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Comparing the Manufacture

and Use of Closed and


Open Ampoules for
Manufacture Parenteral
Products Using FMEA
Charles S. Levine
VPCI
Closed vs. Open
ampoules
Open
Washed
Depyrogenated
Filled
Flame sealed
Terminally
sterilized
Closed
Externally
sterilized
Opened
mechanically or
by flame
Filled
Flame sealed
Terminally
sterilized
Supplier Manufacturer
Cooperation
Drug Product Manufacturer
Sintetica S.A., Lugano, Switzerland
Ampoule Manufacturer
AR.LA.VE.S. s.r.l. (Aritcoli
Lavorazione Vetro Soffiato),
Treviglio (BG) Italy
Supplier Manufacturer
Cooperation
Mutual Goals
Improved quality of Ampoules
Improved quality of Drug Product
Reduced scrap during Drug Product
Manufacturing
Potential for expanded markets for
Closed Ampoules
Potential for expanded markets for
Drug Products manufactured using
Closed Ampoules
Does the use of Closed
Ampoules Benefit the
Patient?
Maintains high Quality Standards
while minimizing Capital
expenditures, which aids in the
control of drug prices.
Presentation outline
Risk analysis technique
Analysis of Ampoule formation process
Analysis of drug product manufacturing
process
Summary of process enhancements
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.
Controlling Risk
At each critical control point identify the
appropriate method for controlling
product quality.
100% inspection
Automated
Manual
Equipment controllers
Process validation
Periodic sampling and inspection
Finished product testing
FMEA
FMEA (Failure Mode and Effects Analysis) is
a systematic method of identifying and
preventing product and process problems
before they occur.*
R. E. McDermott, The Basics of FMEA, 1996
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
FMEA
Failure mode
presence of foreign particulate
matter
Cause of failure
Inadequate control of environmental
conditions during the formation of
the ampoules
Failure effect
Potential injury to the patient
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
Probability of Failure
(P)
P = 5 failure will occur
often
P = 1 unlikely to occur
Severity (S)
S= 5 serious injury to the patient
or employee or high cost to the
company
S= 1 no effect on the patient or
employee
Likelihood of Detection
(D)
D = 5 No method to detect Failure
D = 1 Failure is immediately
detectable
Applications of FMEA in the Pharmaceutical Industry, Pharmaceutical Technology, R. Kieffer
Drug Product
Manufacturing Process
Description
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
What is the difference
between a Closed and
Open Ampoule?
Sealed during transport and
preparation 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 at
the Drug Product manufacturer
Process Control shifts from the Drug
Product manufacturer to the Glass
manufacturer
Risk Analysis Objective
Minimize the risk that the use of
Closed Ampoules versus Open
Ampoules increases the risk of
foreign particulate matter.
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
Analyzing Risk Drug
Product Manufacturing
Process
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
Closed Ampoule Forming
Process (2003)
Ampoules are formed and cut from the glass
tubing
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
Ampoule annealing
oven
Heating phase
140 to 590C
Cooling phase
590 to 70C
Bacterial endotoxin reduction
3 log
Ampoule Forming Line
CLevine_info.pdf
Supplier of Type I
Glass Tubing
Schott Rohrglas, Bayreuth,
Germany
Kimble Italiana, Montelungo, Italy
Tubing Specifications
Densocan tubing from Schott
Length 1500 mm
Sealed at both ends with a vent hole
(>0.5mm)
Glass Particle specification (sample
selection according to ANSI/ASQC z1.4
1993/DIN ISO 2859-1, simple random
sample, 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
Tubing Performance
20 ampoules are produced from
each 1.5m tube
20mm at each end of the tube are
automatically discarded
The tubing is heated to 1200
o
C to
form ampoules
Self Ignition
Temperatures
Polyvinyl Chloride - 507
o
C
Polyethylene - 488
o
C
Cellulose - 260
o
C
National Fire Protection Association (NFPA)
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 the
ampoule sealing station (RPN=24 )
Control of the vacuum level at the score brake
station (RPN=12 )
Maximum possible value of RPN is 125
Critical Control Points
Process step
Transporting open
ampoules to the cooling
tunnel
Filtration of the air
supplied to the cooling
tunnel
Filtration of the air at the
refrigeration Station
Proximity of the score
brake station to the
ampoule sealing station
Control of the vacuum
level at the score brake
station
Critical control point
None
Roughing filters only
Roughing filters only
None
None
Corrective Actions
Process step
Transporting open
ampoules to the cooling
tunnel
Filtration of the air
supplied to the cooling
tunnel
Filtration of the air at the
refrigeration Station
Proximity of the score
brake station to the
ampoule sealing station
Control of the vacuum
level at the score brake
station
Corrective Action
Install protective barrier
Install F8 (EN779) filters
Install F8 (EN779) filters
Relocate score brake
station and install
separation barrier
Install low vacuum alarm
Recalculation of RPN
Ampoule Forming Process
6 12 Control of the vacuum level at the
score brake station
6 24 Proximity of the score brake station
to the ampoule sealing station
6 12 Filtration of the air at the refrigeration
Station
6 12 Filtration of the air supplied to the
cooling tunnel
12 18 Transporting open ampoules to the
cooling tunnel
RPN (2004) RPN (2003) Process step
Closed Ampoule
Manufacturing Process
(2004)
Ampoules are formed and cut from the glass
tubing
Ampoules are transported in a protective
barrier
Cooled from approximately 300C to ambient
temperature with F8 filtered air
Ampoule Chilling (approximately 4C) with F8
filtered air
Ampoule sealing station
Score break (vacuum system equipped with
low level alarm)
Ampoule annealing oven
Ampoule forming Line
1- Cooling Tunnel (open
Ampoules)
2- Refrigerated Air (cool
Ampoules to 4
o
C)
3- Ampoule Sealing
Station
4- Transport Belt
(Closed Ampoules)
5 Vacuum Control
System
6- Score Break Station
1 2 3 4 6 5
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
Prepare Ampoules for
Clean Room Filling
Process
Remove plastic wrap from
modules
Reject any damaged modules
Autoclave ampoules in a double
door jacketed steam autoclave
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 filled
ampoules for defective seals
Periodically remove samples for fill
volume, seal dimensions and cosmetic
inspection
Terminally Sterilize Drug
Product
Load the ampoules in the inverted
orientation
Overkill sterilization cycle at 121
o
C
Post-vacuum hold cycle (leak test)
100% inspection
Automated inspection for
Low Fill Volume (leakers)
Particulate matter
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 )
Critical Control Points
Process Step
Opening ampoules
(generation of glass
particles)
Filling ampoules in a
Class C
environment
Airborne particles
related to facility
design
Airborne particles
related to personnel
gowning
Ampoule leak test
Critical Control
Point
Exhaust Interlock
Monitoring P
Change Filling
Room Operators
Clothing daily
Cycle Review
Corrective Actions
Process Step
Opening ampoules
(generation of glass
particles)
Filling ampoules in a
Class C environment
Airborne particles
related to facility
design
Airborne particles
related to personnel
gowning
Ampoule leak test
Corrective Actions
Validate interlock
Increase Environmental
Monitoring Frequency
Convert to single-use
disposable gowns
Trend PM rejects
Demonstrate sensitivity
of leak test (Validation)
Recalculation of RPN
Drug Product Manufacture
5 10
Ampoule leak test
12 18
Airborne particles related to
personnel gowning
6 12
Airborne particles related to
facility design
12 18
Opening ampoules
(generation of glass
particles)
RPN (2004) RPN (2003) Process step
Ampoule Leak Test
Process
140 minutes at 0.2 Bar (Inverted
Orientation)
100% automated fill volume
inspection
Ampoule Leak Test
Validation
Establish Fill Volume Sensitivity
Label Claim 1.0ml
Challenged with ampoules filled
with
0.80ml
0.90ml
0.95ml
10 of 10 rejected with 0.95ml
Ampoule Leak Test
Validation
Create 20 ampoules each with
holes using Lasers
10m
20m
30m
Ampoules with 10m were empty
after the leak test cycle
Particulate Matter
Reject History
041249 0.2% 262 132371 04069
030537
041249
0.9% 1187 130257 04068
030537 0.9% 1217 128676 04067
030250 0.8% 293 35599 03122
030537 0.8% 1104 129985 03168
030537 0.7% 902 129688 03167
030537 0.6% 740 129461 03166
030250 7% 7428 111861 03099
030227
030250
6% 8225 128151 03098
030227 4% 4779 125570 03097
Ampoules
Lot No.
%
N particulate
matter rejects
Number
Inspected
Batch No.
Customer Complaint
Frequency
No Complaints received for
particulate matter
Summary
FMEA is a tool that can identify
those processes that represent the
greatest risk for failures of various
types.
FMEA is also a tool that can
evaluate an overall control
program to ensure that limited
quality resources are being utilized
in the most cost-effective manner.
Grazie per Tutti
Augusto Mitidieri, General Manager,
Sintetica, S.A.
Osiris Donghi, Technical Director,
ARLAVES
Sergio Randisi, Director QA, ARLAVES
Franco DeVecchi, VPCI

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