Michael W. Spallek, Johannes W. Geser and Otto E. Schubert
Heat effects on PDA: A Global sensitive formulations Association during blow-fill-seal processing
r
Michael Spallek et al. CoolBFS®: Heat Effects
March 12, 2014
Heat effects on sensitive formulations during blow-fill-seal (BFS) processing Overview
1. Intr Introd oduc ucti tion on - the the BFS BFS pro proce cess ss 2.
Objective of of th the st study
3.
Experimental set up
4.
Resu esults & Discussion
5.
Summary
6.
Literature
r
Michael Spallek et al. CoolBFS®: Heat Effects
March 12, 2014
2 of 20
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/
r
Michael Spallek et al. CoolBFS®: Heat Effects
March 12, 2014
3 of 20
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
Michael Spallek et al. CoolBFS®: Heat Effects
March 12, 2014
4 of 20
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/
r
Michael Spallek et al. CoolBFS®: Heat Effects
March 12, 2014
5 of 20
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
r
Michael Spallek et al. CoolBFS®: Heat Effects
March 12, 2014
6 of 20
Many parameters influence the temperature of the formulation inside the BFS-container. Ishikawa Diagram DoE input DoE output
r
Michael Spallek et al. CoolBFS®: Heat Effects
March 12, 2014
7 of 17
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 Ø 0.25mm / Type T Ø 0.5mm
•
IR Thermography Camera: Optris PI200
Ampoules with different filling volumes
r
Michael Spallek et al. CoolBFS®: Heat Effects
March 12, 2014
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 Ø 0.25mm Main Mould
r
Michael Spallek et al. CoolBFS®: Heat Effects
March 12, 2014
The 2nd experimental set-up allowed fast and easy measurements after the BFS process. Ampoule Piercing
r
•
6 ampoules
•
Thermocouples Type T Ø 0.5mm
•
Simultaneous piercing by needle
•
Simultaneous insertion of thermocouples through needles
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
r
Michael Spallek et al. CoolBFS®: Heat Effects
March 12, 2014
11 of 20
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
r
Michael Spallek et al. CoolBFS®: Heat Effects
March 12, 2014
12 of 20
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)
r
Michael Spallek et al. CoolBFS®: Heat Effects
March 12, 2014
Main parameters are formulation temperature, filling volume and wall thickness. 3 Examples machine cycle approx. 16 sec
machine cycle approx. 16 sec
Formulation Temperature
machine cycle approx. 16 sec
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
off
on
on
39-41°C
24-26°C
13-15°C
Run 20/6
Run 20/20
Run 20/15
Mould Cooling Product Temperature (T after BFS)
r
Michael Spallek et al. CoolBFS®: Heat Effects
March 12, 2014
14 of 20
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
r
Michael Spallek et al. CoolBFS®: Heat Effects
March 12, 2014
15 of 20
Design of experiments data allow tailoring of temperature profiles. DoE response curve (Example)
Formulation Temperature
8°C
Filling Volume
0.34 ml…1.67 ml
Wall Thickness
0.4 mm…0,7 mm
Mould & Formulation Cooling
r
Michael Spallek et al. CoolBFS®: Heat Effects
on
March 12, 2014
16 of 20
The 3rd method , IR thermography, shows the local temperature distribution. IR Thermography (method 3)
Thermocouples (method 2)
Head portion 36°C Temp of the liquid: 16 C confirmed by inserted thermocouple (piercing method)
Fill 16°C
r
Michael Spallek et al. CoolBFS®: Heat Effects
March 12, 2014
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, 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
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
Michael Spallek et al. CoolBFS®: Heat Effects
March 12, 2014
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.
r
Michael Spallek et al. CoolBFS®: Heat Effects
March 12, 2014
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.
r
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 Sundström, S., et al., European Journal of Parenteral & Pharmaceutical Sciences, Vol. 15, No. 3, pp. 87-92 (UK, 2010). Sundström, S., et al., European Journal of Parenteral & Pharmaceutical Sciences, Vol. 15, No. 1, pp. 5-11 (UK, 2010). Sundström, 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 Hi stories, pp 393-422, Kluwer Academic Publishers, 2002 Otto E. Schubert, personal Communication Feb, 8, 2014
Michael Spallek et al. CoolBFS®: Heat Effects
March 12, 2014
20 of 20
