A 4 Levine Charles

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Comparing the Manufactureand Use of Closed andOpen mpoules forManufacture ParenteralProducts Using FMECharles S. Levine

VPCI


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Closed vs. Openampoules

Open Washed

Depyrogenated

Filled Flame sealed

Terminally

sterilized

Closed Externally

sterilized

Opened

mechanically or

by flame

Filled

Flame sealed

Terminally

sterilized


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Supplier Manufacturer

Cooperation

Drug Product Manufacturer

Sintetica S.A., Lugano, Switzerland

Ampoule Manufacturer

AR.LA.VE.S. s.r.l. (AritcoliLavorazione Vetro Soffiato),

Treviglio (BG) Italy


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Supplier ManufacturerCooperation

Mutual Goals Improved quality of Ampoules

Improved quality of Drug Product Reduced scrap during Drug Product

Manufacturing

Potential for expanded markets forClosed Ampoules

Potential for expanded markets for

Drug Products manufactured usingClosed Ampoules


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Does the use of ClosedAmpoules Benefit the

Patient?

Maintains high Quality Standards

while minimizing Capitalexpenditures, which aids in the

control of drug prices.


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Presentation outline

Risk analysis technique

Analysis of Ampoule formation process

Analysis of drug product manufacturing

process

Summary of process enhancements


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HACCP

Conduct a hazard analysis Determine the critical control points

Establish critical limits

Establish monitoring procedures

Establish corrective action

Establish verification plan

Establish recordkeeping and

documentation procedures J.G. Surak, HACCP and ISO development of a food is safety management standard, ASQ, FDC Control, No.135, 2003.


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Controlling Risk

At each critical control point identify theappropriate method for controlling

product quality.

100% inspection Automated

Manual

Equipment controllers Process validation

Periodic sampling and inspection

Finished product testing


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FMEA

FMEA (Failure Mode and Effects Analysis) isa systematic method of identifying and

preventing product and process problemsbefore they occur.*

R. E. McDermott, The Basics of FMEA, 1996


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FMEA process Define the process

Select a team of experts Develop the FMEA matrix

Process function

Failure mode

Failure effects Failure causes

Probability of failure

Severity of effects

Likelihood of detection Calculate Risk Priority Number (RPN)

Take preventive and corrective action

Recalculate RPN A. Sahni, Using Failure Mode and Effects Analysis to Improve Manufacturing Processes,1993


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FMEA

Failure mode presence of foreign particulate

matter

Cause of failure

Inadequate control of environmental

conditions during the formation ofthe ampoules

Failure effect

Potential injury to the patient


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Calculation of Risk

Priority Number (RPN)

RPN = P X S X D Where

P = Probability of Failure

S = Severity (Potential harm to patient)

D = Likelihood of detection

For each variable Scaled from 1 to 5

1 is best case

5 is Worst case


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Probability of Failure

(P)

P = 5 failure will occur

often

P = 1 unlikely to occur


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Severity (S)

S= 5 serious injury to the patient

or employee or high cost to thecompany

S= 1 no effect on the patient oremployee


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Likelihood of Detection

(D) D = 5 No method to detect Failure

D = 1 Failure is immediatelydetectable

Applications of FMEA in the Pharmaceutical Industry, Pharmaceutical Technology, R. Kieffer


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Drug Product

Manufacturing ProcessDescription

Product Epinephrine 1mg/ml (1ml in a 2ml Ampoule)

Glass Type I Flint

Filling process Clean Fill (not aseptic)

Sterilization

Terminally sterilized (overkill cycle)

Leak test Vacuum Hold

100% inspection Automated

Wh t i th diff


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What is the difference

between a Closed and

Open Ampoule?

Sealed during transport andpreparation for delivery into Filling area

Sealed at the glass manufacturer with

a slight overpressure

The internal surfaces of the ampoule

are not cleaned or depyrogenated atthe Drug Product manufacturer

Process Control shifts from the Drug

Product manufacturer to the Glassmanufacturer


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Risk Analysis Objective

Minimize the risk that the use of

Closed Ampoules versus OpenAmpoules increases the risk of

foreign particulate matter.


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Analyzing Risk

Ampoule Forming Process

Establish risk assessment team

Osiris Donghi, Technical Director,ARLAVES

Sergio Randisi, Director QA, ARLAVES

Augusto Mitidieri, Director QA, Sintetica

Charles Levine, Consultant, VPCI

Detailed process definition

Identify potential hazards and critical control

points


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Analyzing Risk Drug

Product ManufacturingProcess Establish risk assessment team

E. Giudice, Production Supervisor,

Sintetica

B. Ricardi, Manager QA, Sintetica

N. Caronzolo, Manager QC, Sintetica

A. Angelini, Qualified Person, Sintetica

A. Mitidieri, General Manager, Sintetica

C. Levine, consultant, VPCI


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Closed Ampoule FormingProcess (2003)

Ampoules are formed and cut from the glasstubing

The ampoules exit the forming machine as

open ampoules Cooled from approximately 300C to ambient

temperature

Score break Station

Ampoule Chilling (approximately 4C)

Ampoule sealing station

Ampoule annealing oven


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Ampoule annealing

oven Heating phase

140 to 590C Cooling phase

590 to 70C

Bacterial endotoxin reduction

3 log


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Ampoule Forming Line

CLevine_info.pdf
http://i/PROGRAMS%20&%20MEETINGS%20DEPARTMENT/2005%20Meetings/Rome%202005/Presentations/Web%20Presentations/CLevine_info.pdfhttp://i/PROGRAMS%20&%20MEETINGS%20DEPARTMENT/2005%20Meetings/Rome%202005/Presentations/Web%20Presentations/CLevine_info.pdfhttp://i/PROGRAMS%20&%20MEETINGS%20DEPARTMENT/2005%20Meetings/Rome%202005/Presentations/Web%20Presentations/CLevine_info.pdf


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Supplier of Type I

Glass Tubing Schott Rohrglas, Bayreuth,

Germany Kimble Italiana, Montelungo, Italy


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Tubing Specifications

Densocan tubing from Schott

Length 1500 mm

Sealed at both ends with a vent hole(>0.5mm)

Glass Particle specification (sampleselection according to ANSI/ASQC z1.4 1993/DIN ISO 2859-1, simple randomsample, test level II, normal test

Particle size ( 0.2 0.5 mm)

Maximum number of particles 4

AQL 0.65

Particle size (>0.5 mm) Maximum number of particles 1

AQL 0.65


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Tubing Performance

20 ampoules are produced fromeach 1.5m tube

20mm at each end of the tube areautomatically discarded

The tubing is heated to 1200oC to

form ampoules


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Self Ignition

Temperatures Polyvinyl Chloride - 507oC

Polyethylene - 488oC

Cellulose - 260oC

National Fire Protection Association (NFPA)


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Higher Risk Process

Steps

Transporting open ampoules to the cooling

tunnel (RPN=18 ) Filtration of the air supplied to the cooling

tunnel (RPN=12 )

Filtration of the air at the refrigeration Station(RPN=12 )

Proximity of the score brake station to theampoule sealing station (RPN=24 )

Control of the vacuum level at the score brakestation (RPN=12 )

Maximum possible value of RPN is 125


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Critical Control Points Process step

Transporting openampoules to the coolingtunnel

Filtration of the airsupplied to the cooling

tunnel Filtration of the air at the

refrigeration Station

Proximity of the scorebrake station to theampoule sealing station

Control of the vacuumlevel at the score brakestation

Critical control point

None

Roughing filters only

Roughing filters only

None

None


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Corrective Actions Process step

Transporting openampoules to the coolingtunnel

Filtration of the airsupplied to the cooling

tunnel Filtration of the air at the

refrigeration Station

Proximity of the scorebrake station to theampoule sealing station

Control of the vacuumlevel at the score brakestation

Corrective Action

Install protective barrier

Install F8 (EN779) filters

Install F8 (EN779) filters

Relocate score brakestation and installseparation barrier

Install low vacuum alarm

Recalculation of RPN


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Ampoule Forming Process

612Control of the vacuum level at the

score brake station

624Proximity of the score brake stationto the ampoule sealing station

612Filtration of the air at the refrigeration

Station

612Filtration of the air supplied to the

cooling tunnel

1218Transporting open ampoules to the

cooling tunnel

RPN (2004)RPN (2003)Process step

Closed Ampoule


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Closed Ampoule

Manufacturing Process(2004)

Ampoules are formed and cut from the glasstubing

Ampoules are transported in a protectivebarrier

Cooled from approximately 300C to ambienttemperature with F8 filtered air

Ampoule Chilling (approximately 4C) with F8filtered air

Ampoule sealing station Score break (vacuum system equipped with

low level alarm)

Ampoule annealing oven


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Ampoule forming Line

1- Cooling Tunnel (openAmpoules)

2- Refrigerated Air (coolAmpoules to 4oC)

3- Ampoule SealingStation

4- Transport Belt(Closed Ampoules)

5 Vacuum ControlSystem

6- Score Break Station1 2 3 4 65

D P d t


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Drug Product

Manufacturing Process(2003)

Receive and release of ampoules

Prepare ampoules for clean room

filling process Prepare drug product solution

Fill ampoules Terminally sterilize drug product

100% inspection


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Prepare Ampoules forClean Room Filling

Process

Remove plastic wrap from

modules Reject any damaged modules

Autoclave ampoules in a doubledoor jacketed steam autoclave


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Fill Ampoules

Visually inspect each tray of ampoules

for defective ampoules The filling system automatically

opens the ampoule (inverted)

Fills the drug product

Seals the ampoule

Visually inspect each tray of filledampoules for defective seals

Periodically remove samples for fillvolume, seal dimensions and cosmeticinspection

T i ll St ili D


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Terminally Sterilize Drug

Product

Load the ampoules in the invertedorientation

Overkill sterilization cycle at 121oC Post-vacuum hold cycle (leak test)


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100% inspection

Automated inspection for

Low Fill Volume (leakers) Particulate matter

Hi h Ri k P


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Higher Risk Process

Steps Opening ampoules (generation of

glass particles) (RPN= 18)

Filling ampoules in a Class C

environment Airborne particles related to facility

design (RPN=12)

Airborne particles related to

personnel gowning (RPN=18 )

Ampoule leak test (RPN=10 )

C iti l C t l P i t


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Critical Control Points

Process Step

Opening ampoules

(generation of glassparticles)

Filling ampoules in aClass C

environment Airborne particles

related to facilitydesign

Airborne particlesrelated to personnelgowning

Ampoule leak test

Critical ControlPoint

Exhaust Interlock

Monitoring P

Change FillingRoom OperatorsClothing daily

Cycle Review


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Corrective Actions Process Step Opening ampoules


Filling ampoules in aClass C environment

Airborne particles

related to facilitydesign

Airborne particlesrelated to personnel

gowning Ampoule leak test

Corrective Actions Validate interlock

Increase Environmental

Monitoring Frequency

Convert to single-usedisposable gowns

Trend PM rejects

Demonstrate sensitivityof leak test (Validation)



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Drug Product Manufacture

510Ampoule leak test

1218Airborne particles related to

personnel gowning

612Airborne particles related to

facility design

1218Opening ampoules


RPN (2004)RPN (2003)Process step


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Ampoule Leak Test

Process

140 minutes at 0.2 Bar (Inverted

Orientation) 100% automated fill volume

inspection

A l L k T t


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Ampoule Leak Test

Validation

Establish Fill Volume Sensitivity Label Claim 1.0ml

Challenged with ampoules filledwith

0.80ml

0.90ml

0.95ml

10 of 10 rejected with 0.95ml


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Ampoule Leak Test

Validation

Create 20 ampoules each withholes using Lasers

10m 20m

30m

Ampoules with 10m were empty

after the leak test cycle

Particulate Matter


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Reject History

0412490.2%26213237104069

030537

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0.9%118713025704068

0305370.9%1217128676040670302500.8%2933559903122

0305370.8%110412998503168

0305370.7%90212968803167

0305370.6%74012946103166

0302507%742811186103099

030227

030250

6%8225128151030980302274%477912557003097

Ampoules

Lot No.%

N particulate

matter rejects

Number

InspectedBatch No.


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Customer Complaint

Frequency

No Complaints received for

particulate matter

S


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Summary

FMEA is a tool that can identify

those processes that represent thegreatest risk for failures of various

types.

FMEA is also a tool that can

evaluate an overall control

program to ensure that limitedquality resources are being utilized

in the most cost-effective manner.


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Grazie per Tutti

Augusto Mitidieri, General Manager,

Sintetica, S.A. Osiris Donghi, Technical Director,

ARLAVES

Sergio Randisi, Director QA, ARLAVES

Franco DeVecchi, VPCI

Documents

A 4 Levine Charles