Michael W. Spallek, Johannes W. Geser and Otto E.

Schubert

Heat
effects
on
PDA:
A Global
sensitive formulations
Association
during
blow-fill-seal
processing

Michael Spallek et al. CoolBFS: Heat Effects

March 12, 2014

Heat effects on sensitive formulations during

blow-fill-seal (BFS) processing
Overview

1. Introduction - the BFS process

2. Objective of the study

3. Experimental set up
4. Results & Discussion
5. Summary
6. Literature

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Blow-fill-seal (BFS) is simple & straight forward.

BFS Process
Med. Grade
Polymer

Sterile Air

Sterile Air

Melting polymer &

extrusion of
parison with
sterile air

Transfer in mould
and cutting
(overpressure of
sterile air)

1.Sterile Air
2. Sterile Formulation

Container blow
moulding with
sterile air & filling

Sterile Air

Container closing

See Literature /1/- /5/

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Blow-fill-seal is a high temperature process that

relies on proper temperature management.
BFS Process and Key Temperatures

Melting polymer &

extrusion of parison

Transfer in mould & cutting

4-7 different
temperatures zones
of extruder

Mould
temperature

Container blow
moulding & filling

Formulation
temperature

Container closing

Container head
temperature
Essential for
tight containers

Die temperature
r

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Objective CoolBFS: How to manage heat &

temperatures for sensitive formulations ?
The Challenge

Liquid biotec formulations

e.g. attenuated live virus vaccines are
typically heat sensitive
Stability is a function of temperature
exposure over time
Simulations have a limited value only

See Literature /6/, /13/, /15/

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Heat effects on sensitive formulations during

blow-fill-seal (BFS) processing.
Overview

1. Introduction - the BFS process

2. Objective of the study

3. Experimental set up
4. Results & Discussion
5. Summary
6. Literature

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Many parameters influence the temperature of

the formulation inside the BFS-container.
Ishikawa Diagram
DoE input
DoE output

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A dedicated experimental set up was used.

Key Experimental Equipment

74 mm

95 mm

BFS-Equipment: bottelpack 312

Containers: 2,3 ml Ampules, 6 fold

Formulation: Water

Materials: Two Purell LDPEs

Thermocouples: Type K 0.25mm / Type T 0.5mm

IR Thermography Camera: Optris PI200

Ampoules with different filling volumes

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The 1st experimental set-up allowed direct in

line measurements during the BFS process.
Temperature Measurements within the Mould

Filling Mandrels
(here only three mandrels are installed)

Head Mould
Thermocouples
Type K 0.25mm
Main Mould

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The 2nd experimental set-up allowed fast and easy

measurements after the BFS process.
Ampoule Piercing

6 ampoules

Thermocouples Type T 0.5mm

Simultaneous piercing by needle

Simultaneous insertion of
thermocouples through needles

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Heat effects on sensitive formulations during

blow-fill-seal (BFS) processing
Overview

1. Introduction - the BFS process

2. Objective of the study

3. Experimental set up
4. Results & Discussion
5. Summary
6. Literature

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The in-line measurements were well reproducible

during the BFS-cycles and for the different cavities.
Overview: 3 cavities, 7 cycles
machine cycle
approx. 16 sec

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The In-line temperature data is meaningful.

Head space temperature in empty ampoules
machine cycle approx. 16 sec

Drawback: Thermocouples
removed from product prior to
closing

Filling time approx. 0.6 sec

Filling mandrels remove

(incl. thermocouples)
Filling mandrels move down
(incl. thermocouples)

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Main parameters are formulation temperature,

filling volume and wall thickness.
3 Examples
machine cycle approx. 16 sec

machine cycle approx. 16 sec

Formulation Temperature
Filling Volume
Wall Thickness
Mould Cooling
Product Temperature
(T after BFS)

machine cycle approx. 16 sec

21C

8C

8C

1,3 ml

1,3 ml

1,7 ml

0,7 mm

0,7 mm

0,4 mm

off

on

on

39-41C

24-26C

13-15C

Run 20/6

Run 20/20

Run 20/15

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The combination of the two experimental methods

reveal the temperature over time profile.
In mould set-up
(method1)

Piercing set-up (method 2)

Run 21/3a

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Design of experiments data allow tailoring of

temperature profiles.
DoE response curve (Example)

Formulation
Temperature

8C

Filling Volume

0.34 ml1.67 ml

Wall Thickness

0.4 mm0,7 mm

Mould & Formulation

Cooling

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The 3rd method , IR thermography, shows the

local temperature distribution.
IR Thermography (method 3)

Thermocouples
(method 2)

Head portion 36C

Temp of the liquid:
16 C
confirmed by
inserted
thermocouple
(piercing method)

Fill 16C

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Drug product stability data confirm the validity of

the CoolBFS approach.
BFS compatibility results

BFS Compatibility Testing

rhDNase (Pulmozyme, Genentech) /14/

4 mg/ml formulation, 37C 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

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
r

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CoolBFS: Parameters affecting the product

temperature are understood an can be tailored.
Summary

Dedicated experiments (3 methods) allow direct

temperature monitoring as a function of time and
location.

The maximum product temperature stays less

than a few minutes.

The maximum product temperature can be limited

to the range of
25-35oC without or
15-25oC with auxiliary cooling system.

When container design & material is given, key

influencing parameters are fill volume, wall
thickness and formulation temperature.

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Heat effects on sensitive formulations during

blow-fill-seal (BFS) processing
Literature
1.

2.

3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.

15.

European Commission, EU Guidelines to Good Manufacturing Practice.

Annex 1, Manufacture of Sterile Medicinal Products (Brussels, Nov.
2008).
FDA, Guidance for Industry. Sterile Drug Products Produced by Aseptic
Processing Current Good Manufacturing Practice (Rockville, MD,
Sept. 2004).
EMA, Guideline on Plastic Immediate Packaging Materials (London,
UK, May 2005).
R. Oschmann, and O.E. Schubert, Eds, Blow-Fill-Seal Technology,
(CRC Press, Stuttgart, 1999).
B. Ljungqvist et al., PDA J. Pharm. Sci. Technol. 60 (4), 254-258
(2006).
Jeff Price, Heat Transfer Analysis of BFS Process, Annual Meeting
BFSIOA Boston Massachusetts 1998
Sundstrm, S., et al., European Journal of Parenteral & Pharmaceutical
Sciences, Vol. 15, No. 3, pp. 87-92 (UK, 2010).
Sundstrm, S., et al., European Journal of Parenteral & Pharmaceutical
Sciences, Vol. 15, No. 1, pp. 5-11 (UK, 2010).
Sundstrm, S., et al., PDA Journal of Pharmaceutical Sciences and
Technology, Vol. 63, No. 1, pp. 71-80 (UK, 2010).
Martin Haerer and Urs Lichtenstein, European Journal of Parenteral
Sciences, Vol. 2, No. 4, pp. 119-121 (UK, 1997).
Ljungqvist B., et al., PDA Journal of Pharmaceutical Sciences and
Technology, Vol. 60, No. 4, pp. 254-258 (UK, 2006).
Trevor Deeks, Pharmaceutical Technology Europe, No: 0384 (UK,
1999)
Wei Liu et al. BioPharma International Vol 24,(7), July 2011, pp 22-30
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
Otto E. Schubert, personal Communication Feb, 8, 2014

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