Batch A - Parenteral Drug Association

100% CCI Inspection Data for
Lyophilized Product Vials:
Lessons Learned
PDA: A Global
Association
Dr. Derek Duncan
Director Product Line
Industry case study:
100% CCI Inspection
•
•
•
Suspected raised stopper issue – batch of 11,000 lyo vials
put into quarantine
100% headspace inspection a few weeks after manufacture;
Specified headspace conditions at stoppering was 600
mbar of nitrogen
2
Industry case study:
100% CCI Inspection
Batch C - 500 vials
1000
Headspace pressure
800
600
400
200
800
600
400
200
Sample number
451
401
351
301
251
201
151
101
51
451
401
351
301
251
201
151
101
51
0
1
0
1000
1
Headspace presuure
(mbar)
Batch A - 500 vials
Sample number
1000
AQL 0.1% inspection:
800
600
Batch B is isolated problem
batch
400
200
Sample number
451
401
351
301
251
201
151
101
51
0
1
Headspace pressure
(mbar)
Batch B - 500 vials
Questions
• What is a ‘typical’ container closure integrity
failure rate for a batch of commercial freezedried product?
• How can a validated process produce a batch
having a 20% failure rate for a critical quality
parameter?
Presentation Outline
• Headspace as a CCIT method
• Industry 100% lyo vial CCI inspection results
• Lessons learned
5
Characterizing the headspace
non-destructively
Laser light matches
frequency of target
molecule.
Amount of absorbed laser
light is dependent on
concentration of target
molecule in headspace.
Laser
diode
Detector
O2 H 2 O
What can be measured?
• Headspace oxygen
• Headspace moisture (water vapor)
• Headspace nitrogen pressure/vacuum
levels
• Headspace carbon dioxide
CO2 N2
mbar
6
Laser-based Headspace for CCI
determination
Different types of defects can cause leakage in sterile vials:
Glass issues
•
•
•
•
Cracks in glass
Incoming glass defect
Improper machine setup
Rough handling
Seal issues
•
•
•
•
•
Product on lip
Improperly seated stopper
Improperly applied cap
Bad stopper / vial combination
Stopper pop-up between lyo and capper
defect
AIR
RESULT:
• Increase O2 levels
• Increase H2O levels
• Decreased vacuum
levels
Oxygen ingress by diffusion through
laser drilled defects
Method can be quantitatively validated as a function of defect size
Oxygen ingress into a 3ml container as
a function of defect size
Defect sizes
(microns)
Oxygen egress by diffusion through
capillary
•
Air headspace samples can be stored in a nitrogen environment (e.g. purged
glovebox)
Oxygen leaving the headspace is measured to detect a leaking container.
Nitrogen diffusion into air headspace containers
20
Headspace oxygen (% atm)
•
15
10R vial
10
2R vial
Syringe (11mm)
5
0
0
5
10
15
Time (hour)
20
25
Physical closure integrity test
Blue dye test
• Ingress of methylene blue
Headspace analysis
• Ingress of O2 and/or N2
•
•
•
•
•
•
•
•
•
Qualitative visual inspection
Destructive method
Permanent leaks
Useful for gross leak detection
Methylene blue: C16H18N3SCl
Analytical measurement
Non-destructive method
Permanent and temporary leaks
Sensitive to all leak sizes
Described by gas flow physics
Diatomic gas molecule: O2 and/or
N2
Headspace Leak Rate Model
•
Allows you to model headspace dynamics due to leaks of
all different sizes as function of initial headspace
conditions and headspace volumes.
Book Chapter Reference:
"New Inspection Techniques For Aseptic Processing"
by James Veale
Practical Aseptic Processing, Vol 1
Edited by
Jack Lysfjord
Available online at the PDA Bookstore
•
Headspace will be described in updated USP chapter <1207> on
container closure integrity testing
Questions
• What is a ‘typical’ container closure integrity
failure rate for a batch of commercial freezedried product?
• How can a validated process produce a batch
having a 20% failure rate for a critical quality
parameter?
CCI Inspection Data Overview
Data overview
Overall results
Results per product
type
Results per
company
Data analyzed so far to answer the question
“What is a typical CCI failure rate for commercial
sterile vial product?”:
•
•
Vial size
15.3 million vials manufactured 2008-2013
5 sterile product manufacturers
 2 U.S.
Quarter
 3 EU.
Type of failure
•
Lyo and liquid product under vacuum or partial
pressure of nitrogen
Overall Results
Data overview
Overall results
Results per product
type
Results per
company
Total no. vials
inspected
15305883
Total no. vial rejected
99430
Percentage
0.65%
Vial size
Quarter
Type of failure
Results per Product Type
Total no. vials
1530588
3
Data overview
Total no. rejects
99430
Overall results
Percentage
0.65%
Results per product
type
Results per
company
Liquid
Lyo
Total no. vials
723036
14582847
Total no. rejects
1801
97629
Percentage
0.25%
0.67%
Vial size
Quarter
Type of failure
Results per company
Total no vials
1530588
3
Data overview
Total no. rejects
99430
Overall results
Percentage
0.65%
Results per product
type
Liquid
Lyo
Total no. vials
723036
Results per
company
1458284
7
Total no. rejects
1801
97629
Vial size
Percentage
0.25%
0.67%
Quarter
Type of failure
Company
A
B
C
D
E
Total no.
vials
72303
6
32717
8
158602
3
491235
12178411
Total no.
rejects
1801
2754
4354
5002
85519
Percentage
0.25%
0.84%
0.27%
1.02%
0.70%
Results of company C
Data overview
Overall results
Results per product
type
Results per
company
Vial size
Quarter
Type of failure
Results of company C
Data overview
Overall results
Results per product
type
Results per
company
Vial size
Quarter
Batch
Type of failure
Outlier batch
Results of company C
Data overview
Overall results
Results per product
type
Results per
company
Vial size
Quarter
Batch
Type of failure
Outlier batch
Results of company C
Data overview
Overall results
Results per product
type
Results per
company
Vial size
Quarter
Batch
Type of failure
Outlier batch
Results of company C
Data overview
Overall results
Results per product
type
Avg CCI
failure rate:
0.27 %
Results per
company
Vial size
Quarter
Type of failure
Avg CCI
failure rate:
0.13 %
Results of company E
Process of company E shows similar results…
Data overview
2,50
Results per product
type
2,00
Results per
company
1,50
Vial size
Quarter
Type of failure
Reject rate (%)
Overall results
Reject rate by quarter
1,00
0,50
0,00
Q1 Q2 Q3 Q4
2008
Q1 Q2 Q3 Q4
Q1 Q2 Q3 Q4
Q1 Q2 Q3 Q4
2009
2010
2011
Q1 Q2 Q3 Q4
2012
Q1 Q2
Results of full vacuum lyo
product
Data overview
Overall results
Results per product
type
Initial headspace is full vacuum (0 mbar)
• Gross leak: > 500 mbar
•
Partial leak: < 500 mbar
Results per
company
Situation
Partial leak
(< 500 mbar)
Gross leak
(> 500 mbar)
Vial size
Total No. of rejected vials
31814
53705
Quarter
Percentage
37.2%
62.8%
Type of failure
Most of the rejected vials were gross leaks
23
Inspection data conclusions
• The freeze drying process results in a relatively high risk
for container closure failure
• A validated process can still produce a batch with a
relatively high failure rate
• Container closure failure rates for lyo vials are similar to
the sealing failure rate of ampoules: tenths of a %
Questions
• What is a ‘typical’ container closure integrity
failure rate for a batch of commercial freezedried product?
• How can a validated process produce a batch
having a 20% failure rate for a critical quality
parameter?
CCI failure risks in the freeze
drying process
• Mismatch of packaging components, especially coated
stopper / vial combinations, leading to stopper pop-up
⁻ Renaud Janssen, Datwyler, PDA Freeze Drying 2011, Barcelona
⁻ Sascha Karhoefer, West, PDA Freeze Drying 2011, Barcelona
• Stoppering process in the lyo chamber, sticking stoppers
⁻
Joe Brouwer, IMA, ISL-Freeze Drying 2013, Sao Paolo
• Extended time before vial is capped and crimped
⁻ EU Annex 1: 118. The container closure system for aseptically filled vials is not fully integral until the
aluminium cap has been crimped into place on the stoppered vial. Crimping of the cap should therefore
be performed as soon as possible after stopper insertion.
Regulatory Guidance - FDA
•
Source: US Food and Drug Administration, (2004) Guidance for Industry. Sterile Drug
Products Produced by Aseptic Processing — Current Good Manufacturing Practice (FDA,
Rockville, MD) Paragraph VI. Components and Containers/Closures, Section B-2
Containers/Closures pg 18 Inspection of Container Closure System
A container closure system that permits penetration of microorganisms is
unsuitable for a sterile product. Any damaged or defective units should
be detected, and removed, during inspection of the final sealed product.
……. If damage that is not readily detected leads to loss of container
closure integrity, improved procedures should be rapidly implemented to
prevent and detect such defects.
Regulatory Guidance - EMA
• Source: Good Manufacturing Practice, Annex 1: Manufacture of
Sterile Medicinal Products (Eudralex, February 2008 revision).
117. Containers should be closed by appropriately validated methods. Containers closed
by fusion, e.g. glass or plastic ampoules should be subject to 100% integrity testing.
Samples of other containers should be checked for integrity according to appropriate
procedures.
121. Vials with missing or displaced stoppers should be rejected prior to capping...
123. Containers sealed under vacuum should be tested for maintenance of that
vacuum after an appropriate, pre-determined period.
World Health Organization
•
Source: WHO recommendations
Annex 1, WHO TRS 963 (revised 2007)
Containers of freeze-dried vaccine should be hermetically sealed under
vacuum or after filling with pure, dry, oxygen-free nitrogen or any other gas not
deleterious to the vaccine. All containers sealed under vacuum should be
tested for leaks and all defective containers should be discarded.
29
Managing the risk of CCI
failure for sterile product
• Thorough container closure integrity validation in
packaging development
• Generate statistical CCI data whenever possible from
samples produced with the actual process: clinical
batches, scale-up placebo batches, validation batches
(QbD approach)
• 100% inspection of commercial batches, CCI quality
monitoring program
Headspace Inspection Platforms
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•
Initially developed with FDA funding.
Have been implemented, validated, & registered as IPC for in-line
CCI inspection and as release test for vacuum testing since 2003.
Automated systems:
Packaging, Production
At-/Off-line systems:
Development labs, QC,
Production
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2
Headspace Pressure (mbar)
Pressure (mbar)
400
%Oxygen
1000
20
800
16
600
Temporary Gross
12 Leaker
Temporary
Partial Leaker
Leaking Vial No.
8
200
4
0
0
Headspace Oxygen (%O2)
Industry case study:
100% CCI Inspection
Permanent
Leaker
Current understanding
•
The freeze drying process contains inherent risk to the
container closure integrity of lyo product vials
•
CCI inspection data from batches of commercial freeze
dried product show CCI failure rates similar to sealing
failure rates of ampoules (a few tenths of a percent).
•
A holistic approach to mitigating risk of CCI failure in lyo
vials should include thorough validation of packaging
components, collection of CCI data during process
validation, and ongoing inspection of finished product.
33
Acknowledgements
•
Our clients
•
Jeanette Evers, LIGHTHOUSE
Thank you for your attention!
For further discussion please speak to us at the
Exhibition
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