Case Study Glass Vial Delamination in a Biopharmaceutical Product

Rob Swift, Senior Principal Engineer Primary Container Engineering Rx-360 Glass Delamination Scientific Symposium May 25, 2011, Arlington, VA

Glass Vial Delamination in Pharmaceutical and 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 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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Overview of Amgen discovery and investigation 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.
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%

Photo of lamellae in a drug product vial

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 lamella analyzed in next slide

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

Scanning Electron micrograph

Full Scale 8317 cts Cursor: 4.993 (1 cts)

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.

Image by Forensic Analysis Lab

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The inner surfaces of emptied drug product vials with lamellae revealed areas of delamination
Scar area with apparent missing layer of glass

Highly pitted area

Boundary

Area with pits and incipient lamellae

Image by Forensic Analysis Lab

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Lamellae Formation Was Delayed in Supplier X Vials Compared to Supplier Y Vials

Supplier X Vials
Found
Not Found

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

Lamellae inspection date fill date (days) vs. Detection of lamellae

Data analysis by Quality Engineering

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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

with lameela %Vials lamellae with % Vials

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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Age bracket (days from filling to inspection)

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

%Normal distribution of EP Values

0.04

Axis Title proportion Population

0.035

0.03

0.025

Schott 2006-2010 Supplier X

0.02

Amcor 2005-2010 Supplier Y

0.015

0.01

0.005

0
1 11 21 31 41 51 61 71 81 91 101 111

Surface alkalinity test results (% EP limit for Type I containers)

Data analysis by Quality Engineering
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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

Single Dose Formulation in Supplier Y Vials

Found
Not Found

0d

200 d

400 d

600 d

800 d

1000 d

1200 d

1400 d

Multi Dose Formulation in Supplier Y Vials

Found
Not Found

0d

200 d

400 d

600 d

800 d

1000 d

1200 d

1400 d

Inspect date fill date (days) vs. Detection of lamellae

Data analysis by Quality Engineering
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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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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 formulation development 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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