Glass Extractables

Dr. Jrg Zrcher, Global Pharmaceutical Development/ Packaging Development

Content
Composition of glass Pharmacopoeial requirements Examples for extractables/leachables Risk evaluation of glass extractables Concepts to avoid extractables/leachables Summary and conclusions

Glass Extractables, December 2009, SCHOTT Pharma Symposium Mainz

Composition of glass
Composition of different glass types
borosilicate glass SiO2 B2O3 Al2O3 Na2O/K2O MgO/CaO/BaO molding temp. (C) 80 - 82 12 - 13 2 4 0 1260 neutral glass (tubes) 72 - 75 9 - 11 5-7 6-9 1-3 1145 - 1170 neutral glass (molded) 65 - 70 9 - 11 3-7 9 - 10 4-5 1050 - 1080 soda-lime glass 70 - 75 0-1 2-4 12 - 16 10 15 1015 - 1045

source: Schott-Rohrglas GmbH, Mitterteich

Glass Extractables, December 2009, SCHOTT Pharma Symposium Mainz

Composition of glass
Function of glass ingredients:
SiO2 CaO Al2O3 Na2O, B2O3 backbone structure increasing hardness & chemical resistance increasing chemical resistance lowering melting point

Glass Extractables, December 2009, SCHOTT Pharma Symposium Mainz

Composition of glass
Structure of borosilicate-glass
Silicon Oxygen Boron Sodium Aluminum

Glass Extractables, December 2009, SCHOTT Pharma Symposium Mainz

Pharmaceutical requirements
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

Glass Extractables, December 2009, SCHOTT Pharma Symposium Mainz

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

Glass Extractables, December 2009, SCHOTT Pharma Symposium Mainz

Pharmaceutical requirements
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

Glass Extractables, December 2009, SCHOTT Pharma Symposium Mainz

Pharmaceutical requirements
USP <660> CONTAINERS - GLASS Test methods for glass containers:
Testing for hydrolytic resistance surface hydrolytic resistance test powdered glass test Arsenic Light transmission

Glass Extractables, December 2009, SCHOTT Pharma Symposium Mainz

Pharmaceutical requirements
JP 15 7.01 Test for Glass Containers for injections Test methods for glass containers:
Testing for hydrolytic resistance powdered glass test < 100 ml filling volume surface hydrolytic resistance test > 100 ml filling volume Soluble iron Light transmission

Glass Extractables, December 2009, SCHOTT Pharma Symposium Mainz

Pharmaceutical requirements
Method comparison - glass powder test
Ph. Eur. mesh width (m) mass glass powder (g) water volume (ml) autoclavation cycle 250 - 425 20 100 121C/ 30 min RT USP 300 - 425 10 50 121C/ 19-23 min 121C/ 30 min 121C RT/ 38-46 min 50 0.02 N H2SO4 methyl red JP 300 - 850 5 50 100C/ 120 min

titration volume (ml) titration medium indicator limit (ml) glass type I glass type II/III glass type IV/NP

50 0.01 N HCl methyl red

50 0.01 M H2SO4 bromcresol greenmethyl red limits not comparable with Ph.Eur. and USP

2.0 17.0 30.0

1.0 8.5 15.0

Glass Extractables, December 2009, SCHOTT Pharma Symposium Mainz

Pharmaceutical requirements
Method comparison - surface test
Ph. Eur. fillvolume for testing autoclavation cycle nominal filling capacity USP 90 % of overflow capacity JP 90 % of overflow capacity 121C/ 60 min

100C/ 10 min RT 121C/ 19-23 min 100C 121C/ 20 min 121C/ 60 min 121C/ 60 min 121C RT/ 38-46 min 121C 100C/ 40 min titration after max. 1h 3 ml: > 3 30 ml: > 30 ml: 25 50 100 100

titration volume (ml)

100

titration medium indicator limits (ml)

0.01 N HCl methyl red depending on container volume

0.02 N H2SO4 methyl red 100 ml: > 100 ml: 0.7 0.2

0.01 M H2SO4 bromcresol greenmethyl red > 100 ml: 2

Glass Extractables, December 2009, SCHOTT Pharma Symposium Mainz

Examples for extractables/ leachables

Alkali release - influence of filling volume and storage time
8

0.5 ml filling
7

1 ml filling

Test conditions 1 ml ampoules with WFI filling volumes: 0.5 and 1 ml autoclaving at 121C for 20 minutes store at 25C/65%RH measurement of Na2O by flame photometry

ppm sodium oxide

0 0 1 2 3 4 5 6 7 8

storage period (years)

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

Glass Extractables, December 2009, SCHOTT Pharma Symposium Mainz

Examples for extractables/ leachables

Silica release - influence of filling
80 70 60

Test conditions glass type II containers autoclaving at 121C for 60 minutes measurement of Si by AAS

content Si (ppm)

50 40 30 20 10 0

ac id

id

ac id

ac id

ac i

ac i

ac

ac i

rt ar ic

A sc

Ta

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

Glass Extractables, December 2009, SCHOTT Pharma Symposium Mainz

G lu

cu ro ni

A ce

O xa

La

C it r ic

al ic

lic

tic

or bi c

ct ic

ac i

Examples for extractables/ leachables

Silica release - influence of pH-value
40 35 30

Test conditions 2 ml ampoules autoclaving at 121C for 60 minutes filling: citrate buffer adjusted to the respective pH-value measurement of Si by AAS
3 4 5 6 7 8 9

Si released (ppm)

25 20 15 10 5 0 -5

pH-value

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

Glass Extractables, December 2009, SCHOTT Pharma Symposium Mainz

Risk evaluation of extractables/ leachables

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

Glass Extractables, December 2009, SCHOTT Pharma Symposium Mainz

Concepts to avoid 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 Na2SO4 + NH3 + 2 H+ 2Na+ + (NH4)HSO4

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

Glass Extractables, December 2009, SCHOTT Pharma Symposium Mainz

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

Glass Extractables, December 2009, SCHOTT Pharma Symposium Mainz

Concepts to avoid extractables/ leachables

Surface treatment - treatment of glass type I
8 7 6 treated untreated

Test conditions 1 ml ampoules treated and untreated Treatment (NH4)2SO4 filling volumes: 0.5 (WFI) autoclaving at 121C for 20 minutes store at 25C/65%RH measurement of Na2O by flame photometry
0 1 2 3 4 5 6 7 8

ppm sodium oxide

5 4 3 2 1 0

storage period (years)

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

Glass Extractables, December 2009, SCHOTT Pharma Symposium Mainz

Concepts to avoid extractables/ leachables

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

Glass Extractables, December 2009, SCHOTT Pharma Symposium Mainz

Concepts to avoid extractables/ leachables

Coating of inner surface SCHOTT Type I plus

source: Schott - Product brochure SCHOTT Type I plus

Glass Extractables, December 2009, SCHOTT Pharma Symposium Mainz

Concepts to avoid extractables/ leachables

Coating of inner surface Evaluation: autoclaving at 121C for 6h, AAS-analysis:
type I Na+ Ca2+ B3+ Si4+ Al3+ 3.5 ppm 1.1 ppm 3.5 ppm 5.0 ppm 2.3 ppm type I plus < 0.01 ppm < 0.05 ppm < 0.1 ppm < 0.3 ppm < 0.05 ppm

source: Schott - Product brochure SCHOTT Type I plus

Glass Extractables, December 2009, SCHOTT Pharma Symposium Mainz

Summary and conclusions

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

Glass Extractables, December 2009, SCHOTT Pharma Symposium Mainz

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

Glass Extractables, December 2009, SCHOTT Pharma Symposium Mainz

Thank you for your attention