Prefilled cartridges and syringes: Development of a ... · PDF filePrefilled cartridges and...

Prefilled cartridges and syringes: Development ofa minimal siliconization procedure to ensurecompatibility with the device and stability offormulationKaroline Bechtold-Peters, Ph.D.Boehringer Ingelheim, Biberach/Germany

Karoline Bechtold-Peters, Boehringer Ingelheim 2

Outline of the talk

Introduction into double chamber cartridges Comparison prefilled syringe vs vial – a case study to

learn for the double chamber cartridge Target of siliconization process development, procedures and

equipment Outcome of optimization studies (cartridges) Outcome of stability studies (cartridges)


Double chamber cartridge system: an attractive dosageform with future

In cases where a prefilled liquidsyringe is not stable enough

Self-application, hence in chronicdiseases but trend seen to also easeapplication at medical centers

Single dose or multiple dose In combination with a disposable,

semi-disposable or fully reusablepen system which must allow forreconstitution

More convenient than lyo vial plusreconstitution vial plus – optionally –a vial adapter

Typically a needle is added priorto the application by the patient (nofixed needle)


Comparison of protein product in syringes (free silicone)versus vial: there may be differences……

Particle measurement by lightobscuration

Syringes made from glass,siliconized


…or not

Syringes made from glass orplastics and siliconized with orwithout treatment by heat

Particle measurement bylight obscuration


But are subvisible particles measured relevant for level ofsoluble aggregates?


Syringe and cartridge systems increasing number ofstoppers increases need for siliconization

Three stoppers

Two stoppers

One stopper


Development targets for implementation of doublechamber cartridge technology at pilot scale

Select best siliconization technology (silicone oil versus silicone emulsion,baking-in conditions if relevant)

Select best spray performance of siliconization nozzle Select lowest acceptable silicone amounts to still enable adequate stopper

movement performance Check for impact on particle numbers and protein aggregation by potentially

detaching silicone Establish characterization methods for cartridge performance (mechanical

performance, amount and/or layer thickness of silicone layer) Identify necessary IPCs in order to adequately control the process Implementation of cartridge filler and siliconizer …..and much more


Double chamber cartridges: availability

Common sizes: (DIN ISO 13926-1) :- 2 x 1 mL (76.0 x 10.75 mm)- 2 x 2 mL (115.0 x 10.75 mm)

Possible suppliers:- Schott- MGlas- Nuova Ompi

Quality:- Only bulk so far


Schematic of function of double chamber cartridge


Modular double-chamber cartridge filler (Optima Group):Module 1 + 2

Filling 1Placing of first stopper and filling of cartridgewith lyo formulation

Introduction of emptymetal tubes

Introduction of emptycartridges / syringes (washed,siliconized and depyrogenated)

Cartridge / syringe insertedinto metal tubes, ready forlyophilization

VKVM 3041


Modular double-chamber cartridge filler (Optima Group):Module 2 + 3

Filling 2Filling of cartridge with reconstitution solution andplacing of second stopper

Removal oflyophilizedcartridges frommetal tubes

Exit complete dual chamber cartridge

Exit of empty metaltubes

Unloading of cartridiges inmetal tubes from lyophilizer


Bausch & Ströbel Siliconization (and washing) machines

Bausch + Ströbel FAW 1000 Bausch + Ströbel SVS 9061


Set up of tests

Figure: stopper movement in double chamber cartridgeFor test purposes, here only the second chamber (solvent chamber) was filled with 2 ml ofsodium chloride solution


Testing of Breake Loose and Gliding Force

Zwick testing machine


Force profile

Acceptance criteria:(acc. to DIN ISO 13926-2)

Break loose force: ≤ 30 N

Gliding forces: ≤ 15 N

Breakloose

Gliding forceof both stoppers

Bypassis reached

First chamber is emptied

Both stoppersmove

further forward

Cartridge

Plu

ng

er 1

Plu

ng

er 2

Solvent is transferredvia the bypass

into the first chamber

Distance [mm]

Forc

e[N

]


Outcome of optimization studies (cartridges)Outcome of stability studies (cartridges)


Parameters tested

Two different siliconization machines (macro and micro dosing) Silicone emulsion (three different dilutions) vs. pure silicone oil Various spray pressures Position of cartridge after siliconization prior to fixation (upright vs. upside down) With fixation by heat at 260 - 320°C or air drying at 20°C 3 different kinetics of spray nozzle movement (and hence distribution of silicone

oil) Amount of silicone oil/emulsion sprayed With/without heating of spray nozzle built-up of design space via DoE based program

Read-out parameters– Break loose and gliding force at two movement speeds– Particles as measured by MFI (Brightwell)– Turbidity by nephelometry (for protein-containing solutions only)– HPSEC (for protein-containing solutions only)


Spray position/kinetic

Variant 1

Variant 2

Variant 0


Visualization by fine glass dust

Visualization of differences in siliconization by glass dustdependent on spray kinetics, pure silicone oil

Variant 1 Variant 2


High speed camera to control spray process


Assessment on critical siliconization process parameters

The process parameters spray pressure, spray position/kinetics and amount of siliconehad (within the range tested) different impact on the read-out parameter break looseand gliding force depend on whether pure silicone oil or a silicone emulsion was used

– Oil: pressure had no impact, spray kinetics and essentially amount of silicone oilwere decisive

– Emulsion: amount of silicone emulsion and spray kinetics had no (statisticallysignificant) impact, but spray pressure was decisive and dilution of initialemulsion

– Spray kinetics variant 2 not to be recommended

Silicone oil Silicone emulsion

Amount of silicone oil (mg) Amount of silicone emulsion (mg)

Sp

ray

kin

etic

s

Sp

ray

kin

etic

s


Comparison of cartridges (silicone oil) as regards breakloose and gliding forces without/with heat fixation

Cartridges without heat fixation of the silicone oil reveal slightly higher gliding forces,but significantly higher break loose forceseven distribution of silicone over thecartridge surface under the influence of heat

Without heat fixation After heat fixation

v = 250 mm /min


Siliconization:SEM-pictures / inner cartridge surface

Before siliconisation: After siliconisation,before fixation of

silicone oil:

After siliconisation,after fixation of

silicone oil:

50 µm

50 µm50 µm


Impact of silicone fixation (baked-in silicone) onsubvisible particles number

Air dried at 20°C (silicone oil)

Baked-in at 320°C (silicone oil)

Number of particles in the subvisible range even lower for cartridges with freesilicone (but might be biased due to non-controlled lab conditions duringsiliconization and measurement in the test runs)


Impact of silicone fixation (baked-in silicone) onsubvisible particles aspect ratio

But aspect ratio significantly different: baked-in silicone / even distribution over thewhole aspect ration range; free silicone / mostly round particles which areattributed to be silicone droplets

Without heat fixation After heat fixation


Break loose and gliding forces of siliconized cartridgesusing an emulsion: spray pressure

Two distict force peaks at the beginning of the profile due to break loose force ofboth stoppers (not revealed for the oil siliconization)

After optimization break loose and gliding forces very comparable to pure silicone oil Very smooth profile during dosing phase (end of the force profile)

v = 250 mm /min

Silicone emulsion, 1 bar spray pressure Silicone emulsion, 0.6 bar spray pressure


Stability - Subvisible particles in sodium chloride solution filled intodouble chamber cartridges, measurements by MFI

No svp increase in baked-in siliconized cartridges over storage

Storage at roomtemperature


Subvisible particles in protein solution filled into doublechamber cartridges, measurements by MFI

Low dosedCytokine(µg/ml)

IgG (ca.25mg/ml)

With Polysorbate

No Polysorbate

Differences in svp of double chamber cartridges due to individual protein and presence ofsurfactant


Acknowledgement

Boehringer Ingelheim Pharma GmbH & Co. KG:Christina LichtblauKlaus BojeKristina FrikelBettina MüllerMarkus HemmingerDr. Andrea HerreDr. Stefan BassarabDr. Helmut Hoffmann

Fachhochschule Albstadt-Sigmaringen:Prof. Dr. Bernhard Teubner


Thank you for yourattention!


Backup


Siliconization with pure silicone oil

Comment: the lower silicone quantity was nearly at the low dosing capacity of theprecision pump

Comparison of resulting Gliding Forces after siliconization of double chamber

cartridges (2 x 1 ml) with pure oil dependent on spray pressure and amount of

silicone

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

8.0

9.0

10.0

1Mean of 10 individual cartridges measured

Gli

din

gF

orc

e[N

]

Variant 2, 2 bar, 50%silicone





Siliconization with silicone emulsion

Conclusion: at high spray pressure loss of low viscous silicone emulsion throughopen cartridge throat

Comparison of resulting Gliding Forces after siliconization of double chamber

cartridges (2 x 1 ml) with emulsion dependent on spray pressure and amount of

silicone

0

2

4

6

8

10

12

Mean of 10 individual cartridges measured

Glid

ing

Fo

rce

[N]






Break loose and gliding forces of siliconized cartridgesusing an emulsion: dilution of emulsion

Undiluted emulsion not favourable, highest dilution gave the bestresults

v = 250 mm /min

Silicone emulsion, undiluted emulsion Silicone emulsion, dilution 2

Silicone emulsion, dilution 1


Further comparisons of break loose and gliding forceprofiles

Completely different force profile if needle attached Second stopper increases dramatically break loose and gliding force

Silicone oil, without needle attached

Silicone oil, with needle added

Silicone oil, run as SINGLE chamber

v = 250 mm /min

v = 40 mm /min


Critical parameters for cartridge-quality

Siliconisation:Quantity and degree of homogeneity impact functionality of

cartridge (break loose and gliding forces of plunger)

Crimping force and parameters:Direct influence on CCI and cosmetic appearance


Performed activities for control ofcartridge-quality

Optimisation of siliconisation and heat treatment parameters (forfixation of silicone oil), linkage to plunger-forcesControl of siliconisation

Weight decrease of siliconisation vessel Control of spray beam (light barrier technology)

Control of crimping force and –qualityMonitoring of crimping force Camera control of cap after crimping

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