Advances in the Microbial Control for Biopharmaceutical ...

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

[email protected]

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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FROM: K. Suvarna et al. Am. Pharm. Rev. 2011

http://eofdreams.com/data_images/dreams/river/river-02.jpg



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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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OVERVIEW BIOPHARM PRODUCTION PROCESS

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Laenen, L, et al. Am. Pharm Rev. Dec 2012

UPSTREAM DOWNSTREAM FILL/FINISH


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UPSTREAM

CLASSICAL SMALLPOX VACCINE PRODUCTION

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INFLUENZA VACCINE PRODUCTION

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CELL CULTURE DERIVED BIOPHARMACEUTICALS

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Class 100 - BSC

COMMERCIAL BIOREACTORS

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Need for CIP / SIP

COMPLEXITIES IN CLEANING / DISINFECTING

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PROCESS IMPROVEMENTS

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Sterile Sampling Systems

Disposable Filter Capsules

Aseptic Tube Welders

COMMERCIAL BIOREACTORS (SINGLE USE)

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DOWNSTREAM

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YELLOW FEVER VACCINE PRODUCTION

DOWNSTREAM PURIFICATION IMPROVEMENTS

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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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http://ihm.nlm.nih.gov/luna/servlet/detail/NLMNLM~1~1~101437243~141412:Filling-the-vaccine-bottles-before-


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UPSTREAM DOWNSTREAM

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


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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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PROPER ATTIRE

Typical Lab Environment Clean Room – class 100

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PROPER GOWNING PROCEDURES

X

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PROPER CLEAN ROOM BEHAVIOR

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ADVANCES IN MICROBIAL DETECTION AND IDENTIFICATION

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TYPICAL QC MICROBIOLOGY LABORATORY

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Classical Growth Methods Late 1800’s

Early 1900’s

ADVANCES IN STERILITY TESTING

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Sterility Testing being performed

using Laminar Flow Hoods

Sterility Testing being performed

in Isolator Systems

VIABLE AIR SAMPLING

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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

TYPICAL QC MICROBIOLOGY LABORATORY

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Phenotypic Characterization Classical Growth Methods

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

FUTURE FOR MICROBIAL DETECTION & IDENTIFICATION

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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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THANK YOU

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Advances in the Microbial Control for Biopharmaceutical ...

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