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8/13/2019 02 Rob Swift
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Case Study Glass Vial
Delamination in aBiopharmaceutical Product
Rob Swift, Senior Principal EngineerPrimary Container Engineering
Rx-360 Glass Delamination Scientific Symposium May 25, 2011, Arlington, VA
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Glass Vial Delamination in Pharmaceuticaland Bio-pharmaceutical Products
Several formulation factors affecting glass surface interactions are
documented in the literature:
Ion exchange between Na+ ions in the glass and H3O+ ions during rinsing,
subsequent heating for depyrogenation and drug product shelf life.
Dissolution of Si-O-Si by OH- in alkaline solutions and by anion complexes,principally citrate, in neutral or mildly acidic solutions
Vial forming and annealing time & temperature and glass compositionmay affect the propensity to form lamellae
Local modification of surface glass composition during glass forming
Vial surface alkalinity provides an indication of susceptibility todelamination in general, higher alkalinity implies greater susceptibility
Hotter forming increases vaporization of alkali borates Annealing time and temperature may contribute to borate phase separation
and affect re-integration of condensed alkali borates
In susceptible systems, physical delamination is a probabilistic, multi-factor event at the level of individual vials
2
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3
Overview of Amgen discovery andinvestigation of a delamination event
Glass delamination phenomenon Typically, high pH or unbuffered formulations (local high pH at glass surface)
In the literature, chelating agents such as citrate and EDTA also are cited
Surface destabilization by ion exchange: Na+glass H3O+
solution
SiOSi dissolution separates unstable surface layer from underlying glass
Thin, transparent pieces of the surface layer (lamellae) are shed into the solution
Discovery of glass lamellae in non-distributed drug product batches
Product quality was evaluated extensively Drug product attributes were not impacted and no other products were affected
Lamellae and vial inner surface characterization
Root cause analysis Vial characteristics
Formulation characteristics
Corrective and preventive actions
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Background
Following unrelated investigations for glass breakage, drug product
batches were being re-inspected visually for glass fragments.
The drug product batches had been produced at different times and
used vials from different batches and different suppliers.
The re-inspections took place > 3 months after filling.
During the re-inspections, lamellae were observed at low frequency. In response, an investigation was launched.
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Drug Product
Batch
Vials re-
inspected
Vials with
lamellae
Percent with
lamellae
Batch 1 10,000 2 0.02%Batch 2 414,000 162 0.04%
Batch 3 146,911 16 0.01%
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Photo of lamellae in a drug product vial
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lamellae
30x
Magnification
Image by Forensic Analysis Lab
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The lamellae are extremely thin, roughlyrectangular and variable in size
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Lamellae in liquid on glass Petri dish with combined
transmitted and oblique reflected illumination.
Glass lamellae
The lamellae are ~ 1micron thick.
Length and width
were observed to
range from subvisible
(< 15 microns) up to ~
1 mm.
When lamellae were
observed in a vial, the
number of lamellaewere in the range of
100 to 750 per vial.500microns
Image by Forensic Analysis Lab
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Special techniques were needed to isolate
lamellae from individual vials onto filters
Glass lamella
analyzed in next slide
Glass lamellae
200 microns
7Image by Forensic Analysis Lab
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Scanning Electron micrograph
AlNa
Si
C O
0.5 1 1.5 2 2.5
Full Scale 8317 cts Cursor: 4.993 (1 cts)
Elements detected by EDS
Most abundant elements in
borosilicate glass are O, Si,
Na, Al and B.
Boron has a low energy X-Ray response. The signal
appear at near-baseline levels. The boron signal also
overlaps significantly with that of carbon.
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Once isolated, SEM / EDS analysis confirmedthe lamellae were boro-silicate glass
Image by Forensic Analysis Lab
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Boundary
Scar area withapparent missing
layer of glass
Highly pittedarea
Area with pits and
incipient lamellae
The inner surfaces of emptied drug product vialswith lamellae revealed areas of delamination
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Image by Forensic Analysis Lab
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Lamellae Formation Was Delayed in SupplierX Vials Compared to Supplier Y Vials
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Lamellae inspection date fill date (days) vs. Detection of lamellae
0 d 200 d 400 d 600 d 800 d 1000 d 1200 d 1400 d
Found
Not Found
Supplier Y Vials
0 d 200 d 400 d 600 d 800 d 1000 d 1200 d 1400 d
Found
Not Found
Supplier X Vials
Data analysis by Quality Engineering
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Drug Batches in Supplier X Vials Had Fewer Vialswith Lamellae Compared to Supplier Y Vials
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0%
2%
4%
6%
8%
10%
12%
14%
16%
60
120
180
240
300
360
420
480
540
600
660
720
780
840
900
960
1020
1080
Expired
%Vialswithlame
ela
Single Dose
vials lamellae/vials inspected(%) vs. age bracket
Schott
Amcor
Age bracket (days from filling to inspection)
Lamella inspection date fill date (days) vs. % vials with lamellae
%V
ialswithla
mellae
Vials with lamellae / vials inspected (%) vs. age bracket
Supplier X
Supplier Y
Data analysis by Quality Engineering
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Supplier X Vial Batches Had Lower SurfaceAlkalinity Compared to Supplier Y Vials
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0
0.005
0.01
0.015
0.02
0.025
0.03
0.035
0.04
0.045
1 11 21 31 41 51 61 71 81 91 101 111
AxisTitle
%Normal distribution of EP Values
Schott 2006-2010
Amcor 2005-2010
Normal distribution curves fitted to supplier alkalinity data
Surface alkalinity test results (% EP limit for Type I containers)
Supplier X
Supplier Y
Populationp
roportion
Normal distribution curves fitted to empty vial surface alkalinity test results
Data analysis by Quality Engineering
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Corrective and preventive measures
Implemented rolling recalled of affected batches.
Reduced expiration dating based on age data.
Initiated exclusive use of Supplier X vials for this product.
Tightened specification for empty vial surface alkalinity.
Enhanced stability program.
Engaged suppliers to reduce susceptibility to delamination.
Began analytical method development for vial screening.
Incorporated delamination risk assessment into formulationdevelopment for pipeline molecules.
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Acknowledgments
Forensic Analysis Lab & Process Development David Martinez, Abdin Suarez, Yanira Melendez, Eric Acevedo, Alex Artau
Omark De Leon, Luis Romn, Miguel Carrin, Nelson Lpez, Graham Milne
Product Quality, Quality Engineering & Supplier Quality Incoming Inspection Team, Maribel Torres
John Farris, Jose Nieves, Frank Wackes, Dan Weese, Simon Szeto
Formulation and Analytical Research Camille Vergara, Shawn Cao, Chris Sloey, Margaret Ricci
Peter Masatani, Gianni Torraca, Zai-Qing Wen,
Kiyoshi Fujimori, Yasser Nashed-Samuel
The Investigation Team including both suppliers
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