories IV Bottle - New Cap Design 1970
Elastomer Liner
Old Design
Metal Slip Disc
Glue
Plastic Disc
New Design
Metal Slip Disc
Red Rubber Disc
Gilsonite
IV Bottle Contamination CaseContamination Intrusion
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
IV Bottle Contamination CaseInvestigation Findings and Recommendations
Abbott Laboratories:Facility CleanupScrew Cap InadequateSpun off IV Business
Hospital Procedures: ~24 hr Changeout Minimize IV Integrity Breach Avoid Disrupting Contents Never Replace Cap
IV Bottle Contamination CaseApplicable cGMPs
§211.110 Sampling and testing of in-process materials and drug products.
(c) In-process materials shall be tested for identity, strength, quality, and purity as appropriate, and approved or rejected by the quality control unit, during the production process, e.g. at commencement or completion of significant phases or after storage for long periods.
§ 211.113 Control of microbiological contamination
(b) Appropriate written procedures, designed to prevent objectionable microorganisms in drug products purporting to be sterile, shall be established and followed.
IV Bottle Contamination CaseSummary
What went wrong?
What can we learn?
CASE #2Hemodialysis Filters
Hemodialysis Filter Case
Hemodialysis Filter CaseTimeline
August 2001
Dialysis Patient Deaths - Spain
Cardiac Arrest; 15 min – 7 hrs
21- 35 age range
Gas bubbles in blood
Hemodialysis Filter Case Commonality Observed
Althane™ A, AF, AX dialysis filters
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
Hemodialysis Filter Case Timeline (cont.)
Aug-Sept 2001
Baxter investigation exonerates filters
Voluntary Limited Recall by Baxter
Hemodialysis Filter Case Timeline (cont.)
Oct 2001
Croatia 23 Deaths
Independent investigation exonerates filters
JMS/Nikkoso Initiate Recall
Hemodialysis Filter Case Timeline (cont.)
Oct-Nov 2001
Deaths in Texas & Nebraska
Worldwide Recall
Investigation finds root cause
Hemodialysis Filter Case Manufacturing Process
PASS
Filter IntegrityQC Test
FAIL
FAIL
PASS
QC
FAIL
Filter Integrity RetestWith PF-5070
H2O
PF- 5070Chemical Properties
An Industrial Solvent Cooling/heat transfer/cleaning solution for electronic equipment Virtually non-toxic Fast evaporating 160 µL = fatal dose*
*Journal of the American Society of Nephrology Study 2005
Dialysis Filter Case Outcome
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
Hemodialysis Filter CaseSummary
What went wrong?
What can we learn?
Proventil® Asthma Inhaler Case
CASE #3Proventil® Asthma Inhaler Case
Schering-PloughCompany Background
$9.8 Billion Annual Sales
Areas of Focus:Allergy & RespiratoryAnti-InfectionCancerCardiovascular
Consumer Division:Dr. Scholl's ®, Coppertone ®, Bain de Soleil®
Schering-PloughProventil® Asthma Inhaler Timeline
1998 1999 2000 20011998 1999 2000 2001… … Q3 Q4Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 … Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 …
PuertoRicoIRE
KenilworthNJ
PuertoRico Kenilworth
NJ
FDA
FDA
AACFDA
190KUnits
60MMUnits
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
Schering-PloughAAC Audit Findings -- 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
Schering-PloughPublic Citizen’s Health Research Group Letters
March 1, 2001 Urges Investigation Regarding Asthma Inhalers Knowingly
Shipped w/o Active Ingredient
August 9, 2001 Alleges Criminal Intent
August 15, 2001
Schering-Plough Rebuttal: “Every inhaler involved in a patient’s claim of injury that has been tested by the company has been shown to date to contain active ingredient”.
Proventil® Asthma Inhaler Case Outcome
Consent Decree $500 Million Fine
Stock Plummets -- >$10 Billion Market Value Lost
Reduced Earnings Expectations
Delayed Product Approval
CEO, COO Resign
$50 Million Equipment/Facilities Investment
3 ½ years “Climb to Compliance”
Proventil® Asthma Inhaler Case FDA Compliance Inspectional Outcomes
FDA 483 Form
Establishment Inspection Report
Warning Letter
Consent Decree
NOIRRegulatory Action
Continued Operation
No R
egulatory A
ction
Criminal Charges
Proventil® Asthma Inhaler Case Applicable cGMPs
§ 211.22 Responsibilities of Quality Control Unit
(a) There shall be a quality control unit that shall have the responsibility and authority to approve or reject all 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 have occurred.
§ 211.110 Sampling and Testing of In-Process Materials and Drug Products
(c) In-process materials shall be tested for identity, strength, quality, and purity as appropriate, and approved or rejected by the quality control unit.
How Could This Happen?
Inertia
Group Anonymity
“Legacy” Effects
Bureaucracy
Corporate Arrogance
What About Amylin?
What controls do we have in place that would prevent the following?
Bacterial contamination in our product?
An apparent “innocuous” change in raw materials adversely impacting patient safety?
Product produced/shipped without active ingredient?
Why Follow cGMPs?
Protects the patient
Protects the company
Protects our jobs
It’s the law!
Some Final Thoughts…
We are empowered with an awesome responsibility -- the work we do has the power to heal or injure patients.
cGMP compliance is our assurance that the work is performed the right way, each and every time.
Q & A
Questions/CommentsQuestions/Comments
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