Advances in the Microbial Control for Biopharmaceutical ...
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FDA / PQRI Conference on Evolving Product Quality
Bethesda, MD September 16 - 17, 2014
Ed Balkovic, Ph.D. SME Microbiologist - Contamination Control
Genzyme - a Sanofi company
Framingham, MA
508-271-3660
edward.balkovic@genzyme.com
Advances in the Microbial Control for Biopharmaceutical Production
“The views and opinions expressed in this presentation are those of the presenter and should not be attributed to Genzyme Corporation or Sanofi, their directors, officers or employees. This presentation includes intellectual property that belongs to the presenter, to Genzyme Corporation and to third parties which is protected under the copyright, trademark and other laws of the United States of America and other countries. All rights are reserved.”
DISCLAIMER
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After completion of this presentation, you should be able to:
See the limitations of earlier biologics production methods
Recognize the potential sources for microbial contamination
Understand the improvements made in microbial control
within upstream, downstream, and fill / finish operations
Appreciate the advances made in detection and
identification systems for microbes encountered in
biopharmaceutical production environment
LEARNING OBJECTIVES
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USP <1115> BIOBURDEN CONTROL OF NONSTERILE DRUG SUBSTANCES AND PRODUCTS
POTENTIAL SOURCES OF MICROBIAL CONTAMINATION
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POTENTIAL SOURCES OF MICROBIAL CONTAMINATION
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FROM: K. Suvarna et al. Am. Pharm. Rev. 2011
POTENTIAL SOURCES OF MICROBIAL CONTAMINATION
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FROM: K. Suvarna et al. Am. Pharm. Rev. 2011
Old Biologics Facilities - Out in the Country
Different biologic products manufactured in separate buildings
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FACILITY DESIGN, CONSTRUCTION, OPERATIONS
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Integrated, Technically Advanced Modern Facilities:
Sophisticated HVAC Systems with Controlled Air Flow
Design meets Material and Personnel Work Flow needs
Complex Treatment Systems to produce Pharmaceutical Waters
Comprehensive Contamination Control Program
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Laminar flow
HOW DO MICROBES GET INTO OUR MANUFACTURING ENVIRONMENT?
Air
Personnel
Raw Materials & Components
Water
Equipment
Cleanroom or other Controlled Environments
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POTENTIAL SOURCES OF MICROBIAL CONTAMINATION
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FROM: K. Suvarna et al. Am. Pharm. Rev. 2011
OVERVIEW BIOPHARM PRODUCTION PROCESS
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Laenen, L, et al. Am. Pharm Rev. Dec 2012
UPSTREAM DOWNSTREAM FILL/FINISH
Filling the vaccine bottles
before freeze-drying, one of the
final steps in smallpox vaccine
production - WHO photo
FILL / FINISH OPERATION IMPROVEMENTS
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VISION OF FUTURE BIOMANUFACTURING PLATFORM
27 FROM: Chris Hwang, Genzyme Presentation at PDA Mtg. 2014
UPSTREAM DOWNSTREAM
FULLY CONTINUOUS BIOMANUFACTURING PLATFORM
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Bioreactor
ATF Cell Retention
Media Feed
Vessel
4-C
olu
mn
PC
C
Columns
4-C
olu
mn
PC
C
Columns
mem
bra
ne
Viral inactivation
In-line buffer adjustment
Unformulated Drug Substance
Break tank
In-line buffer adjustment
MAb Process
FROM: Chris Hwang, Genzyme Presentation at PDA Mtg. 2014
• Cycle time: 22hrs from media to DS (12hrs Upstream + 10hrs downstream)
• Fully automated continuous operations for > one month
• In-process performance monitored by UV, pH, conductivity, pressure and flow rates
• Consistent chromatographic profiles and CQA’s meet spec
POTENTIAL SOURCES OF MICROBIAL CONTAMINATION
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FROM: K. Suvarna et al. Am. Pharm. Rev. 2011
PERSONNEL – MAJOR SOURCE OF CONTAMINATION
“It is safe to assume that the operator is always
contaminated.”
“An operator is really a ‘mobile contamination
generator.”
“The more intensely we ask operators to work, the
more likely they are to contaminate the
environment.”
Jim Akers Principal of Akers, Kennedy, and Associates Chair of Microbiology and Sterility Assurance Committee for USP
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ADVANCES IN STERILITY TESTING
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Sterility Testing being performed
using Laminar Flow Hoods
Sterility Testing being performed
in Isolator Systems
ADVANCES IN MICROBIAL DETECTION
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ATP Bioluminescence
Direct Rapid Detection Methods
Rapid Detection of Bacterial Endotoxins
Quantitative LAL results within 15 minutes
Results within 5 - 90 minutes
based on the system
ADVANCES IN MICROBIAL DETECTION
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Growth Enhanced Rapid Detection Methods
Detection Time reduced to
24 – 72 Hours
ADVANCES IN MICROBIAL IDENTIFICATION
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Genotypic Characterization
16S rRNA Sequencing
Matrix-Assisted Laser Desorption Ionization Time of Flight Mass Spectrometry
(MALDI-TOF MS)
Proteotypic Characterization
After completion of this presentation, you should be able to:
See limitations of early biologic production methods
Identify potential sources for microbial contamination
Understand improvements made in microbial control within
upstream, downstream, and fill / finish operations
Appreciate advances made in detection and
identification of microbes encountered in
biopharmaceutical production environment
REVIEW ----- LEARNING OBJECTIVES
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