Filling of heat sensitive products / biologicals with BFS ... - BFS IOA€¦ · Training Seminar...

BFS IOA

Training Seminar 2018 Kunming

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Filling of heat sensitive products / biologicals with BFS equipment

Presented by Stefan Kiesel

Senior Manager Rommelag Pharma Service

BFS International Operators Association

Copyright © by BFS IOA

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Overview/Index

I. Introduction – Biological Products

II. Introduction – BFS process

III. Temperature Sensitivity

IV. Methods

V. Results & Discussion

VI. Summary

VII. Literature


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Biological

Products

Similarities

Often parentenalapplication

Temperature

sensitiv

Tendency to

agglomerate

Stress

sensitive

Defined via production process

non via startinggene

Shear

Light

Shaking

Tender

Stability

Complex

structures

Oxidative or

reductive

stress

Surfaces,

interfaces

Chemical

Instability

Physical

Instability


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Overview/Index




IV. Methods


VI. Summary

VII. Literature


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II. Introduction – BFS ProcessBFS

• -

• -

• -

• Newly created container

• Transport and storage only for

resin material

• Immediately filled

• No cleaning necessary

• No sterilization necessary

• Very few particles

• Single automated equipment


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The BFS process minimizes the risk of contamination by

reducing particles, process steps & human interaction

Potential risk of contamination by filling technology based

on air quality and exposure time

11 Reference: Verjans, B.

Reed, C. (2012).

“Assessing Filling

Technologies for

Contamination Risk.”

Biopharm International.

25(3), pp. 46-58.


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Overview/Index




IV. Methods


VI. Summary

VII. Literature


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Biological

Product

Fill&Finish

Temperature

Fill Pumps

AdsorptionAir-WaterInterface

(«Headspace»)

Leachables

(Extractables)

PermeationGas/Water

Vapor

Others

Tiungsten

Glue

Silicone

Foreign

Particles

Parameters Influencing BioProducts during Fill& Finish


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Rubella

Typhoid

PS

JE

live

Freeze dried

Liquid, no adjuvant

Liquid, with alum

adjuvant

Vaccine formulation

Rota-

virusRota-virus

HPV

Pneumo

PS-PCV

JEinactivated

Measles

OPV

BCG

Hib

HepB

DTwP

Penta-

valent

T, DT, dT

Rabies

Yellow

fever

MenA

PS-PCV*

Hib

Least

sensitive

Most

sensitive

Vaccines to the

left of the line

are not damaged

by freezing

Most sensitive

Least sensitive

Heat sensitivity

Freeze sensitivity

HepA

Influenzainactivated

IPV

MMR

Varicella-

zoster virus

DTaPHexa-

valent

MenC

PS-PCV

*The diluent for MenA PS-

PCV contains alum adjuvant

and is freeze sensitive.

Cholerainactivated

Not

sensitive

Temperature Sensitivity Vaccines

12 Darin Zehrung

Next-Generation Vaccine Delivery

Technology Meeting

Geneva, Switzerland, Feb. 2014


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Many parameters influence the temperature ofthe formulation inside the BFS-container

DoE output

DoE input


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Overview/Index




IV. Methods


VI. Summary

VII. Literature


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Extruder

Temperature

regulator

Coolant:

5 x water

1x glycol

P&ID optimized for CoolBFS®


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1. Temperature measurement within the mould

(Thermocouples: Type K Ø 0.25mm / Type T Ø 0.5mm)

2. Temperature probes

(inside ampoule and surface)

(testo 935 & temperature probes TE type K)

3. IR Thermography

(IR Thermography Camera: Optris PI200)

Methods for temperature measurement insideand outside the container


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Ampoules with different filling volumes

• BFS-Equipment: bottelpack 3012

• Containers: 2,3 ml Ampules, 6 cavities

• Formulation: Water

• Materials: Two Purell LDPEs

• Thermocouples: Type K Ø 0.25mm /

Type T Ø 0.5mm

• IR Thermography Camera:

Optris PI200

74 mm

95 mm

Key experimental equipment


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Overview/Index




IV. Methods


VI. Summary

VII. Literature


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machine cycle

approx. 16 sec

Overview 3 cavities, 7 cycles


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machine cycle approx. 16 sec

Filling mandrels remove

(incl. thermocouples)

“Head space” temperature in empty ampoules

Drawback: Thermocouples

removed from product prior to

closing

Filling mandrels move down

(incl. thermocouples)

Filling time approx. 0.6 sec


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Piercing set-up (method 2)

Run 21/3a

In mould set-up

(method1)The combination

of two experimental

methods reveal the

temperature over

time profile


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Formulation Temperature 21°C 8°C 8°C

Filling Volume 1,3 ml 1,3 ml 1,7 ml

Wall Thickness 0,7 mm 0,7 mm 0,4 mm

Mould Cooling off on on

Product Temperature

(T after BFS) 39-41°C 24-26°C 13-15°C

Run 20/6 Run 20/20 Run 20/15

machine cycle approx. 16 sec machine cycle approx. 16 sec machine cycle approx. 16 sec

3 examples for main parameters


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Formulation

Temperature 8°C

Filling Volume 0.34 ml…1.67 ml

Wall Thickness 0.4 mm…0,7 mm

Mould &

Formulation

Cooling on

DoE data allows tailoring of temperature profiles


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rhDNase (Pulmozyme, Genentech) /14/

4 mg/ml formulation, 37°C for 15 min.

Visual inspection, ELISA, CD, UV SEC,

activity assay

Fully active, no aggregates, no permanent changes

to conformational states

2-year refrigerated stability verified

EPO (Erytropoetin, Epoetin-Beta) /15/

200 mycl with 500 bis 10`000 I.E.

BFS-Process with Purell 3020D

Visual inspection, ELISA, CD, UV SEC,

activity assay

Fully active, no aggregates, no permanent changes

to conformational states

2-year refrigerated stability verified

4 Biotec BFS drug products


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Attenuated Live-Virus Vaccines (flu vaccine and Rota-Virus vaccine) /15/

0.2 and 2.3 ml

BFS-Process with Purell 1840H

No statistically significant differences in stability

compared to conventional filled market products

(glass & LDPE container)

2-year (flu vaccine) & 1-year (Rota-Virus) stability

verified

Model monoclonal antibody

Catalent® Biologics Case Study:

Compatibility assessment of a model monoclonal

antibody formulation with ADVASEPT® and glass

container system

1. This study confirms compatibility of

monoclonal antibody formualtion in glass and

ADVASEPT® vial demontrating plastic BFS

vial suitability for for protein therapeutics.

2. Activity data indicates comparable potency

levels in Glass and ADVASEPT® vial.

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4 Biotec BFS drug products


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There is a biological product in BFS at the market sincesome years


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Overview/Index




IV. Methods


VI. Summary

VII. Literature


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• The filling of temperature sensitive

products is possible with an adapted

BFS machine.

• At time being this is not a generally

accepted statement, but must be

proofed on a case by case basis.

• A stringent QbD approach revealed the

most important parameters to deal with

heat sensitive products.

• Main influence parameters are container

design, fill volume, wall thickness and

formulation temperature.

• BFS can generate some advantages in

filling of Biological products.

YE

S i

t´s

po

ss

ible


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Overview/Index




IV. Methods


VI. Summary

VII. Literature


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1. Hanns-Christian Mahler, “ Development of Dosage Forms for Biologics “,

(LAK BW 2015)

2. Dingermann “Gentechnik Biotechnik”, WVG

3. Kayser/Müller (Hrsg) “Pharmazeutische Biotechnologie”, WVG, 1. Auflage,

2000

4. Mark Cornell Mannig et al., Stability of Protein Pharmaceuticals: An

Update, Pharmaceutical Research, Vol. 27, No. 4, Aoril 2010 (© 2010)

5. Hanns-Christian Mahler et al., Protein Aggregation: Pathways, Induction

Factors and Analysis, Journal of pharmaceutical sciences 98(9):2909-2934.

6. European Commission, EU Guidelines to Good Manufacturing Practice.

Annex 1, Manufacture of Sterile Medicinal Products (Brussels, Nov. 2008).

7. FDA, Guidance for Industry. Sterile Drug Products Produced by Aseptic

Processing – Current Good Manufacturing Practice (Rockville, MD, Sept.

2004).

8. EMA, Guideline on Plastic Immediate Packaging Materials (London, UK,

May 2005).

9. R. Oschmann, and O.E. Schubert, Eds, Blow-Fill-Seal Technology, (CRC

Press, Stuttgart, 1999).

10. B. Ljungqvist et al., PDA J. Pharm. Sci. Technol. 60 (4), 254-258 (2006).

11. Verjans, B. Reed, C. (2012). “Assessing Filling Technologies for

Contamination Risk.” Biopharm International. 25(3), pp. 46-58.

12. Darin Zehrung, Next-Generation Vaccine Delivery Technology Meeting

Geneva, Switzerland, Feb. 2014

13. Wei Liu et al. BioPharma International Vol 24,(7), July 2011, pp 22-30

14. Steven J. Shire in Rodney Pearlman, Y. John Wang (eds) Formulation,

Characterization and stability of protein drugs Vol 9: Case Histories, pp

393-422, Kluwer Academic Publishers, 2002

15. Otto E. Schubert, personal Communication Feb, 8, 2014

16. Gregory Bleck, Ph.D. Global Head R&D Biologics Madison, Wisconsin,

Biologics Case Study: Compatibility assessment of a model monoclonal

antibody formulation with ADVASEPT ® and glass container system, 2015

Catalent Pharma Solutions

17. Jeff Price, Heat Transfer Analysis of BFS Process, Annual Meeting

BFSIOA Boston Massachusetts 1998


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Thank you very

much for your

Attendance!


Filling of heat sensitive products / biologicals with BFS ... - BFS IOA€¦ · Training Seminar...

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