EDQMGlass containers for pharmaceutical use

European Pharmacopoiea 8.3

Ongoing revision of Chapter 3.2.1 : an overviewon hydrolytic resistance and delamination risk

Emanuel GuadagninoPast Chairman of ICG/TC 2 Chemical Durability and Analysis

Webinar, Strasbourg, 10.12.2015

Borosilicate glass structure

Average chemical

composition of Type I

tubing glass containers

OxidesWeight %

Pyrex Type A

NeutralType B

SiO₂ 80,0 73,0

B₂O₃ 13,0 11,0

Al₂O₃ 2,0 6,0

Na₂O + K₂O 5.0 8,0

CaO + BaO - 2,0

Exp.coeff. 33 51

Glass Containers for Pharmaceutical UseChemical Composition of Type I Glasses

Glass / water interactions

• The first stage of the reactions between a glass surface and a liquid phase (water or water vapor e.g. humidity) is always an ion-exchange ruled out by interdiffusion between the alkaline ions in the glass and the hydrogen ion

H+(nH2O) + Na+SiO- (glass) Na+ + SiOH (nH2O) (1)

• There is another mechanism based on the diffusion of water into the glass and its adsorption at the NBO sites

nH2O+ Na+SiO- (glass) Na+ + OH- (soln)+SiOH (nH2O) (2)

• Reactions (1) e (2) are leaching reactions and produce:a) hydration of the glass surface;b) formation of an alkali-depleted layer;c) deposits of alkaline species on the top surface, especially in humid environments

or in minimum extraction volumes

Water Corrosion MechanismStage 1: Leaching | Stage 2: total dissolution

Si and H Enrichment Profiles

Relative concentration/Depth

Si

H

1

1,2

1,4

1,6

1,8

2

0 0,2 0,4 0,6 0,8 1 1,2

Profondità, µm dalla superficie

Co

nc

. re

lati

va

di S

i e

H

Exchange with H+ ions increases

the concentration of surface OH

Modifiers depletion causes Si

surface enrichment

The silica enriched layer behaves

as a barrier to further leaching

Surface alkalinity of tubing glass containers

• The vast majority of injectable preparations is distributed in tubing glasscontainers

• To test surface alkalinity, EP prescribes a water extraction at 121°C for 1hand the titration of the following extract solution

• The test simulates roughly a storage time of 2-3 years at room temperatureand gives an information about possible pH changes over the years

• Under these conditions only a minor release of sodium and boron is expecteddue to the nature of the glass itself

• The conversion of the tubing glass canes into finished containers affects themorphology of inner surface and has a strong inluence on alkalis release

Lef t turret

Central turret

Right turret

Production of Tubing Glass Containers for Canes Loading and distribution

Pre-heating Pre-heating Cutting

Production of Tubing Glass ContainersPre-heating and cutting stage

FlameDrilling

Production of Tubing Glass ContainersFlame drilling to open the mouth

Production of Tubing Glass ContainersBottom Forming and Polishing

BottomForming

F. Nicoletti - 2014

Do not reproduce without permission

Variability of the Surface State

• The exposure to flames has a strong impact on the surface state of the finished container

• Extensive surface flaming causes evaporation and re-deposition of boratesalts wich results in local silica enrichment

• Bottom and shoulder are in a vial the most exposed area and localcompositions are different from the wall

• The within-sample variabilty will affect the between- samples variability of any single lot

• The reproducibility of the forming conditions at the conversion plant is the key factor to obtain a low alkali release and to reduce surface alterations

• A strict control over flame temperatures and exposure times willcontribute to reduce delamination propensity as well

The surface chemical composition of tubing vials is different in different zones: sodium decreases at the bottom, due to evaporation during forming (the hottest region), and

increases where condensation takes place, in the coldest regions.

From Schott Newsletters No. 14, April 2011

Sodium Surface Analysis of Container Bottom And Wall

Other Sources of Variability

• The endogenous alkali contribution of the base glass

• Within-batches variability of the inner surface of the raw cane

• Small, uncontrolled fluctuations of high temperature flames

• Significant differences in containers of the same base glass produced by different vendors

• Quality of the raw material : small dimensional variations along the lengthof the cane require flame adjustments to re-distribute the glass aroundthe most critical points

• All these factors contributes to increase the alkali release, to cause phaseseparation and surface pitting and to make the glass surface more exposed to delamination risk

Minimization of AlkalinityMeasurements Uncertainty

• Sodium release is a measure of the variability of the surface, hence of the quality of the entire process

• Any improvement in its measurement contributes to minimize the totalprocess uncertainty and to freeze disputes between parties

• In the 90’s collaborative tests were carried out by ICG/TC2 in connection with the EU Research Centre in Geel to improve data quality

• About 10 experienced labs belonging to the glass industry and academicinstitutions participated in the project

Laboratory IntercomparisonSoda-lime containers – Extraction at 121°C for 1h

Obvious outliers, spread, errors in autoclaving (lab No3,10), errors in FAAS (lab 6)

Main Sources of Errors

• Some autoclaves could not be programmed to reproduce the thermalcycle, manual operation was required

• The real temperature in the containers was not known by most labs

• Different temperatures inside/outside containers, the thermal cycle wasnot followed correctly

• Heating ramp from 100 to 121°C not strictly followed

• Variations in heating rate resulted in a sensible difference in finaltemperatures (up to 3°C)

• 1°C corresponds to about 10% difference in Na release

Analytical Protocol

• The temperature was measured with a calibrated thermocouple insertedin one container

• Participants were requested to monitor and record the entire cycle, alsomanually if necessary

• Tests carried out under conditions of strict repeatability, 6 replicate measurements in different days

• A detailed testing protocol was distributed, significant improvementswere achieved

• The reference material IRMM 435 was certified

• The testing protocol, with minor changes, was enforced in the ISO 4802 norm

Improvement of Data QualityBorosilicate Glass Containers - Titration Results

Lab Nr. Replicate measurements / mL mean / mL s / mL

1 0.39 0.37 0.40 0.44 0.40 0.39 0.398 0.023

2 0.40 0.39 0.38 0.39 0.38 0.38 0.387 0.008

3 0.36 0.37 0.36 0.36 0.36 0.36 0.362 0.004

4 0.37 0.39 0.36 0.40 0.40 0.33 0.375 0.027

5 0.39 0.39 0.39 0.38 0.39 0.39 0.388 0.004

mean (n=5) and s 0.382 0.014

srel / % 3.7

Mean values + std. dev.

EUROPEAN COMMISSION

JOINT RESEARCH CENTRE

Institute for Reference Materials and Measurements

CERTIFIED REFERENCE MATERIALIRMM – 435

CERTIFICATE OF ANALYSIS

PHARMACEUTICAL GLASS CONTAINERS

Alkali leaching and release

Certified value 1)

[mL]

Uncertainty 2)

[mL]

Volume of titration solution 0.01

mol/L HCl per 50 mL of leachate 0.38 0.04

Certified value 1)

[mg/L]

Uncertainty 2)

[mg/L]

Sodium release per volume of

leachate 1.41 0.14

Release of Na2O per volume of

leachate 1.91 0.19

1) Unweighted mean of 5 accepted mean values, independently obtained by 5 laboratories. The value is traceable to the adapted method

for alkali release based on the European Pharmacopoeia method and ISO 4802, and to the International System of Units (SI) as far as

gravimetrically prepared brants are concerned.

2) Expanded uncertainty with a coverage factor k = 2, corresponding to a level of confidence of about 95 %.

EP 8.3 Chapter 3.2.1Autoclaving process current requirements

• Insert a calibrated thermocouple in a container

• Raise temperature to 100°C within 30 mins

• Freesteaming for10 mins

• Raise temperature to 121°C at 1°C/min

• Hold temp. at 121°C for 60 +/- 1 min

• Cool down to 100°C at 0.5°C/min

• Adjust temperature curve acc. to thermocouple readings

• Automatic recording temperature vs time

Time/Temperature Plot

Classic Autoclave with Heating Coils

Insertion of Calibrated Thermocouple

Calibrated Thermocouple (Yellow) and Autoclave Resistance Thermometer (Purple)

Steam autoclave and boiler

Autoclave Resistance Thermometer and Housingfor Calibrated Thermocouples

Temperature Measuring Device and Draining Pipe

Temperature Distribution in the Autoclave Chamber

Autoclaving process ongoing revision

• Better focus on the reference thermal curve

• Separation of autoclave calibration stage from routine analysis

• Distinction between classic old model and steam autoclaves wherefreesteaming is not always possible

• Notes to clarify reasons for more accurate measurements and highlight potential sources of errors

• Calibration frequence to be set by the user on the basis of sound QC criteria

• Files record to give evidence of compliance

Glass Delamination

Separation of thin glass layers (lamellae) that appear as shiny, needle shaped particles floating in the contact liquid

The formation of a silica-rich layer poorly bonded to the substrate is the first stage of an extended delamination

Glass-liquid interactions are responsible for the formation of an altered layer

Long time storing of a solution with a high ionic strength (NaCl, KCl) and/or sterilization cycles may favor the delamination mechanism

Typical Flakes Aspect

Delamination of Pharmaceutical Glass

• The first stage is always the formation of an altered layer

• When vials are filled with the liquid preparation, this layer is subject to a strong re-hydration and swelling

Glass flakes

Delamination of Tubing Glass Containers

OH-

• Some preparations may favour delamination

• Alkaline solutions strongly affect the dissolution of the silica layer.

• SiO2 concentration in the extraction liquid increases steeply

• Flakes appearance, by increasing pH some particles redissolve

SEM Micrographs of SilicaEnriched Corroded Surfaces

Exp.33, sulphur treated vial, bottom- Extensive corrosion- Scales detachment

Exp. 51, vial bottom- Initial crizzling- Signs of incipient corrosion

EDS analysis showed flakes were mostly made of silica and alumina

Phase Separation with InterconnectedMorphology in Borosilicate Glasses

B.Wheaton and A Clare, J.Non-cryst.Solids, 2007,Vo.53, 4767-78

Scales Detachment and Pitting in Droplets

From Wen et al., J.Pharma.Sci., 2012, 101, 1378-1384

Pitting (borate-richphase dispersed on a silica-rich phase) isobserved on the detaching layer and the residual surface

Factors Affecting Delamination of Pharma Glasses

Sulfur Treatment Siliconization

Coating

Speed of the Transformation ProcessBurners Flame Temperature

Improper Annealing Stage, Tensile StressesType of Glass

Chemistry of the Buffer Supporting the Active Principle pH & Ionic Strength of the Drug Solution

Organic Acids Sterilization ProcessStorage Conditions

Conversion process

Drug formulation & post-treatments

Surface treatments

Open Questions

• How can delamination be predicted?

• What parameters can be used to investigate delamination propensity?

• Are EP values still a good indicator of delaminationresistance?

• Which glass Type is more suitable to whichpreparation?

• What are typical weak areas in a vial?

!

Glass typeE.P. titration

values

Exp33 0.93

Exp 51/b 0.92

Exp 51/a 0.63

E51S sulfur treated

0.51

0

10

20

30

40

50

60

70

0 1 2 3

SIO2 ppm

Extraction number

0,9% KCl pH 6.0 @ 121°C, 1h

Exp 51/b

Pyrex

Exp 51/a

Sulphur treated

FLAKES

FLAKES

• No flakes observed for treated/untreated Exp51 vials

• Flakes obseved after the first extraction in Exp33 vials

• Strong increase of soluble silicain solution in connection with flakes appearance

• No correlation with EP value

Extraction in Neutral Aqueous Solution Correlation With EP Values

Extractions with Slightly Alkaline Solutions

Exp 51

Glass typeE.P. titration

values

Exp51/b 0.92

Exp51/a 0.63

Exp 51 Sulfurtreated

0.51

• Exp51 vials : SiO2 increases with increasing extraction number, Flakes recoverd after 2° extraction

• Sulphur treated vials produced flakes since the 1° extraction, even if EP allkalinity is excellent and SiO2 in solution is very low

0,00

50,00

100,00

150,00

200,00

250,00

300,00

350,00

0 10 20 30 40 50 60

SiO2 ppm

t (h)

3% Citric acid pH 8 @ 80°C

Exp51/a

Exp51/b

Sulfur treated

Exp33

Extractions with 3% Citric Acid

• Visual inspection indicated early flaking.

• In Exp33 and Exp51 sulfur treated vials flakes appear after the first 2 hours

Organic Acids Extractions

Glass Treatment3% Glutaric Acid + 1 % KCl pH=8.0 3% Citric Acid + 1% KCl pH=8.0

SiO2 pH SiO2 pH

Exp 51/A

1 h121°C 16.78 F 8.14 36.36 F 8.54

2 h121°C 28.15 F 8.31 49.20 F 8.68

Exp 51/B

1 h121°C 17.20 F 8.56 43.85 F 8.79

2 h121°C 26.76 F 8.86 47.06 F 8.71

Sulf. treated1 h121°C 10.56 F 8.54 47.70 F 8.51

2 h121°C 19.42 F 8.91 31.87 F 7.97

Exp 33

1 h121°C 65.21 F 7.94 140.11 F 8.24

2 h121°C 148.76 F 8.11 198.93 F 8.42

EARLY PREDICTION BY METHYLENE BLUE COLORIMETRIC TESTING

Flakes (+++) SiO2 50 ppmSamples as received

Sulfur Treated EXP 33 VialsMethylene blue testing 1 autoclave cycle

Delamination of Tubing Glass And Preventive Indicators

• The use of high burners flames in the formation of bottom and shoulder of Type I tubing glass vials alters the surface state exposing areas with a silica-rich surface

• Phase separation and pitting are other phenomena

• In principle, neutral solutions do not cause scales detachment but flakes are observed at semi neutral pH, for low SiO2 values

• Slightly alkaline solutions affect the dissolution of the silica layer, especially in Exp.33 glass vials. The formation of flakes is possible also at moderately alkaline pH

• With increasingly alkaline solutions the concentration of SiO2 in the extraction liquid increases steeply

• When SiO2 solubility limits are exceeded, suspended particles shall appear

• SiO2 concentration is a risk parameter, no strict correlation with EP alkalinity values

ConclusionsEP Version 8.3 - § Production

• The propensity to delamination of glass containers from different sources can be assessed and ranked by exposing the container to accelerated degradation testing, carried out at specified temperatures for a short time and using the solutions associated with the actual pharmaceutical preparation as extractants.

• Accelerated degradation testing can be used as a predictive tool to select the most appropriate container for the intended preparation, but the full compatibility of the active substance with the glass leachate can only be assessed by a stability test under normal conditions of use.

Thank You for Your Attention!

Emanuel Guadagnino ©2014 EDQM, Council of Europe. All rights reserved.48