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Reason cause For Major Batch Failures in BIO pharmaceutical Industry
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Prepared by: Sandip Patel Group No: 2Hemin ShahMunir ShahHiren PatelParesh PatelRajeshkumar Patel
Introduction Sources and type of contamination How contamination can be
controlled? Emerging technologies or
procedures to improve yield Example of batch failure Conclusion Reference
Complex biopharmaceutical process Factor affecting cost
(source) ([9] Seymour, May 22, 2006) ([8] Scott M. Wheelwright)
Huge investment wants profit
(source) ([4] Langer, Aug 1 2008 (Vol. 28, No. 14))
Batch failureCauses
Statistics
(source)([4] Langer, Aug 1 2008 (Vol. 28, No. 14))
Consequences Most Obvious Less Obvious
Major cell contaminants Biological Chemical
Contaminant General Indications Microscopic Appearance Common Source
Bacteria pH change
Turbidity/Cloudiness
Precipitation
Fine Granules Cell culturist
Water bath
Yeast Cloudiness
pH change
Oval organisms
Budding/chains
Airborne
Fungus Spores
Furry Growths
pH change
Thin spores Airborne
Mycoplasmas Often covert
Poor cell adherence
Reduced growth
- Cell culturist
Other cell lines
Virus Sometimes cytopathic - Serum
Cell lines
• Protozoa• Invertebrates
Source: Reference [3]
Source: Reference [18]
# Culture Tested # Positive
Netherlands 1,949 488 (25%)
Czechoslovakia 327 121 (37%)
Argentina 65%
Japan 80+%
Israel 32%
# Cultures Tested # Positive
FDA (1970’s to 1990’s) (11)
20,000 Cultures Tested
Over 3000 (15%)
Bionique Testing Laboratory (several years prior to 1993) (41)
11,000 Culture Tested 1218 (11.1%)
Microbiological Associates (1985 to 1993) (13)
2,863 Culture Tested
370 (12.9%)
American Type Culture Collection (ATCC) (1989 to 1994) (42)
5,362 Culture Tested 752 (14%)
Source: Reference [7]
Contact with non sterile supplies, media or solutions. Improper sterilization Use of membrane filtration.
Airborne particles and Aerosols Equipment and Activities Laboratory Personnel
Source: www.smart-publications.com
Growing and crawling In to cultures. Top and Bottom
side walk of Dish
•Fohn Ryan, “Understanding and Managing Cell Culture Contamination,” Corning Incorporated, Corning, NY, Report No. CLS-AN-020 Rev. 2, March 8, 2008
Cross contamination from other cell cultures. Accidents Actual case demonstration
Media Major source. How they enter? Prevention
Water Leaching of metal ions, organic and
inorganic compounds. Deposition of water on instrument Prevention
SERA Sources Uncontrollable variation of
sera components Prevention
Storage vessels Material of construction Leaching Prevention: 316L stainless
steel http://www.pharmaceutical-machines.com/gifs/storage-vessel.jpg
Fluorescent Lights Exposure of media HEPES (N-[2-hydroxylethyl] piperazine-N’-
[2-ethanesulfonic acid]) – an organic buffer Production of hydrogen peroxide and free
radicals Incubators
Chemical and biological contamination source
Toxic and volatile impurities
Good Aseptic Techniques
Good Aseptic Techniques
Strategic Use of Antibiotics
Strategic Use of Antibiotics
Strategic Use of Cell Repository
Strategic Use of Cell Repository
Good Housekeeping by Everyone
Good Housekeeping by Everyone
Understanding Nature of Contamination
Understanding Nature of Contamination
Contamination Controlling Program
Contamination Controlling Program
Building Blocks for successfully managing cell culture contamination [7]
Use of good aseptic technique
Use good aseptic techniques
Reduce accidents
Keep the laboratory clean
Routinely monitor for contamination
Use frozen cell repository strategically
Use antibiotics sparingly if at all
Steps for Reducing Contamination Problems Source: Reference [7]
Vented cap flasks greatly reduce the opportunities for contamination in culture systems requiring gas exchangeSource: Reference [7]
Reduce opportunities for accidents Proper labeling Written protocol Identification and causes of contaminants
Clean up the work area and surroundings Periodical cleaning and lower level of
particulates Removal of waste materials Proper maintenance of equipment Paste control program
Sterility testing Routine monitoring of supplies Sterilization of equipments Microscopic observation of media Karyotyping, DNA fingerprinting,
Electrophoresis and immunological techniques
Detection of chemical contaminants
Strategic Use of a Frozen Cell Repository A cryogenic cell
repository Strategic use of
antibiotics Use of antibiotics Drawback of long term
and continuous use of antibiotic
Source: biorep.sevenlab.net
Implementation of single use systems Pre-sterilized assembly Reduced risk of contamination
Element Technology use Addition information Company
Disposable sensor oxygen, pH, and carbon dioxide sensors (fluromatrix technology)
LEDs & photo-detectors.
Inexpensive, useful for FDA imitative technology
Sartorius Biotechnology
Mixing Single Use Mixer Levitate and drive a disposable impeller inside a single-use bag. Scalability and reduced contamination, operating costs, and downtime associated with cleaning and validation of conventional mixing systems.
LevTech, Hyclone
Bag Flexel 3-D bag system Reduce contamination Applikon, SAFC Biosciences
Sterile sampling Integrated one-way valve that prevents any of the withdrawn cell culture media sample returning to the main bioreactor.
Reduce contamination Cellexus Sample
Disposable with Latest technologies Source: Reference [16]
New Disposable Filling System Source: Reference [11]
Rapid Molecular Method Testing standard during production Emerging as the gold standard for
contaminant and impurity analysis Based on polymer chain reactions If positive result, identify the exact
amount of mycoplasma.
Other latest tools for prevention of batch failure PAT(Process Analytical Technology)
Real-time, on-location measurement of quality control parameters.
Examples: Personal Scanning Electron Microscope (PSEM), technology by Millipore, rapid automated microbiological testing technologies
QbD (Quality by Design) “Quality cannot be tested into products; it has
to be built in by design” Approach Used to create Robust Manufacturing Process.
Other latest tools for prevention of batch failure Risk management and the CAPA
Identification of risks Classifying different types of impact Next step corrective and preventive
action FMEA (Failure Modes Effect Analysis)
Identification of effect on failure Preventive action
Production of EPO erythropoietin Serious failures in manufacturing
like QC failures for the batch Concern about the safety
Problem like Glycosylation and its control Change in manufacturing conditions
and parameters
True batch failure: final specification
False batch failure: wrong identification of aberrant glycosylation
Safety compromised: Aberrant glycosylation
Non standard efficacy: abnormal glycosylation
Solution Understand the structure and glycosylation
in life cycle Molecular specification
Structural activity relationship and other drug designing documents
Measurement specification Measurement of glycosylation parameters
Review and Modify at regular interval Parameters
Appropriate glyco analysis method Monosaccharide profile Oligosaccharide profile Glycosylation site profile Glycoform profile
Different causes of failure Large organization Small and medium organization
Eric S. Langer, “Biotech Facilities Average a Batch Failure Every 40.6 Weeks,” Bioprocess Internaional, September 2008.
By Dr Daryl Fernandes, Founder and CEO of Ludger Ltd., “Reducing Risk in Biopharmaceutical Production by Controlling Glycosylation,” European Biopharmaceutical Review, Winter 2004, pp 92 - 97.
Simon P. Langdon, “Cancer Cell Culture: Methods and Protocols,” Chap. 7, Page no. 310, Humana Press.
Eric S. Langer, “Batch Failure Rates in Biomanufacturing,” Genetic Engineering and Biotechnology News, Vol. 28, No. 14, Aug 1 2008.
Carolyn Kay Lincoln, “Cell Culture Contamination, Is It Just Mycoplasma?,” Bionique Testing Laboratories, Inc., USA, January 24, 2006.
David B. Prescott, “Methods in Cell Biology,” Chap. 6, Page No. 144-201, Vol. VI, Academic Press Inc.
Fohn Ryan, “Understanding and Managing Cell Culture Contamination,” Corning Incorporated, Corning, NY, Report No. CLS-AN-020 Rev. 2, March 8, 2008
Scott M. Wheelwright, Ph.D., “Cost drivers for the biopharmaceutical,” Strategic Manufacturing Worldwide, available on:biog.berkeley.edu/cbo/uploads/ADMIN/UCB%2017Oct07%20SMW%20v2.ppt
Patricia Seymour, “Successfully Managing Biopharmaceutical Manufacturing Outsourcing,” Pre-Conference Workshop, IQPC 4th Annual Contract Manufacturing Forum, BioProcess Technology Consultants, Inc. Acton, MA, May 22, 2006.
Ramon Rivera Gonzalez, “Quality and Compliance Challenges for Biopharmaceutical Products,” USA: Amgen Manufacturing, Limited, available on: www1.uprh.edu/micro/proyectos/BIOTECH2007.ppt
John Boehm, “A Next Step in Implementing Disposables: Transfer Lines,” BioPharm International Supplements, Nov 2, 2007 http://biopharminternational.findpharma.com/biopharm/article/articleDetail.jsp?id=473326&sk=&date=&pageID=3
Marie Vicéns, PhD, “Contamination Control | Make Contamination Detection Automatic,” Pharmaceutical formulation and Quality, by John Wiley & Sons. Inc, December/January 2009.
Kazutomo Yokoya Kdm Communications Bedford, UK, “Early Detection in Drug Production,” PharmaAsia, January 01, 2009.
Don Straus, “Rapid micro tests can improve quality and efficiency,” Carpe Diem-A Wiley Co., 111 River Street, Hoboken, NJ 07030, April 25, 2009.
Gail Dutton, “In-Line Analytics Improve Manufacturing,” Genetic Engineering & Biotechnology News, Vol. 28, No. 15, Sep 1, 2008.
“Disposable Bioreactors Gaining Favor,” Genetic Engineering & Biotechnology News, Vol. 26, No. 12, Jun 15 2006.
Peter K. Kang, PhD, “Trends in Contamination Control,” Pharmaceutical Processing, 2009, available on:http://www.pharmpro.com/ShowPR.aspx?PUBCODE=021&ACCT=0000100&ISSUE=0707&RELTYPE=PR&ORIGRELTYPE=ATO&PRODCODE=0000&PRODLETT=M&CommonCount=0
Yih-Horng Shiao, Ph.D, “Identification and Elimination of Contaminations in Cell Culture and Polymerase Chain Reaction Laboratories,” Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Maryland, USA, June 25, 2005.