Quality / Compliance

Supply Reliability

Cost / Cash /Value

Compromise to quality and compliance is not an option

A peek into lyophilization at PfizerJim Searles, Ph.D.

Technical FellowGlobal Technology Services, Pfizer Global Supply

Pfizer CentreOne Symposium, AAPS National Meeting, Denver, CO 15 Nov 2016

• Pfizer Lyo Network overview• A new mechanism for vial breakage elucidated using

strain gauges

2

Outline

The main goal is to deliver business value in freeze-drying– Support process transfer and optimization– Develop and implement cost-sparing and process

enabling PAT tools, formulations, and freeze-drying alternatives

– Provide high-value training– Enhance communications across the Network

• Company-wide including R&D as well as manufacturing globally

3

Pfizer Lyo Network charter

Over 270 colleagues United States – Andover, Collegeville, Groton, Kalamazoo, McPherson,

Pearl River, Peapack, San Diego, Sanford, St. Louis, Lake Forest Australia – Melbourne Belgium - Puurs Canada - Montreal China – Wuxi, Hsinchu, India – Chennai, Vizag, Ahmedabad Ireland – Grange Castle Italy – Catania, Liscate Spain – Algete United Kingdom – Sandwich

4

Where are PLN colleagues located?

• Monthly seminar (anyone can listen/watch, speakers can be from anywhere)

• Subteams• Email forum• Best practices• Problem solving• Advanced technologies• LyoSchool• Bridge R&D and MFG

5

Major activities

Contributions to:− Lyo Hub (Lyo Consortium):

Develop a technology roadmap – activity initiated with industry, FDA, and academia colleagues

Draft a Best practices document on process instrumentation− BioPhorum (LyoPAT team) – Implement current technologies

(PAT tools implementation, Modeling in process design and scale up)

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External memberships and conference contributions

Conferences− AAPS National Meeting− AAPS National Biotechnology Conference− Freeze-Drying of Pharmaceuticals and Biologicals (Breckenridge

and Garmisch)− CHI PepTalk− CHI Bioprocessing Summit− ECA Lyophilization Conference− ISL-FD− PDA Europe− SMi Lyophilization USA Conference− SP Scientific Webinar Series

7

External memberships and conference contributions

Quality / Compliance

Supply Reliability

Cost / Cash /Value

Compromise to quality and compliance is not an option

Elucidating vial breakage mechanisms during lyo cycle

optimization using strain gaugesJim Searles, Ekneet Sahni and Dina Lyne

Global Technical Services, Pfizer Global Supply, McPherson, KS

8

• Problem: Extensive vial breakage while attempting to optimize a lyo cycle

• Approach: Implement strain gauges in the lab to confirm the breakage mechanism

• Published works:– Craig et al. (2004 presentation): Strain gauges during

lyophilization (first published/presented work)– Milton et al. (2007): Strain due to crystallization of NaCl– Jiang et al. (2007a):Strain due to mannitol crystallization– Jiang et al. (2007b): Strain due to “break-free” event during

freezing

9

Background

10

Example Lyo Cycle

SHELF INLET T SHELF_SP TC04 TC05 TC06 TC07 TC08 CHAMBER_CM CHAMBER PIRANI CONDENSER P VACUUM_SP

Time

Tem

pera

ture

(C)

Pres

sure

(mTo

rr)

Sridhar Aravapalli

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Extreme Breakage

-30 -25 -20 -15 -10 -5 00

5

10

15

20

25

30

35

40

45

50Thinner Vials, ProcessedThicker Vials, ProcessedThinner Vials, Not Processed

Product Temperature Early in Primary Drying (C)

# Br

oken

Via

ls (5

0 to

tal p

er ru

n)

with Mark Nachtigall

• Stress (σ) = Force/ Area (units of pressure)• Strain (Ɛ)= Dimension Change/Original Dimensions

(dimensionless)

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Strain vs. Stress

Pfizer Confidential. For Internal Use Only.

Strain gauge

Strain gauges purchased from Micro Measurements and Kyowa. Instrument purchased from Micro Measurements

Freeze Thaw: 0.1 C/min to -45 C,⁰3 breakages

Freeze Thaw ̶ Comparison of Horiz SG for freezing temps: 0.1 C/min, -25 C and -45 C⁰ ⁰

• Strain gauged vials can be used in development of formulations and process cycles to insure acceptably low levels of strain and reduce or eliminate vial breakage.

• Strain gauged vials are useful for troubleshooting and remediation of manufacturing issues.

• For this product, vial breakage occurred during re-warming, not freezing.

Conclusions

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• Hirakura Y, Kojima S, Okada A, Yokohama S, Yokota S. (2004) Int J Pharm 286:53–67.

• Gordon D. Craig, Mark Moreno, Dinesh Mishra, Nathaniel Milton, Michael Roy, Lian Yu (2004) Presentation at Breckenridge Protein Stability Conference, Breckenridge, CO, July 28 – 31

• Milton, N., Gopalrathnam, G., Craig, G.D., Mishra, D.S., Roy, M.L. and Yu, L. (2007) J. Pharm. Sci., 96: 1848–1853.

• Ge Jiang, Mike Akers, Manish Jain, Jeremy Guo, Adrian Distler, Rob Swift, Manpreet-Vick S. Wadhwa, Feroz Jameel, Sugu Patro, and Erwin Freund (2007a) PDA J Pharm Sci Technol 61:441-451

• Ge Jiang, Mike Akers, Manish Jain, Jeremy Guo, Adrian Distler, Rob Swift, Manpreet-Vick S. Wadhwa, Feroz Jameel, Sugu Patro, and Erwin Freund (2007b) PDA J Pharm Sci Technol 61:452-460

References