11 Glass Extratcables Bayer Zuercher

Glass Extractables

Dr. Jörg Zürcher, Global Pharmaceutical Development/ Packaging Development

Glass Extractables, December 2009, SCHOTT Pharma Symposium Mainz

• Composition of glass

• Pharmacopoeial requirements

• Examples for extractables/leachables

• Risk evaluation of glass extractables

• Concepts to avoid extractables/leachables

• Summary and conclusions

Content


Composition of different glass types

source: Schott-Rohrglas GmbH, Mitterteich

borosilicateglass

neutral glass(tubes)

neutral glass(molded)

soda-limeglass

SiO2 80 - 82 72 - 75 65 - 70 70 - 75

B2O3 12 - 13 9 - 11 9 - 11 0 - 1

Al2O3 2 5 - 7 3 - 7 2 - 4

Na2O/K2O 4 6 - 9 9 - 10 12 - 16

MgO/CaO/BaO 0 1 - 3 4 - 5 10 – 15

molding temp. (°C) 1260 1145 - 1170 1050 - 1080 1015 - 1045

Composition of glass


Function of glass ingredients:

SiO2 backbone structure

CaO increasing hardness & chemical resistance

Al2O3 increasing chemical resistance

Na2O, B2O3 lowering melting point



Structure of borosilicate-glass

Silicon

Oxygen

Boron

Sodium

Aluminum



Ph.Eur.

3.2.1. GLASS CONTAINERS FOR PHARMACEUTICAL USE

Classifies glass types according to hydrolytic resistance:

• type I: They are of neutral glass of high hydrolytic resistance due to the chemical composition of the glass itself

• type II: They are usually of soda-lime-silica glass and have high hydrolytic resistance resulting from suitable treatment of the surface

• type III: They are usually of soda-lime-silica glass and have only moderate hydrolytic resistance

Pharmaceutical requirements


Ph.Eur.

3.2.1. GLASS CONTAINERS FOR PHARMACEUTICAL USE

Test methods for glass containers:

• Testing for hydrolytic resistance– surface hydrolytic resistance test– powdered glass test– hydrolytic resistance test of the etched surface

• Arsenic (applies to containers for aqueous parenterals only)

• Light transmission • Resistance to thermal shock

• Resistance to centrifugation



USP

<660> CONTAINERS - GLASS

Classifies glass types according to hydrolytic resistance:

• type I: high resistant, borosilicate glass

• type II: treated soda-lime glass

• type III: soda-lime glass

• type NP: general-purpose soda-lime glass



USP

<660> CONTAINERS - GLASS


• Testing for hydrolytic resistance– surface hydrolytic resistance test– powdered glass test

• Arsenic

• Light transmission



JP 15

7.01 Test for Glass Containers for injections


• Testing for hydrolytic resistance– powdered glass test < 100 ml filling volume– surface hydrolytic resistance test > 100 ml filling volume

• Soluble iron

• Light transmission



Method comparison - glass powder test

Ph. Eur. USP JP

mesh width (µm) 250 - 425 300 - 425 300 - 850

mass glass powder (g) 20 10 5

water volume (ml) 100 50 50

autoclavation cycle 121°C/ 30 min RT 121°C/ 19-23 min121°C/ 30 min

121°C RT/ 38-46 min

100°C/ 120 min

titration volume (ml) 50 50 50

titration medium 0.01 N HCl 0.02 N H2SO4 0.01 M H2SO4

indicator methyl red methyl red bromcresol green-methyl red

limit (ml)glass type Iglass type II/IIIglass type IV/NP

≤ 2.0≤ 17.0≤ 30.0

≤ 1.0≤ 8.5≤ 15.0

limits notcomparable withPh.Eur. and USP



Method comparison - surface test

Ph. Eur. USP JP

fillvolume for testing nominal filling capacity 90 % of overflowcapacity

90 % of overflowcapacity

autoclavation cycle 100°C/ 10 min100°C 121°C/ 20 min

121°C/ 60 min121°C 100°C/ 40 min

titration after max. 1h

RT 121°C/ 19-23 min121°C/ 60 min

121°C RT/ 38-46 min

121°C/ 60 min

titration volume (ml) ≤ 3 ml: 25> 3 – 30 ml: 50

> 30 ml: 100

100 100

titration medium 0.01 N HCl 0.02 N H2SO4 0.01 M H2SO4

indicator methyl red methyl red bromcresol green-methyl red

limits (ml) depending on containervolume

≤ 100 ml: ≤ 0.7> 100 ml: ≤ 0.2

> 100 ml: ≤ 2



Alkali release - influence of filling volume and storage time

source: Dr. J. Pfeifer, Schott-Rohrglas GmbH, DPhG Fachgruppentagung Analytik 2003

0

1

2

3

4

5

6

7

8

0 1 2 3 4 5 6 7 8

storage period (years)

ppm

sod

ium

oxi

de

0.5 ml filling 1 ml filling

Examples for extractables/ leachables

Test conditions

1 ml ampoules with WFI

filling volumes: 0.5 and 1 ml

autoclaving at 121°C for 20 minutes

store at 25°C/65%RH

measurement of Na2O by flame photometry


Silica release - influence of filling

source: Dr. E. Spingler-Kloess, Swiss Pharma, 10/99, p. 11ff

0

10

20

30

40

50

60

70

80

Lactic

acid

Acetic

acid

Ascor

bic ac

id

Malic a

cidTart

aric a

cid

Oxalic

acid

Glucuro

nic ac

id

Citric

acid

cont

ent S

i (pp

m)


Test conditions

glass type II containers


measurement of Si by AAS


Silica release - influence of pH-value

source: Dr. E. Spingler-Kloess, Swiss Pharma, 10/99, p. 11ff

-5

0

5

10

15

20

25

30

35

40

3 4 5 6 7 8 9

pH-value

Si re

leas

ed (p

pm)


Test conditions

2 ml ampoules


filling: citrate buffer adjusted to the respective pH-value

measurement of Si by AAS


Alkali release might induce pH-shift of an unbuffered filling

• reduced shelf-life

• precipitation of product ingredients

Silicon release might induce glass flaking or delamination

• increasing particle load

Risk evaluation of extractables/ leachables


Surface treatment - glass type III type II

• relevant for molded glass containers

• (NH4)2SO4 is injected before annealing:

reaction:

(NH4)2SO4 (NH4)HSO4 + NH3

2Na+ + (NH4)HSO4 Na2SO4 + NH3 + 2 H+

• the water soluble Na-salt on the glass surface is removed by rinsing

Concepts to avoid extractables/ leachables


Surface treatment - glass type III type II

• surface treatment with (NH4)2SO4 can also be used for glass type I containers to reduce the increased alkali release after molding



Surface treatment - treatment of glass type I

source: Dr. J. Pfeifer, Schott-Rohrglas GmbH, DPhG Fachgruppentagung Analytik 2003

0

1

2

3

4

5

6

7

8

0 1 2 3 4 5 6 7 8storage period (years)

ppm

sod

ium

oxi

de

treateduntreated


Test conditions

1 ml ampoules treated and untreated

Treatment (NH4)2SO4

filling volumes: 0.5 (WFI)


store at 25°C/65%RH

measurement of Na2O by flame photometry


Siliconization of container surface

• siliconized surfaces are hydrophobic reducing the wettability of the container surface

• thus siliconized glass surfaces are reducing potential interactions with aqueous fillings

• the release of alkali ions is reduced compared to non-siliconized containers

• but: potential silicone oil contamination of the filling needs to be considered



Coating of inner surface

• SCHOTT Type I plus®


source: Schott - Product brochure SCHOTT Type I plus®


Coating of inner surface

Evaluation: autoclaving at 121°C for 6h, AAS-analysis:

type I type I plus®

Na+ 3.5 ppm < 0.01 ppm

Ca2+ 1.1 ppm < 0.05 ppm

B3+ 3.5 ppm < 0.1 ppm

Si4+ 5.0 ppm < 0.3 ppm

Al3+ 2.3 ppm < 0.05 ppm


source: Schott - Product brochure SCHOTT Type I plus®


Extractables/leachables from glass are inorganic components of the glass bulk material

• major extractables: Si and Na

• minor extractables: K, B, Ca, Al

• trace extractables: Fe (in colored glass)

Relatively low levels of extractables are found in fillings at pH 4-8, much greater levels for fillings with pH > 9

Summary and conclusions


The composition of the filling impacts the extent of extraction,especially:

• pH, type of buffer system, surfactants, complexing agents

Container size, fill volume and storage conditions are also influencing the mass of extractables

Manufacturing processes (e.g. sterilization time and temperature) impact the extent of extraction

Viable concepts to reduce extractables are surface treatment and coatings

Summary and conclusions

Thank you for your attention

11 Glass Extratcables Bayer Zuercher

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