9th/10th april 2019, rio de janeiro · extractables & leachables extractables are components of...

© SCHOTT AG, Dr. Folker Steden, Technical Glass Symposium Rio de Janeiro

1st Technical Glass Symposium

9th/10th April 2019, Rio De Janeiro

Agenda


1. Glass Basics – A fascinating material

2. Not every Type I glass is the same – How minor differences can impact

3. Dimensional accuracy and cosmetic quality – How a zero-defect philosophy

can support superior container properties

2

Quartz crystall Quartz glass

Glass Composition and Structure

© SCHOTT AG, Dr. Folker Steden, Technical Glass Symposium Rio de Janeiro3

Glass Composition and Structure

Amorphous silica Borosilicate glass Soda lime glass

- 0,24 nm -

Oxygen

Silicon

Boron

Network

formersSodium

Calcium

Network

modifiers

Alkali metals

e.g. Na, K

Alkaline earth metals:

e.g. Ca, Ba, Mg

chemical resistance

- 0,28 nm -

H2O



Glass Properties: Viscosity

5

Glass Properties: Thermal ExpansionThe coefficient of thermal expansion (CTE or ) describes how much a material expands when it is

heated.

The smaller the CTE the less it expands


Different types of Type I glasses


Glass Properties: Thermal Shock resistanceTemperature resistance depends on both the CTE and the wall thickness.


The smaller the CTE the higher the

thermal shock resistance.

The thinner the wall the higher the

thermal shock resistance.

9

Glass Properties: Chemical stabilityChemical stability is the resistance of the glass to chemical attack by defined agents

Water and acid attack cause an ion exchange

Water

+

Acid

OH-

H+ Cl-

Na+

Na+

H+

+


Glass Properties: Chemical stabilityChemical stability is the resistance of the glass to chemical attack by defined agents

Alkali attack causes a dissolution of the network


Hydrolytic ResistanceTwo methods to determine the glass quality – principle

Type III

Type I


Depending on the

composition

Performed by Tubing

Also depending on the

converting process

Performed by

converter

Type III

Type I

12

Hydrolytic ResistanceConstant resistance of glass grains due to constant composition


Hydrolytic ResistanceType I and III classification

Type I Type III

Amount of released ions Low High

Hydrolytic Resistance of glass grains High Low

Hydrolytic Resistance of inner surface High Low

Application All, especially parenteral packagingOnly recommended for non-

parenteralia (tablets, sprays, etc.)

Glass Type Borosilicate Glass Soda-Lime Glass

Glass Type SCHOTTFIOLAX®,

BORO-8330TM AR-GLAS®, ILLAX®


Hydrolytic ResistanceType II classification – Ammonium sulfate treatment

Na

Na

Na Ammonium

sulfate

NH4

SO4

Na

SO4

Na

NH4

Increasing the hydrolytic resistance of the surface

BUT: compromising the surface integrity and increasing the risk of flake creation


Movie Pharma Glass


Agenda






17

Every Tubing Manufacturer has its own composition


SCHOTT

FIOLAX®

Corning

51-V

Corning

51-D

Nipro NEG

SiO275 72.0 73.0 75 72

B2O310.5 11.5 11.2 11.5 11

Al2O35 6.8 6.8 6 7

Na2O/K2O 7 8.9 8.0 8 8

MgO/CaO 1.5 0.7 1.0 0.5 1

BaO - - 0.02 1

A change of the tubing supplier automatically implies a change in the glass composition

Small Differences in the composition can have a huge impact

Worst Case: New Elements which are not present in the former glass (e.g. Barium, which is known to

cause precipitation in combination with. E.g. sulfate containing solutions)

18

A change in the glass composition requires prior approval by

FDA


A change of the tubing supplier and thus a change in the glass composition is rated as a major change

Thus it requires additional stability studies and approval by FDA prior to the change

Source: FDA Code of Federal Regulations, 21 CFR 314.70

19

Small Differences in Glass Composition can have a Huge

Impact on the Impurity Profile

Comparison of different 5.0 Type I borosilicate glasses

Despite only small differences in compositions multiple levels of extractables


Surface Alkalinitydepends on the converting process


Surface AlkalinityNot every Type I tubing becomes a Type I container


pH shift


pH shift


‚high alkalinity converting‘ ´‘low alkalinity converting‘

25

pH shiftWhat can influence the pH value of WFI in e.g. an ampoule?


Extractables & Leachables

Extractables are components of the packaging

material that are released into the solution during a

certain stress procedure (e.g. autoclaving at 121 °C)

Leachables are coming out of the glass under realistic

storage conditions

The composition of a glass gives evidence for

potential extractables

The level of extractables may change during

converting and possible treatments


Extractables & LeachablesInfluencing factors

Glass composition: Type I 5.0 borosilicate glass

Converting process: smooth with low alkalinity

Container size/volume ratio: use container capacity

Rubber components

Drug product: pH value, complexing agents

Storage conditions: the colder the better


Different 10 ml Tubing Vials Type I

60 minutes Autoclaving,

Extraction with water

Different pH values

S.J.Borchert, M.M.Ryan, R.L.Davison, W.Speed;

Journal of Parenteral Science & Technology

1989; 43 (2); 67 - 79:

Accelerated Extractable Studies of Borosilicate

Glass Containers

Extractables & LeachablesInfluence of pH value


Extractables & LeachablesConstant glass composition globally ensures a stable and low extractables profile

Extractables study with FIOLAX® and

converted vials from other tubing suppliers:

2 ml vials were stored at 40°C with WFI,

pH 5.5

Sum of all Extractables was measured by

ICP-OES and ICP-MS


Extractables & LeachablesConstant glass composition globally ensures a stable and low extractables profile

Extractables study with FIOLAX® and

converted vials from other tubing suppliers:

2 ml vials were stored at 40°C with Citric

acid, pH 6.0

Sum of all Extractables was measured by

ICP-OES and ICP-MS


Extractables & LeachablesComparison of 5.0 and 7.0 glass types

0

2

4

6

8

10

12

14

16

18

20

Sum

of

Extr

acta

ble

s m

g/l

FIOLAX® Supplier C Supplier D

1h 121°C WFI

Extractables study with 2 ml vials from two different 7.0 – CTE glasses from the market


0

0,02

0,04

0,06

0,08

0,1

0,12

0,14

7.0 tubingChina

7.0 tubingChina

7.0 tubingChina

FIOLAX® clear5.0 tubing

Usa

ge m

L 0

.01

M H

Cl/

g g

lass

Hydrolytic Resistance acc. to ISO 719

0

0,02

0,04

0,06

0,08

0,1

0,12

7.0 tubingChina

7.0 tubingChina

7.0 tubingChina

FIOLAX® clear5.0 tubing

Usa

ge m

L 0

.02

M H

Cl/

g g

lass

Hydrolytic Resistance acc. to Ph. Eur. / USP


Extractables & LeachablesComparison of 5.0 and 7.0 glass types

33

Extractables & LeachablesComparison of 5.0 glass with 7.0 glass

Acc. Leachables study with 2 ml vials from two different 7.0 – CTE glasses from the market

0

10

20

30

40

50

WFI, pH 5.5 Citrate, pH 6 Phosphate, pH 7 Carbonate, pH 8Sum

of

all E

xtra

ctab

les

[mg/

L]

6 months, 40°C

FIOLAX® Supplier X Supplier Y


Agenda






35

What have been your requirements?

Determined by chemical glass composition

Better hydrolytic resistance of container surface

Delamination free containers

Improved Extractables & Leachables Profile

Determined by Tubing production and therewith

a perfeXionTM topic!

Tighter tolerances for improved container performance

„Zero cosmetical defects“

No inner surface open airlines (CCI)

Tube End Quality

36

Na+

Na+

OH-

OH-

Extractables

Leachables


A Focus on Patient SafetyFrom AQL to Zero Defect

Patient Safety is the most important direction in the pharmaceutical industry

Patient Safety is established by uncompromised quality standards

Uncompromised quality standards are directly connected to 100% controlled

stability and transparency of a production process

Therefore the future standard will be to change from a statistical quality control

concept (AQL) towards a single piece control concept (Zero defect) as it is

established already at the converter and pharma companies

Sand Tubing Convert Filling

AQL

Quality based on

statistical sampling

Zero Defect

ppm

Quality based on

100% measurement


Data Management

Geometry

Glass Defects

Tubing Defects

Outside Diameter, Wall Thickness

Circularity and Straightness

Airlines-, Knot- Stone- Detector

Tube End Inspection

Historical and Quality Database

Tube End Quality

Cross Section Control

perfeXionTM

The Components



Glass Tubing Production: Raw Materials

39


Glass Tubing Production: Melting

40


Glass Tubing Production: Tube Drawing

41


Glass Tubing Production: perfeXion®

42

Tube Drawing Single Tube processing Data Processing

dimensional cosmetic dimensional cosmetic

Before

perfeXionTM

100% control of

• Outer diameter

100% control of

• Airlines

• Stones / knots

Statistical measurement of

• Straightness

• Circularity

• Outside diameter

• Square cut

Statistical control of

quality relevant

parameters

Data stored in

disconnected data

management

systems

With

perfeXionTM

100% control of

• Outer diameter

• Inner diameter

• Wall Thickness

• Siding

100% control of

• Airlines –

differentiation

between open and

closed

• Stones / knots

Measurement of each single

tube for

• Straightness

• Circularity

• Outside diameter

• Square cut

Measurement of

each single tube for

• Tube ends

• Particles

• Contamination

Integrated PI

database

collecting all data

from melting to

pallet



Benefits at a glance

perfeXionTM is based on figures,

data and facts

perfeXionTM facilitates superior

cosmetic quality

perfeXionTM enables more

precise geometry



Customizable inside

diameter tolerances

down to ± 0.05 mm

support dosage

accuracy

Customized perfeXion® Tubing Quality

Zero defect on inside

open airlines enable

high security on

container closure

integrity

Customizable wall

thickness tolerance

down to ± 0.03 mm

support accurate bottom

and neck forming

Narrowed

dimensional

specification supports

consistant opening

break forces



0,05mm (50µm) ID API Production (10.60/9.70), 4h production

With perfeXionTM Process Standard


Customized perfeXionTM Tubing Quality 100% inside diameter measurement

46


Customized perfeXionTM Tubing Quality Cross-Section Measurement and Control

47


Customized perfeXionTM videoCross-Section Measurement and Control

48

Timing: The perfeXion™ based tighter tubing quality

specification was made available with publication of the new

SCHOTT Technical Performance Specification (TLB) 2017

Customizing: perfeXion™ in addition to the tightened quality

standard offers the customizing of critical quality parameters

Data Management: SCHOTT has started the dialog with its

industry partners to identify opportunities to materialize the

holistic quality data of the perfeXion™ process. There is more

to come…

49

perfeXionTM

Take away Messages


9th/10th april 2019, rio de janeiro · extractables & leachables extractables are components of...

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