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8/13/2019 gmpcasestudytrainingnov13rev3-090330153728-phpapp02

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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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Oct 2001

Croatia 23 Deaths

Independent investigation exonerates filters

JMS/Nikkoso Initiate Recall


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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

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