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Research ArticleTechnology/Application

Enhancing Patient Safety through the Use of a Pharmaceutical Glass Designed To Prevent Cracked Containers

Robert A. Schaut, Kyle C. Hoff, Steven E. Demartino, William K. Denson and Ronald L. Verkleeren
PDA Journal of Pharmaceutical Science and Technology November 2017, 71 (6) 511-528; DOI: https://doi.org/10.5731/pdajpst.2017.007807
Robert A. Schaut
Corning Incorporated, Corning, NY 14831
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  • For correspondence: schautra@corning.com
Kyle C. Hoff
Corning Incorporated, Corning, NY 14831
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Steven E. Demartino
Corning Incorporated, Corning, NY 14831
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William K. Denson
Corning Incorporated, Corning, NY 14831
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Ronald L. Verkleeren
Corning Incorporated, Corning, NY 14831
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  • Article
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Article Figures & Data

Figures

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  • Figure 1
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    Figure 1

    Cracked borosilicate vial of contaminated human albumin, which upon injection resulted in blood stream infections for patients (4).

  • Figure 2
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    Figure 2

    Cross-sectional schematic of a glass article under uniform applied tension, showing low level stress (grey shading) throughout the part and high stress concentration (dark grey shading) near the flaw tip.

  • Figure 3
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    Figure 3

    Vial schematic labeled with common locations. The highlighted regions (Body, Heel, & Footprint) show where more than 90% of cracks are introduced.

  • Figure 4
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    Figure 4

    Photograph of a borosilicate vial returned from the field with a bump check crack that extends through the glass wall that was formed during shipping to the health care facility.

  • Figure 5
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    Figure 5

    Mechanical testing equipment designed to replicate the features of a bump check crack by loading a vial heel with a sacrificial borosilicate glass ball.

  • Figure 6
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    Figure 6

    Optical microscopy comparison between a field return bump check crack and the laboratory replication, showing key fractographic features: frictive material transfer, crescent-shaped initial crack, and fracture propagating away from the origin creating “wing-shaped” features. The replication of these features demonstrates that the mechanical testing equipment is able to generate bump check cracks in borosilicate vials.

  • Figure 7
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    Figure 7

    Schematic of two-step process of creating lens cracks. At left, the borosilicate glass vial is pressed into silicon carbide fixed abrasive paper (textured surface contacting vial footprint) with a 10N load, creating initial surface damage in the footprint region. At right, the center bottom is then lightly struck with a low-pressure pneumatic actuator putting the footprint in tension and propagating the initial damage to a lensing crack.

  • Figure 8
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    Figure 8

    a) Field-returned borosilicate vials that experienced a lensing crack that propagated up the sidewall from additional applied stress but did not break the vial. b) Optical microscopy image of two vials from controlled lab experiments that replicated these lensing cracks.

  • Figure 9
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    Figure 9

    a) At left, seal crimping equipment configured to shape aluminum caps on vials. When operating, the crimping wheel (at lower left of image) is displaced a fixed distance toward the neck OD (at lower right), bending the aluminum cap under the flange. The vial being processed has larger neck OD, causing the crimping wheel to damage the glass surface in the vial neck. b) At right, rotary disc blade cutting into vial neck mimicking the location of damage from seal crimping equipment contact. Cutting through the vial neck with the rotary disc without the vial breaking demonstrates the stable nature of cracks in conventional glass vials. However, if the vial breaks before the disc can completely penetrate through the neck, that vial is not at risk to cause patient harm through the injection of contaminated drug product.

  • Figure 10
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    Figure 10

    Positive control population for semi-quantitative comparison of dye ingress tests. The vial set shows (from left to right) a process blank (no methylene blue) and serial dilutions of methylene blue dye from 0.000049% to 0.1%.

  • Figure 11
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    Figure 11

    Illustration of the engineered stress profile resulting from ion-exchange of a thin-walled glass article, where the abscissa is the wall thickness (t, radial direction) and stress is the ordinate. High compressive stress (CS) is installed at the surfaces, and it decreases to the depth of the compressive stress layer (DOL). The compressive strain energy induced by this ion-exchange process is balanced by tensile strain energy, measurable as central tension (CT).

  • Figure 12
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    Figure 12

    Percent of containers exhibiting stable cracks from damage introduction, as a function of increasing central tension. The response shows a clear “threshold” response, above which damage (severe enough to cause cracks) causes obvious breaking into fewer pieces with clean edges, facilitating detection.

  • Figure 13
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    Figure 13

    a) At left, an image of a conventional borosilicate vial neck showing rotary disc damage going through the neck thickness without flange separating from the neck. b) At right, an image of a strengthened aluminosilicate vial neck after a rotary disc damage demonstrating that the disc penetrated less than 75% of the way through the thickness before central tension from the engineered stress profile (ESP) initiated the glass fracture and separated the flange from the neck. This response prevents the vial from being at risk of containing a contaminated drug product that could be administered to a patient.

  • Figure 14
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    Figure 14

    a) At left, an illustration shows the orientation of a state-of-the-art automated inspection camera designed to reject vials with cracks in the lensing crack region, with an example photo at bottom. b) At right, a photo of vials that were accepted as good by the automated inspection system shows that they clearly failed the dye ingress testing as indicated by the presence of blue dye.

Tables

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    TABLE I

    Eleven Recalls Issued for Injectable Pharmaceuticals within the Last 5 Years due to a Lack of Sterility Associated with Cracked Glass Containers

    DrugDateCompanyCountrySourceRecall Number
    Yervoy10/18/2014Bristol-Myers SquibbCanadahttp://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2014/41861a-eng.php*
    Amoxil10/15/2014GSKUKhttps://www.gov.uk/drug-device-alerts/drug-alert-amoxil-vials-for-injection-500mg-and-1g-augmentin-intravenous-600mg-and-1-2g-cracks-in-vials-used-for-packaging*
    Methotrexate Sodium12/18/2013TevaCanadahttp://www.healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2013/37319a-eng.php*
    Oncaspar11/15/2013Link Medical Products Pty LtdAustraliahttp://apps.tga.gov.au/PROD/SARA/arn-detail.aspx?k=RC-2013-RN-01226-1RC-2013-RN-01226-1
    Pegaspargase Oncaspar11/1/2013Sigma-Tau PharmaceuticalsUSAhttp://www.fda.gov/Safety/Recalls/Enforcementeports/default.htmD-736-2014
    Recombivax HB6/26/2013MerckUSAhttp://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm359493.htmB-0625-14
    Cefazolin5/30/2013SandozUSAhttp://www.fda.gov/Safety/Recalls/EnforcementReports/default.htmD-597-2013
    Vancomycin Hydrochloride2/7/2013Pharmaceutical Partners of CanadaCanadahttp://www.healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2013/23809r-eng.php*
    Cyanocobalamin9/27/2012Fresenius KabiUSAhttp://www.fda.gov/Safety/Recalls/EnforcementReports/default.htmD-0297-2015
    Cyanocobalamin Injection4/2/2012American RegentUSAhttp://www.fda.gov/Safety/Recalls/ucm298545.htm*
    Midazolam/Heparin/Ketorolac Tromethamine/Ondansetron/Diazepam7/8/2011HospiraUSAhttp://www.fda.gov/Safety/Recalls/EnforcementReports/ucm282859.htm*
    • View popup
    TABLE II

    Results of Dye Ingress Testing for Borosilicate and Strengthened Aluminosilicate Vials after Experiencing Bump Check Damage Replication

    Glass TypeDye Ingress Testing
    Quantity TestedPercent Leaking
    Borosilicate10020%
    Strengthened Aluminosilicate1000%
    • No leaking cracks were observed for the aluminosilicate vials strengthened with an engineered stress profile, while 20% of the borosilicate vials experienced leaking cracks under the same conditions.

    • View popup
    TABLE III

    Statistical Analysis of the Probability of Producing a Leaking Crack in Aluminosilicate and Conventional Borosilicate Vials for Bump Check and Lensing Crack Replication Methods, Based upon Values in Tables II and V

    MethodGlass95% Two-Sided
    80% Two-Sided
    Median
    0.02500.10000.50000.90000.9750
    Bump CheckBorosilicate0.13490.15770.20600.26070.2918
    Aluminosilicate<0.0003<0.0011<0.0069<0.0228<0.0362
    Lensing CrackBorosilicate0.57510.62280.70860.78540.8214
    Aluminosilicate<0.0005<0.0021<0.0138<0.0450<0.0711
    • Both 80% and 95% two-sided confidence intervals are calculated, though the intervals reported for the aluminosilicate vials represent upper bounds due to the absence of failures.

    • View popup
    TABLE IV

    Inspection and Dye Ingress Testing Results for Vials Processed with Misaligned Capping Machine, Replicating Neck Crack Damage Introduction

    Glass TypeVial Quantity Processed by Capping MachineHuman InspectionDye Ingress Testing
    Percent CrackedPercent Leaking
    Borosilicate4003.25%0.5%
    Strengthened Aluminosilicate2000%0%
    • Human inspection identified 13 (3.25%) borosilicate vials that contained neck cracks, while no (0%) strengthened aluminosilicate vials were identified as cracked. Leak testing of these vials showed that two (0.5%) of borosilicate vials exhibited leaking cracks and none (0%) of the strengthened aluminosilicate vials leaked.

    • View popup
    TABLE V

    Automated Inspection and Dye Ingress Testing Results for Vials That Had Experienced Lensing Crack Replication Damage

    Glass TypeAutomated Inspection ResultsDye Ingress Testing
    Quantity TestedPercent Leaking
    Borosilicate26% Accepted1735%
    74% Rejected3388%
    Strengthened Aluminosilicate100% Accepted500%
    0% Rejected00%
    • The automated inspection rejected 74% of the damaged borosilicate vials, 88% of which leaked in dye ingress testing. Of the 26% damaged borosilicate vials that were accepted, 35% of them leaked in dye ingress testing. While the strengthened aluminosilicate population experienced the same damage replication event, 100% of the vials were accepted by the automated inspection equipment and none of the vials leaked.

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PDA Journal of Pharmaceutical Science and Technology: 71 (6)
PDA Journal of Pharmaceutical Science and Technology
Vol. 71, Issue 6
November/December 2017
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Enhancing Patient Safety through the Use of a Pharmaceutical Glass Designed To Prevent Cracked Containers
Robert A. Schaut, Kyle C. Hoff, Steven E. Demartino, William K. Denson, Ronald L. Verkleeren
PDA Journal of Pharmaceutical Science and Technology Nov 2017, 71 (6) 511-528; DOI: 10.5731/pdajpst.2017.007807

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Enhancing Patient Safety through the Use of a Pharmaceutical Glass Designed To Prevent Cracked Containers
Robert A. Schaut, Kyle C. Hoff, Steven E. Demartino, William K. Denson, Ronald L. Verkleeren
PDA Journal of Pharmaceutical Science and Technology Nov 2017, 71 (6) 511-528; DOI: 10.5731/pdajpst.2017.007807
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  • Article
    • Abstract
    • Introduction
    • Understanding Crack Formation in Conventional Glass Containers
    • Three Methods for Replicating Stable Cracks in Parenteral Containers
    • Dye Ingress Leak Testing
    • Preventing Formation of Stable Cracks
    • Demonstrating Prevention of Stable Cracks
    • Engineered Safety Benefits of Glass in Other Industries
    • Conclusions
    • Conflict of Interest Statement
    • Acknowledgments
    • References
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  • References
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