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02 Rob Swift
02 Rob Swift
Rob Swift, Senior Principal Engineer Primary Container Engineering Rx-360 Glass Delamination Scientific Symposium May 25, 2011, Arlington, VA
Vial forming and annealing time & temperature and glass composition may affect the propensity to form lamellae
Local modification of surface glass composition during glass forming Vial surface alkalinity provides an indication of susceptibility to delamination 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, multifactor event at the level of individual vials
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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
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.
Drug Product Batch Batch 1 Batch 2 Batch 3 Vials reinspected 10,000 414,000 146,911 Vials with lamellae 2 162 16 Percent with lamellae 0.02% 0.04% 0.01%
lamellae
30x Magnification
Image by Forensic Analysis Lab
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The lamellae are extremely thin, roughly rectangular and variable in size
The lamellae are ~ 1 micron 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 lamellae were in the range of 100 to 750 per vial.
Image by Forensic Analysis Lab
Glass lamellae
500microns
Lamellae in liquid on glass Petri dish with combined transmitted and oblique reflected illumination.
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Special techniques were needed to isolate lamellae from individual vials onto filters
Glass lamellae
200 microns Image by Forensic Analysis Lab
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Once isolated, SEM / EDS analysis confirmed the lamellae were boro-silicate glass
C O
Most abundant elements in borosilicate glass are O, Si, Na, Al and B. Elements detected by EDS
Si
Na
Al
0.5
1.5
2.5
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.
The inner surfaces of emptied drug product vials with lamellae revealed areas of delamination
Scar area with apparent missing layer of glass
Boundary
0d
200 d
400 d
600 d
800 d
1000 d
1200 d
1400 d
Supplier Y Vials
Found
Not Found
0d
200 d
400 d
600 d
800 d
1000 d
1200 d
1400 d
Drug Batches in Supplier X Vials Had Fewer Vials with Lamellae Compared to Supplier Y Vials
Dose Vials with lamellae / vials Single inspected (%) vs. age bracket vials lamellae/vials inspected(%) vs. age bracket
16%
Supplier X
Schott Amcor
14%
Supplier Y
12% 10%
8% 6%
4% 2% 0%
Lamella inspection date fill date (days) vs. % vials with lamellae
Data analysis by Quality Engineering
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Expired
60
120
300
360
420
600
660
840
900
180
240
480
540
720
780
960
1020
1080
Supplier X Vial Batches Had Lower Surface Alkalinity Compared to Supplier Y Vials
0.045
Normal distribution curves fitted to supplier alkalinity data Normal distribution curves fitted to empty vial surface alkalinity test results
0.04
0.035
0.03
0.025
0.015
0.01
0.005
0
1 11 21 31 41 51 61 71 81 91 101 111
Formulation with Higher Citrate and pH Induced Lamellae Formation More Readily
Single Dose Formulation: 20 mM sodium citrate, pH 6.9 Lots with Lots Lamellae Inspected % 27 41 128 91 21% 45% Multi Dose Formulation: 5 mM sodium citrate; pH 6.1 Lots with Lots Lamellae Inspected % 5 9 44 47 11% 19%
Vial Supplier
Supplier X Supplier Y
0d
200 d
400 d
600 d
800 d
1000 d
1200 d
1400 d
0d
200 d
400 d
600 d
800 d
1000 d
1200 d
1400 d
Conclusions The observed phenomenon was classical glass delamination as described in scientific literature. Vials formed using a process yielding higher alkalinity were more susceptible to delamination. Even in susceptible vials, delamination occurred only in a small percentage of vials and only several months post-fill. Susceptible vials were more likely to delaminate in a formulation with higher citrate concentration and pH. Delamination did not occur in susceptible vials when filled with other, non-citrate drug product formulations.
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Incorporated delamination risk assessment into formulation development for pipeline molecules.
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