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Transcript of 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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Recalculation of RPN
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
(generation of glassparticles)
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)
Recalculation of RPN
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Recalculation of RPN
Drug Product Manufacture
510Ampoule leak test
1218Airborne particles related to
personnel gowning
612Airborne particles related to
facility design
1218Opening ampoules
(generation of glassparticles)
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
041249
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