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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

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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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