Lessons Learned: cGMP Case Studies

Chet French
Manager, Global Safety Amylin Pharmaceuticals, Inc. November 2007

cGMP Case Studies Training Session

Agenda Agenda:

Introduction
Case #1: IV Bottle Contamination (Abbott Laboratories)

Case #2: Hemodialysis Filters (Baxter Pharmaceuticals)

Case #3: Albuterol Inhalers (Schering Plough)

21 CFR Parts 210/211

cGMPs Subparts: A B C General Provisions Organization and Personnel Buildings and Facilities

D
E F G H I J

Equipment
Control of Components and Drug Product Containers and Closures Production and Process Controls Packaging and Labeling Controls Holding and Distribution Laboratory Controls Records and Reports

Returned and Salvaged Drug Products

cGMPs
Raising the Bar of Expectations

The Bar of Expectations

Tragedies Technology

Evolution

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 #1
IV Bottle Contamination

IV Bottle Contamination Case

Background

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 Case

Background

Enterobacter Cloacae

Gram-Negative Organism

A relatively common ICU bug

Opportunistic pathogen among the vulnerable (i.e.
infants and the elderly)

Abbott Laboratories
Company 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

IV Bottle Contamination Case

IV-Associated Septicemias 1970-1971

8 6 4 2 0 1
9/26/70

Hospital A Hospital B Hospital C

11

13

15

17

19
1/23/71

21

23
3/13/71

Week of Onset

IV Bottle Contamination Case

Abbott Laboratories IV Bottle - New Cap Design 1970

USP 5% Dextrose Saline Abbott Laboratories

IV Bottle Contamination Case

Abbott Laboratories IV Bottle - New Cap Design 1970
Metal Slip Disc Red Rubber Disc Gilsonite Plastic Disc Metal Slip Disc Glue

Elastomer Liner

Old Design

New Design

IV Bottle Contamination Case

Contamination Intrusion

IV Bottle Contamination Case

Outcome

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 Case

Investigation 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

IV Bottle Contamination Case

Applicable 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 Case

Summary

What went wrong?

What can we learn?

Hemodialysis Filter Case

CASE #2
Hemodialysis Filters

Hemodialysis Filter Case

Timeline

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 Pharmaceuticals
Background 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 Filter Integrity QC Test PASS

H2O
QC

FAIL

Filter Integrity Retest With PF-5070

FAIL

PF- 5070
Chemical Properties

An Industrial Solvent Cooling/heat transfer/cleaning solution for electronic equipment Virtually non-toxic Fast evaporating 160 L = 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/closed

Ronneby Sweden Miami Lakes, FLA

500 layoffs $150 million allocated to date for damages

Hemodialysis Filter Case

Summary

What went wrong?

What can we learn?

Proventil Asthma Inhaler Case

CASE #3
Proventil Asthma Inhaler Case

Schering-Plough
Company Background

$9.8 Billion Annual Sales

Areas of Focus:
Allergy & Respiratory Anti-Infection

Cancer
Cardiovascular

Consumer Division:
Dr. Scholl's , Coppertone , Bain de Soleil

Schering-Plough
Proventil Asthma Inhaler Timeline 1998 1999 2000 2001 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3

Puerto Rico IRE Kenilworth NJ

FDA

Kenilworth NJ
FDA

Puerto Rico

AAC

FDA

190K Units

60MM Units

Schering-Plough
Proventil Asthma Inhaler Deaths 1998-2000

Number of Deaths 5 4 3 2 1 0 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4
1998 1999
Recall 1

2000
Recall 2

Schering-Plough
AAC 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-Plough
Public Citizens 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 patients

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 years Climb to Compliance

Proventil Asthma Inhaler Case

FDA Compliance Inspectional Outcomes

FDA 483 Form

Warning Letter

Establishment Inspection Report

No Regulatory Action Continued Operation

NOIR Regulatory Action Consent Decree

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

Its 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

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Questions/Comments