Bio Pharm The Science & Business of Biopharmaceuticals INTERNATIONAL www.biopharminternational.com INTERNATIONAL BioPharm International DECEMBER 2015 Bespoke Bioprocessing Resins I Quality Testing of Biotherapeutics I Rapid Mycoplasma Testing Volume 28 Number 12 December 2015 Volume 28 Number 12 MOVING UP THE BIOPHARMA CAREER LADDER LYOPHILIZATION QUANTITATIVE POST-PROCESSING CHARACTERIZATION TECHNIQUES FOR FREEZE-DRIED PRODUCTS PEER-REVIEWED VARIABLE PATHLENGTH FIBER- OPTIC SPECTROPHOTOMETRY FOR PROTEIN DETERMINATION IN IMMUNOGLOBULIN CONCENTRATES REGULATIONS GMP CHALLENGES FOR ADVANCED THERAPY MEDICINAL PRODUCTS
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BioPharmThe Science & Business of Biopharmaceuticals
INTERNATIONAL
www.biopharminternational.com
INTERNATIONAL
Bio
Ph
arm
Intern
atio
nal
DEC
EM
BER 2
015
B
esp
oke
Bio
pro
cessin
g R
esin
s I Qu
ality
Testin
g o
f Bio
thera
peu
tics I R
ap
id M
yco
pla
sma T
estin
g
Vo
lum
e 2
8 N
um
ber 1
2
December 2015
Volume 28 Number 12
MOVING UP THE
BIOPHARMA
CAREER LADDER
LYOPHILIZATION
QUANTITATIVE POST-PROCESSING
CHARACTERIZATION TECHNIQUES
FOR FREEZE-DRIED PRODUCTS
PEER-REVIEWED
VARIABLE PATHLENGTH FIBER-
OPTIC SPECTROPHOTOMETRY
FOR PROTEIN DETERMINATION
IN IMMUNOGLOBULIN
CONCENTRATES
REGULATIONS
GMP CHALLENGES FOR
ADVANCED THERAPY
MEDICINAL PRODUCTS
www.tosohbioscience.com
Tosoh Bioscience and TOYOPEARL are registered trademarks of Tosoh Corporation.
Tom Ehardt, EVP & Senior Managing Director, Life Sciences Tom Mahon, Senior VP, Finance Georgiann DeCenzo, EVP & Managing Director, UBM Medica Mike Alic, EVP, Strategy & Business Development Dave Esola, VP & Managing Director, Pharm/Science Group Johanna Morse, VP & Managing Director, CBI/IVT Becky Turner Chapman, VP & Managing Director, Veterinary Group Joy Puzzo, VP, Marketing & Audience Development Francis Heid, VP, Media Operations Jamie Scott Durling, Director, Human Resources
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EDITORIAL ADVISORY BOARDBioPharm International’s Editorial Advisory Board comprises distinguished specialists involved in the biologic manufacture of therapeutic drugs, diagnostics, and vaccines. Members serve as a sounding board for the editors and advise them on biotechnology trends, identify potential authors, and review manuscripts submitted for publication.
K. A. Ajit-Simh President, Shiba Associates
Rory Budihandojo Director, Quality and EHS Audit
Boehringer-Ingelheim
Edward G. Calamai Managing Partner
Pharmaceutical Manufacturing
and Compliance Associates, LLC
Suggy S. Chrai President and CEO
The Chrai Associates
Leonard J. Goren Global Leader, Human Identity
Division, GE Healthcare
Uwe Gottschalk Vice-President,
Chief Technology Officer,
Pharma/Biotech
Lonza AG
Fiona M. Greer Global Director,
BioPharma Services Development
SGS Life Science Services
Rajesh K. Gupta Vaccinnologist and Microbiologist
Jean F. Huxsoll Senior Director, Quality
Product Supply Biotech
Bayer Healthcare Pharmaceuticals
Denny Kraichely Associate Director
Johnson & Johnson
Stephan O. Krause Director of QA Technology
AstraZeneca Biologics
Steven S. Kuwahara Principal Consultant
GXP BioTechnology LLC
Eric S. Langer President and Managing Partner
BioPlan Associates, Inc.
Howard L. Levine President
BioProcess Technology Consultants
Herb Lutz Principal Consulting Engineer
Merck Millipore
Jerold Martin Independent Consultant
Hans-Peter Meyer Lecturer, University of Applied Sciences
and Arts Western Switzerland,
Institute of Life Technologies.
K. John Morrow President, Newport Biotech
David Radspinner Global Head of Sales—Bioproduction
Thermo Fisher Scientific
Tom Ransohoff Vice-President and Senior Consultant
BioProcess Technology Consultants
Anurag Rathore Biotech CMC Consultant
Faculty Member, Indian Institute of
Technology
Susan J. Schniepp Fellow
Regulatory Compliance Associates, Inc.
Tim Schofield Senior Fellow
MedImmune LLC
Paula Shadle Principal Consultant,
Shadle Consulting
Alexander F. Sito President,
BioValidation
Michiel E. Ultee Principal
Ulteemit BioConsulting
Thomas J. Vanden Boom VP, Biosimilars Pharmaceutical Sciences
Pfizer
Krish Venkat Managing Partner
Anven Research
Steven Walfish Principal Scientific Liaison
USP
Gary Walsh Professor
Department of Chemical and
Environmental Sciences and Materials
and Surface Science Institute
University of Limerick, Ireland
4 BioPharm International www.biopharminternational.com December 2015
Contents
BioPharmINTERNATIONAL
BioPharm International integrates the science and business of
biopharmaceutical research, development, and manufacturing. We provide practical,
peer-reviewed technical solutions to enable biopharmaceutical professionals
to perform their jobs more effectively.
COLUMNS AND DEPARTMENTS
BioPharm International ISSN 1542-166X (print); ISSN 1939-1862 (digital) is published monthly by UBM Life Sciences 131 W. First Street, Duluth, MN 55802-2065. Subscription rates: $76 for one year in the United States and Possessions; $103 for one year in Canada and Mexico; all other countries $146 for one year. Single copies (prepaid only): $8 in the United States; $10 all other countries. Back issues, if available: $21 in the United States, $26 all other countries. Add $6.75 per order for shipping and handling. Periodicals postage paid at Duluth, MN 55806, and additional mailing offices. Postmaster Please send address changes to BioPharm International, PO Box 6128, Duluth, MN 55806-6128, USA. PUBLICATIONS MAIL AGREEMENT NO. 40612608, Return Undeliverable Canadian Addresses to: IMEX Global Solutions, P. O. Box 25542, London, ON N6C 6B2, CANADA. Canadian GST number: R-124213133RT001. Printed in U.S.A.
BioPharm International�JT�TFMFDUJWFMZ�BCTUSBDUFE�PS�JOEFYFE�JO��r�Biological Sciences Database (Cambridge Scientific Abstracts)�r�Biotechnology and Bioengineering Database (Cambridge Scientific Abstracts)�r�Biotechnology Citation Index (ISI/Thomson Scientific)�r�Chemical Abstracts (CAS) rŞScience Citation Index Expanded (ISI/Thomson Scientific)�r�Web of Science (ISI/Thomson Scientific)
6 From the Editor
Biopharma employees in different market segments note subtle differences in job satisfaction. Rita Peters
8 US Regulatory Beat
FDA confirmed quality focus while Congress moved to bolster biomedical innovation. Jill Wechsler
12 European Regulatory Beat
Finalizing GMP requirements and quality standards for ATMPs in the EU is proving to be a complex task. Sean Milmo
16 Perspectives on Outsourcing
CMO industry consolidation may be frustrated by a dearth of attractive assets.Jim Miller
65 New Technology Showcase
65 Product Spotlight
65 Ad Index
66 Biologic News Pipeline
2015 EMPLOYMENT SURVEY
Moving Up the
Biopharma Career Ladder
Rita PetersLimited career and salary growth
complicate a somewhat positive
employment picture. 20
UPSTREAM PROCESSING
Combining Microbioreactors
and Advanced Statistical
Techniques to Optimize a
Platform Process for a New
Host-Cell Line
Colin Jaques and Daniela LegaUse of a subspace model is a viable
method to characterize process
space variables and optimize process
performance. 28
DOWNSTREAM PROCESSING
Bespoke Bioprocessing Resins
Randi HernandezAvitide’s Kevin Isett discusses the
company’s approach to purification resins. 38
PEER-REVIEWED
Variable Pathlength Fiber-
Optic Spectrophotometry
for Protein Determination
in Immunoglobulin
Concentrates
Alfred Weber and Heinz AnderleSoloVPE fiber-optics spectrophotometry
Wyatt Technology, a 33-year old family-owned and operated enterprise, is the world’s largest company dedicated to SEC–MALS detectors for absolute macromolecular characterization. Our
instrumentation provides the essential techniques for characterizing macromol-ecules and nanoparticles in solution, in order to deter-mine molar mass, size, charge, and interactions. Wyatt’s extensive applica-tions laboratories and its full-time staff (including more than 18 PhD scien-
tists) means our customers receive deep technical expertise and support. To ensure the personal touch, “Light Scattering University” (LSU) is included with most of our instruments. We bring you to Santa Barbara to de-mystify light scattering, work you hard but feed you well, and, of course, explain how to get the most from your Wyatt Technology equipment.
Wyatt’s products are the most widely used multi-angle lightscattering (MALS) detectors in the world. They are employed in thousands of labo-ratories including, but not limited to, companies involved in biotechnology, pharmaceutical devel-opment, chemical, and petrochemical research, in addition to government national labs and academic facilities.
Major Products/Services
WTC’s family of instruments includes:
t� DAWN HELEOS: An 18-angle SEC–MALS detector that can be used at ambient,
Wyatt Technology Corp.elevated, and below ambient temperatures for polymers, particles, and biopolymers.
t� miniDAWN: A SEC–MALS detector ideal for proteins and peptides and molar mass materials below 1 million Da.
t� μDAWN: The world’s first MALS detector for UHPLC. Compatible with all UHPLCs for molar mass and size determinations.
t� UT-rEX: The world’s first refractive index (RI) detector for UHPLC. Operates at the same wavelength of light as the μDAWN.
t� Eclipse system: For separation of macromol-ecules and nano particles in solution.
t� Optilab TrEX: The most advanced RI detec-tor in the world with 256 times the detection power and 50 times the dynamic range of any other RI detector. The TrEX can be oper-ated below or above ambient temperature and determine dn/dc at the same wavelength of light as the lightscattering instrument.
t� WyattQELS: A quasi-elastic (dynamic) light-scattering instrument that can be interfaced to the DAWN HELEOS or the miniDAWN TREOS to determine particle sizes as small as 1 nm.
t� ViscoStar viscometer: A state-of-the-art intrin-sic viscosity detector that can be operated above or below ambient temperature with its precise Peltier thermostatic controls.
t� WTC Protein Columns: A family of new silica based columns specifically designed for SEC–MALS protein applications. These col-umns retain all the important features of a first-class SEC column for protein separations.
Facility
WTC maintains more than 35,000 ft2 of mod-ern electronics, optical prototype, machine shop, and laboratory facilities in Santa Barbara, California.
We Call Him Dad.Dr. Philip Wyatt is the father of Multi-Angle Light Scattering (MALS) detection. Together with his sons, Geof and Cliff, he leads his company to produce the industry’s most advanced instruments by upholding two core premises: First, build top quality instruments to serve scientists. Check.
For essential macromolecular and nanoparticle characterization—The Solution is Light™
Then delight them with unexpectedly attentive customer service. Check. After all, we don’t just want to sell our instruments, we want to help you do great work. Because at Wyatt Technology, our family extends beyond our last name to everyone who uses our products.
12 BioPharm International www.biopharminternational.com December 2015
European Regulatory Beat
Vis
ion
so
fAm
eri
ca
/Jo
e S
oh
m/G
ett
y I
ma
ge
s
A consultation period on GMP guide-
l ines (1) in the European Union,
specif ical ly for advanced therapy
medicinal products (ATMPs), comprising
gene- and cell-therapy products and tissue-
eng ineered t reatments, was due to be
completed in November 2015. The guidelines,
which will be drawn up by the European
Commission, however, are taking a long time
to complete. They are a requirement of an EU
regulation on ATMPs (2) which was approved
in 2007.
The objective behind the guidelines is to
bring together in a single document GMP
standards from a variety of sources, mainly
other pieces of EU legislat ion. But even
when the first dedicated GMP guidelines for
ATMPs are finalized, probably in 2016, they
are likely to have to be constantly revised.
Compliance with GMP standards has been
a major challenge for ATMP developers in
Europe. In fact, these difficulties could be
a prime reason why, up until 2014, only
four medicines under the ATMP regulation
had been given marketing authorization
in the EU’s centralized medicines licensing
procedure. Just how GMP problems for
advanced medicines are sorted out in Europe
could be a key influence over the
future of personalized medicines
and other new pharmaceut ica l
technologies in the region.
THE CURRENT R&D STRUCTUREAt the core of the difficulties with
GMP is the R&D structure in the
advanced medicines sector. Much
of the development work on ATMPs
is carried out by academic scientists
and clinicians attached to hospitals
of universities and other research
institutes. They lack the regulatory expertise
and resources to establish and operate GMP-
compliant manufactur ing processes. In
particular, they often do not have adequate
systems in place for evaluating the quality
of starting and raw materials, which is a
vital necessity in the production of advanced,
usually biological, medicines.
Academics seeking to arrange preclinical
and cl inical tr ials for their innovations
are so concerned about the complexities of
compliance with GMP that they try to avoid
having them classif ied as ATMPs by the
regulatory authorities, according to AGORA,
an EU-funded research project on solutions
to GMP problems in the sector (3).
LACK OF HARMONIZATION IN APPLYING GMP STANDARDSThe difficulties with GMP are aggravated by
the lack of harmonization in the way GMP
standards are applied by the EU’s member
states. “Research [has] found substantial
heterogeneity in the regulatory practice
across member states, which is leading to
confusion and uncertainty and is creating
a severe barr ier to the development and
delivery of [ATMP] medicines,” said AGORA
in a prog ress repor t to the European
Commission on its project (3). “[This is]
GMP Challenges for Advanced Therapy Medicinal ProductsFinalizing GMP requirements and quality standards for the development, manufacture, and clinical testing of ATMPs in the EU is proving to be a complex task.
With a proven track record of providing qual-ity testing services for the largest pharma-ceutical and biopharmaceutical companies
in the world, Eurof ins Lancaster Laboratories is a global leader in bio/pharmaceutica l labora-tory services providing comprehensive, innova-tive, and timely solutions to streamline all of your CMC test ing require-ments.
A s a m e m b e r o f Eu rof in s Sc ient i f ic ’s B i oPh a r m a P r o d u c t
Testing Group—the largest network of har-monized bio/pharmaceutical GMP product testing laboratories worldwide—Eurofins Lancaster Laboratories provides comprehen-sive laboratory services to support all func-tional areas of bio/pharmaceutical production.
Facilities
With a global capacity of more than 500,000 square feet, our network of GMP labora-tories operates under the same strict qual-ity procedures, LIMS, and centralized billing system across 14 locations worldwide to make working with any of our global operations seamless. In addition to these laboratory locations, we also have teams of scientists placed at more than 40 client facili-ties throughout the US and Europe through our Professional Scientific Services (PSS) insourcing program. We also provide secure 24-hour data access from all of our laborato-ries via LabAccess.comSM.
Markets Serviced
We provide complete CMC Testing Services to support more than 800 virtual to large
Eurofins Lancaster
Laboratories, Incbio/pharmaceutical companies and CMOs, including testing of all starting material, process intermediates, drug substance, fin-ished product, and manufacturing support through our broad technical expertise in Biochemistry, Molecular & Cell Biology, Virology, Chemistry, and Microbiology.
Comprehensive Services
We offer the f lexibility to manage your testing programs more efficiently through your choice of three unique service models, including our award-winning Professional Scient i f ic Ser v ices (PSS), Fu l l Time Equivalent (FTE) or traditional fee-for-ser-vice. You can choose the best, most cost-effective service solution for your project goals. Our breadth of services include:t� Method establishment, including method
development, feasibility, optimization, cGMP qualification and validation, as well as verification of compendial methods
t� Comprehensive stability and release pro-grams for clinical and marketed products
t� Complete biochemical and chemical char-acterization and microbial identification
t� Raw material and excipient testing (USP/
NF, EP, JP)t� Production and non-production cell bank-
ing including full characterizationt� Lot release/unprocessed bulk testingt� Process/facilities validation, including
viral clearance, residual impurities testing, extractables & leachables, water testing, environmental monitoring, disinfectant efficacy, and on-site sample collection
What drives you to pursue novel medicines?With high costs, declining productivity, ever-more stringent regulations and increasing scientific and engineering complexity. Why do you do it?
We know why.Lives are depending on you. At EMD Millipore, we share your drive to make a difference. For nearly 350 years, our people
have been trusted partners to all the risk-takers at work in the Life Sciences community; from research institutions and
laboratories, to manufacturing facilities around the world.
Scepter, SteriTest, EMD Millipore, Merck Millipore, and the M mark are trademarks of Merck KGaA, Darmstadt, Germany. Milli-Q and Mobius are registered trademarks of Merck KGaA, Darmstadt, Germany.
Emergent is a fully integrated specialty phar-maceutical company seeking to protect and enhance life. It is also a recognized leader in the production of sterile biopharmaceuticals. Emergent serves as the client’s single source
of ser v ice . Emergent mainta ins compliance with regulatory, customer and corporate standards. From clinica l through commercial production, Emergent has the expe-rience, knowledgeable personnel and involved management team to ensure our partners’ prod-ucts proceed from project
initiation through manufacturing quickly with an emphasis on quality. We operate with integrity, committed to the safety of our products and the service of our customers!
Major Markets
Emergent’s Contract Development and Manufacturing capabilities support bulk drug substances and finish drug products for Phase I through Phase III clinical trials and provides commercial production for its clients. Incorporating research, full prod-uct/process development, and non-clinical/clinical skill sets, this experienced group is responsible for discovering, developing, and/or commercializing innovative therapeutic products and technologies. Emergent’s state-of-the-art single use manufacturing facility enables turnkey upstream and downstream development for microbial, mammalian, and viral cell lines (Bioreactors range from 50L to 2000L). Current Fill/Finish capacity includes vials and syringes, for both liquid and lyophi-lized products, including lyo cycle devel-opment. Emergent can accommodate vials from 3mL to 100mL and pre-fi lled syringe products (0.5–20mL). Emergent’s facilities
EMERGENT BIOSOLUTIONS
INC.
400 Professional Drive, Suite 400 Gaithersburg, MD 20879 USA
TELEPHONE
800.441.4225
FAX
301.795.1899
WEBSITE
www.emergent biosolutions.com
NUMBER OF EMPLOYEES
1400
DATE FOUNDED
1998
Emergent BioSolutions Inc.
meet the international regulations required to service clients from all over the world. Emergent has submitted a Drug Master File with the FDA as well as many other agencies and currently manufactures 20 commercial products approved for distribution in over 50 countries including the United States, Canada, Japan, Brazil, and most of Europe. Emergent’s manufacturing facilities (located in Baltimore, MD) have supported over 200 clinical drug product candidates.
Services Offered
Drug Substance Manufacturet� Clinical & Commercial Scalet� Single-Use Platform (up to 2000L)t� Process Developmentt� Upstream & Downstream
SGS Life Science Services is a leading con-tract service organization providing clini-cal research services, analytical development,
biologics characterization, utilities qualification, bio-safety, and quality con-trol testing. SGS provides Phase I-IV clinical trial management and services encompassing PK /PD simulation and modeling, data management, phar-macovigilance and regu-latory consultancy. SGS also offers contract labo-ratory services (detailed
below) that include analytical chemistry, microbiology, stability studies, method devel-opment, and protein analysis. SGS is the world’s leading inspection, verification, test-ing, and certification company.
Technical Services
t� Quality control testing of raw materials, APIs, and finished products
t� Monograph testing (USP, EP, BP, and JP)t� Analytical method development and
validationt� Microbiological testingt� Container testing (extractables and
leachables)t� Stability testing according to ICH guide-
lines or customer specificationst� Utilities qualification (air, gas, water &
surface)t� Preformulation and formulation
developmentt� Medical device testingt� Protein/peptide analysis and quantificationt� Glycosylation analysist� Biologics safety testing (endotoxin, virus
and mycoplasma)t� Cell-line characterizationt� Host-cell impurity testing (residual DNA)
SGS Life Science Services
t� Virus testing (cell bank and virus seeds characterization)
With truly global coverage and a strong local footprint in North America, SGS has facili-ties in Lincolnshire (Illinois), Fairfield (New Jersey), West Chester (Pennsylvania), Carson (California), and Mississauga (Canada), as well as a clinical trial management office in Germantown (Maryland). SGS’ laboratories operate according to high quality standards (cGMP, GLP, ISO 17025) and have been inspected by the US-FDA or local regulatory authorities.
Markets Served
SGS serves various lifescience companies including pharmaceutical, biopharmaceutical, biotechnology, and medical device manufac-turers. SGS operates a global, wholly-owned network of 18 Life Science Services labo-ratories with facilities in the US, UK, Canada, Belgium, France, Germany, Italy, Switzerland, China, India, and Singapore. The Top 20 pharmaceutical companies trust SGS as a partner for their quality control testing needs.
Hamilton Company is an industry leader in the design and manufacture of liquid handling, process
analytic sensors and systems, robotics, and automated storage solutions. For more than 60 years, Hamilton Company has been satisfy-ing customer needs by com-bining quality materials with skilled workmanship to ensure the highest level of performance. Hamilton’s life-long commitment to preci-sion and quality has earned
us global ISO 9001 Certification.Founded on the technology of analytical
Microliter™ and Gaslight® syringes, Hamilton has a broad offering of laboratory products including precision fluid measuring instruments, chromatography products, process sensors, labo-ratory electrodes, pipettes, and more.
Measurement Techniques Supported
Online Measurement of:Viable Cell Density (Capacitance)Total Cell Density (Optical)Dissolved Oxygen, Optical and PolarographicpH ORPConductivity
nology of analytical syringes and has evolved with advances in scientific techniques to provide a broad offering of products.
Analog and Digital Sensors
Our electrochemical pH, ORP, Conductivity and DO sensors are reliable tools for application-oriented use and are characterized by high qual-ity and long life. Along with standard analog sensors, our unique Arc technology incorporates a digital/analog transmitter into the sensor head and also enables wireless Bluetooth communica-tion directly to cell phones, tablets, and similar devices.
Leadership in Dissolved Oxygen Measurement
Our Optical DO sensors have brought large gains in accuracy and longevity while eliminat-ing routine maintenance and polarization wait-ing times. Both trace and standard measurement ranges are offered. Polaragraphic sensors are offered in both trace and standard ranges too. All DO sensors are available with Arc technol-ogy and are offered in all sizes and mounting configurations.
Cell Density
Hamilton’s inline Cell Density sensors are avail-able for both Viable and Total Cell Density. Incyte is the viable cell density sensor based on capacitance. It measures only living cells, ignoring dead cells, debris, changes in media, and microcarriers. Online measurement allows detection of events in real time without sampling. Dencytee is the total cell density sensor that utilizes optical density measurements in the NIR range. Dencytee increases light source intensity to compensate for increasing turbidity. Thus it can measure across a much larger range than conventional OD sensors.
Smart Process ControlDissolved Oxygen, pH, and Conductivity measurements connect directly to your PLC
Robust 4-20 mA and Digital signals generated directly from the sensor
Eliminate weak signal problems and transmitter costs with direct connection to PLC
In lab pre-calibration and digital sensor management
Several monitoring options including wireless monitoring of multiple sensors
Optical and amperometric Dissolved Oxygen sensors for all applications
pH sensors with self-pressurized reference for best performance and longevity
For more information, visit www.ham-info.com/1059 or contact us toll free below.
Web: www.hamiltoncompany.com
USA: 888-525-2123To fi nd a representative in your area, please visit hamiltoncompany.com/contacts.
36 BioPharm International www.biopharminternational.com December 2015
Due to a number of cultures
having zero values, it was not
possible to develop a robust
response surface model for lac-
tate concent rat ion. Instead,
a PCA model was developed to
study the correlation patterns
in the data. The loadings of the
PCA model indicated that lactate
concentration at harvest was not
influenced by culture pH but was
strongly influenced by trace ele-
ment concentrations and amino
acid concentrations.
The derived models were used
to perform simultaneous in-silico
optimization of multiple process
outputs. Optimization focused
on increasing viability at harvest,
reducing lactate accumulation at
harvest, and maintaining antibody
concentration at harvest. The opti-
mized process was evaluated with
two cell lines in 10-L airlift reac-
tors. Cell line 1 was known to dis-
play acceptable lactate metabolism
and culture viability at harvest.
Cell line 2 was known to display
unacceptable lactate metabolism
and culture viability at harvest.
Profiles for lactate concentration
and culture viabil ity in both
processes for both cell lines are
presented in Figures 5A and 5B.
Lactate concentration at harvest
was decreased for both cell lines,
and the onset of late-lactate accu-
mulation was delayed in the new
process. Viability at harvest was
substantially increased for both
cell lines with positive implica-
tions for the downstream process.
The availability of automated
miniature bioreactor systems has
made the execution of large exper-
iments like this straightforward.
However, it exposes new bottle-
necks in the development process.
The design and coding of such
large experiments is demand-
ing and the preparation of large
numbers of feeds and/or medium
var iants requi res innovat ive
approaches. The large number of
samples produced challenges the
throughput of existing analyti-
cal technologies. Assimilating all
of the knowledge generated can
be so overwhelming that the full
benefit of the techniques is not
extracted.
CONCLUSIONAutomated miniature bioreac-
tors and advanced stat ist ica l
techniques such as multivariate
data analysis and response sur-
face optimization now available
to the bioprocess developer are
changing the face of bioprocess
development. By applying these
tools in a single round of opti-
mization, it is possible to make
substantial improvements to a
mature plat form process and
optimize process conditions for
cell l ines derived from a new
host. However, advances in high-
throughput analytics, data pro-
cessing, and medium and feed
preparation are also warranted. x
Upstream Processing
Figure 4: Response surface model predictions of viability at harvest as a function
of initial and final pH for (A) the original process, and (B) the optimized process.
7.1
(A) (B)
7.0
6.9
6.8
7.1
7.1
7.0
Fin
al
pH
Fin
al
pH
7.0
6.9
6.96.8
Initial pH Initial pH
6.87.17.06.96.8
90 95
9080
8060
60
40
20
Figure 5: Comparison of (A) culture viability profiles and (B) lactate
concentration profiles for the original and optimized process in 10-liter
cultures.
100
(A) (B)12
10
8
6
4
2
0
Cu
ltu
re v
iab
ilit
y (
%)
La
cta
te c
on
cen
tra
tio
n (
g/L
)
90
80
70
60
50
40
30
20
10
24 48 72 96 120 144Elapsed time (h)
168 192 216 240 264 288 312 336 3600
0 24 48 72 96 120 144Elapsed time (h)
168 192 216 240 264 288 312 336 3600
Cell line 1 optimizedCell line 2 optimized
Cell line 1 optimizedCell line 2 optimized Cell line 1 optimized
Cell line 2 optimizedCell line 1 optimizedCell line 2 optimized
Cell line 1 standardCell line 2 standard
Cell line 1 standardCell line 2 standard
Contin. from page 33Lactate metabolism
is known to be
influenced by pH and
by the concentrations
of key trace elements.
ADVERTORIAL December 2015 BioPharm International 37
The Abzena g roup, wh ich inc lude s PolyTherics and Antitope, has undergone a significant transformation following the acquisition of US-based Pacif icGMP in
September 2015. The addition of PacificGMP’s manufactur-ing and process development capabilities allows Abzena to support customers’ projects seamlessly from lead optimi-sation and selection through to GMP manufacturing for clini-cal trials.
T he compa n ie s in t he Abzena group have been devel-oping and offering their tech-nologies and services for over 10 years and their scientists have provided expertise to a wide
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42 BioPharm International www.biopharminternational.com December 2015
For decades, spectrophotometry
has been used to accurately and
precisely measure purified pro-
tein concentrations, with the
extinction coefficient (usually at 280
nm) determined either experimentally
or calculated from amino-acid com-
position. To reduce the overall instru-
mental uncertainty in absorbance
measurement, samples require dilution
to an absorbance of 0.6–0.7/cm. The
uncertainty in the sample preparation
step can be minimized in gravimetric
dilution, but measurement of a larger
series of samples generally involves
considerable work to ensure flasks and
cuvettes are clean.
To overcome the limitations of
conventional cuvette-based spectro-
photometry, a spectrophotometric
technique based on measurement
of the incremental absorbance upon
path length variation has recently
been introduced (1). This variation is
achieved by moving an optical light-
guide fiber immersed into the sample
solutions in a stepwise fashion, with
the absorbance readout at every step
and the calculation of the slope from
the absorbance vs. distance plot. This
technique is called “slope spectros-
copy” by the manufacturer and is
intended for use in measuring con-
centrated sample (protein) solutions
without dilution. The SoloVPE system
(C Technologies, Inc.) has been com-
mercially available for a few years and
has been evaluated mainly for concen-
tration measurement of recombinant
proteins such as monoclonal antibod-
ies (2).
In plasma fractionation, an interest-
ing candidate for assessment of the
slope spectroscopy technique would
be immunoglobulin G for intravenous
administration (IVIG), highly purified
by chromatography and formulated as
a liquid concentrate. Gammagard liq-
uid is a polyvalent IgG product, con-
taining 10% protein of more than 98%
purity in a 250 mM glycine solution,
pH=4.8 (3). Currently, the protein is
ABSTRACT
As an innovative and time- and resource-saving single-step technique that avoids sample
pre-dilution, the use of hazardous reagents, and high-power consumption, SoloVPE
fiber-optics spectrophotometry may be able to substitute or replace the current
Kjeldahl protein determination procedure for 10% IgG in the future.
Variable Pathlength Fiber-Optic Spectrophotometry
for Protein Determination in Immunoglobulin Concentrates
Alfred Weber and Heinz Anderle
Heinz Anderle is senior scientist and
Alfred Weber is senior manager; both
at Baxalta Innovations GmbH.
PEER-REVIEWED
Article submitted: July 31, 2015.
Article accepted: Aug. 17, 2015.
Peer-Reviewed: Protein Characterization
December 2015 www.biopharminternational.com BioPharm International 43
IVIG
Lot no.
SoloVPE(mg/mL)
Kjeldahl(mg/mL)
Slope(1/cm)
E0.1% (1/cm)(Recalculated)
1 100.41 100.943 140.47 1.392
2 100.49 100.629 140.59 1.397
3 99.41 99.651 139.07 1.396
4 101.82 100.91 142.45 1.412
5 100.05 99.283 139.97 1.410
6 101.63 100.434 142.18 1.416
7 100.61 99.070 140.75 1.421
8 99.10 100.087 138.64 1.385
9 100.09 100.340 140.03 1.396
10 99.91 100.432 139.77 1.392
11 98.87 99.790 138.32 1.386
12 101.58 100.559 142.11 1.413
13 100.32 100.119 140.35 1.402
14 99.31 101.276 138.93 1.372
15 100.33 100.479 140.36 1.397
16 100.44 99.273 140.52 1.415
17 98.92 99.204 138.39 1.395
18 99.81 99.584 139.63 1.402
19 100.57 99.085 140.70 1.420
20 100.17 100.431 140.14 1.395
21 97.11 96.930 135.86 1.402
22 99.64 99.113 139.40 1.406
23 98.42 99.204 137.69 1.388
24 99.33 99.446 138.96 1.397
25 100.61 99.140 140.75 1.420
26 100.64 98.955 140.80 1.423
27 99.39 97.804 139.05 1.422
28 100.14 99.750 140.10 1.404
29 99.72 99.074 139.51 1.408
30 98.96 99.544 138.45 1.391
31 99.99 97.855 139.89 1.430
32 100.48 99.892 140.57 1.407
33 99.74 97.580 139.54 1.430
34 99.55 99.161 139.27 1.404
35 98.94 99.968 138.42 1.385
36 99.68 99.240 139.45 1.405
37 98.76 97.818 138.17 1.412
38 98.67 99.257 138.04 1.391
Table I: Comparison of SoloVPE and Kjeldahl protein
concentration results for 10% IgG batches with recalculation
of the extinction coefficient E as slope/Kjeldahl protein.
measured by differential Kjeldahl determina-
tion of the total and the non-protein nitro-
gen content (4). Despite the automation in
reagent dosing and titration, which min-
imizes handling of hazardous substances
such as sulfuric acid, sodium hydroxide solu-
tion, and hydrochloric acid, the Kjeldahl
technique remains a time- and energy-inten-
sive method and requires effective removal
of acid fumes.
W hi le not spec i f ica l ly in use for
Gammagard liquid, the other available nitro-
gen-based technique, the Dumas method,
does not require hazardous liquids, but
instead an oxygen-helium stream to sup-
port sample combustion in steel crucibles
or single-use tin capsules, which are heated
electrically in a furnace to approximately
1000 °C (5). Although the Dumas method,
with its higher throughput, has been almost
fully automated, the power requirement and
reagent consumption remain significant.
The batch-to-batch consistency of the pro-
tein composition allows total protein mea-
surement by ultraviolet (UV) absorbance as
an alternative to nitrogen-based techniques
in a sample dilution containing about 0.5
mg IgG/mL with physiological saline as the
diluent and blank. 10 percent IgG must be
diluted approximately 200-fold in a volu-
metric flask. The turbidity is corrected by
measurement at 320 nm, and the extinction
coefficient E0.1% is calibrated to 1.399/cm on
the Kjeldahl data.
For Kjeldahl digestion, Dumas combustion
of the protein solution, and UV absorbance
measurement with gravimetric dilution, the
sample density needs to be first measured
in an oscillating tube densimeter. If the
slope-spectroscopy technique (by way of the
of SoloVPE device) yields equivalent results,
time-consuming sample preparation and
measurement steps can be reduced to a sin-
gle-step procedure, cleaning of the equip-
ment may be eliminated, consumption of
reagents can be decreased, and the electrical
power obviated.
Equivalence of this assay technique with
the Kjeldahl method must be demonstrated
first by adherence to the AOAC acceptance
criteria for precision and accuracy: At an
analyte concentration of 10%, recovery must
remain within 98–102% and precision no
higher than 2.8% (6, 7); accuracy is con-
Peer-Reviewed: Protein Characterization
44 BioPharm International www.biopharminternational.com December 2015
firmed by agreement with an independent,
validated reference method (such as the
Kjeldahl digestion). Inter- and intra-assay
precision must be determined by six-fold
repeated measurements as outlined in the
respective regulatory guidelines; linearity
should be at least at 80–120% of the working
level. Furthermore, due to the commercial
importance of IVIG, the bias (difference in
results) between both methods should be
as small as possible, as shown by the Bland-
Altman statistical analysis of the datasets (8).
A 20% subcutaneous IgG concentrate, for-
mulated in the same slightly acidic environ-
ment as the corresponding licensed 10%
IVIG concentrate, is now on the market,
thus, 5–25% IgG would cover the entire
range during production. For rheological
investigation, even higher IgG concentra-
tions (up to 38%) have been obtained exper-
imentally (9).
MATERIALS AND METHODST h i r t y- e ig ht batc hes o f 10 % I V IG
(Gammagard liquid), with known protein
concentration as determined by Kjeldahl
method with solution density measurement,
were obtained in the original bottles, from
which aliquots were drawn antiseptically
with a syringe. An experimental ultra-high
IgG concentrate (target: more than 30%)
was prepared by centrifugal ultrafiltration
(Centriprep 10 kDa) of an 0.03% azide-pre-
served aliquot, and the permeate retained to
mix dilutions (5%, 10%, 15%, 20%, and 25%
IgG) with the stock concentrate (32%). Of
these preparations, protein concentrations
were determined by UV absorbance mea-
surement at 280 nm (with turbidity correc-
tion at 320 nm) and by Dumas combustion
method in a VarioMax analyzer (Elementar),
with the permeate (glycine/azide) as the base
value. Solid acetanilide served as the stan-
dard for the nitrogen content, which was
assumed to be 16% for Kjeldahl and Dumas
determination (10).
For conventional UV-absorbance measure-
ment, a Hitachi U-3000 spectrophotometer
with standard 1-cm quartz cuvettes and a
Hitachi U-3310 high-sensitivity spectro-
photometer with 0.1-mm thin-layer quartz
cuvettes in a spring-clamp holder were used.
The SoloVPE fiber-optic spectrophotom-
eter, comprising the variable pathlength
fiber/detector unit and an Agilent Cary 60 as
the light source/spectrometer unit, was pro-
vided by C Technologies, Inc., together with
the single-use plastic well cuvettes and the
polyimide-coated 0.6-mm diameter quartz
“fibrettes” as the consumables.
VARIABLE PATHLENGTH VS. CONVENTIONAL SPECTROPHOTOMETRY In the SoloVPE device, monochromatic light
fed from the fiber-optic light guide passes
through the quartz fibrette and is absorbed
by the sample solution in the adjustable path
between the fibrette end window and the
plastic well cuvette (Figure 1). A silicon pho-
todiode at the bottom of the cuvette cavity
measures the transmitted light intensity. In
the solution, the light pathlength d can be
increased in increments as small as 0.05 μm,
and the absorbance values A are read out at
all 10 measurement points. To remain within
a linear regression (R2≥0.999), at least five
results are required for slope calculation. The
slope ΔA/Δd obtained from the absorbance
vs. pathlength regression calculation is then
divided by the mass specific or molar extinc-
tion coefficient (E or ε) to calculate the mass
or molar concentration, respectively.
Peer-Reviewed: Protein Characterization
Figure 1: Photograph of a light path from the
SoloVPE fibrette dipping into fluorescein solution.
AL
L F
IGU
RE
S A
RE
CO
UR
TE
SY
OF
TH
E A
UT
HO
RS
.
December 2015 www.biopharminternational.com BioPharm International 45
Spectrophotometric measurement is inher-
ently limited by both dark signal and noise of
the detector as well as by the bit-depth of the
analog/digital signal converter. A deviation
from linearity caused by monochromator stray
light may be readily observed above 3 absor-
bance units (i.e., 0.001 residual transmission).
High-sensitivity spectrophotometers such as
the Hitachi U-3310 with its additional auxil-
iary stray light-eliminating monochromator
may extend the upper absorbance range limit
from about three to four absorbance units (i.e.,
from 0.001 to 0.0001 residual transmission),
above which the thermal detector noise of the
common red-sensitive photomultiplier (PMT)
becomes dominant. For routine ultraviolet–vis-
ible spectrophotometry (UV–VIS) instruments,
equipping the detector with a blue-sensitive
PMT and cooling it from ambient temperature
to –20 °C for example, is not a viable option.
A straightforward and presumably user-
friendly approach to overcome these instru-
mental limitations was proposed through
pathlength reduction by the use of thin-layer
cuvettes. Several manufacturers offer cuvettes
with a pathlength of 0.5, 0.2, and even 0.1
mm, and a detachable cover window. The
suitability of such a technique for measur-
ing a monoclonal antibody up to a concen-
tration of 90 mg/mL has been described by
Watson and Veeraragavan (11). Although an
absorbance value of 1.4 for 10% IgG in a 0.1-
mm cuvette would remain unaffected by spec-
trophotometer interference from stray light,
dark signal, or noise, the authors’ experience
discourages from routine use of such cuvettes
because of the delicate handling and cum-
bersome cleaning involved, and the practical
impossibility of applying sample concentra-
tions above 20% IgG due to their high viscosity.
RESULTS AND DISCUSSION 10% IgG solutions and
inter-assay precision
For all 38 batches of 10% IgG, protein con-
centration data obtained using the SoloVPE
Peer-Reviewed: Protein Characterization
TestConcentrations in mg/mL (batch no.)
3 4 26 30 31 36 38
1 99.82 100.96 99.95 99.46 99.48 99.66 98.79
2 99.57 101.01 98.71 99.45 99.35 100.03 98.56
3 99.46 101.22 98.72 99.51 99.41 99.49 98.40
4 99.45 101.18 98.71 99.48 99.65 99.43 98.29
5 99.46 101.18 98.80 99.47 99.74 99.38 98.13
6 99.56 101.19 98.69 99.52 99.72 99.38 98.10
Mean 99.55 101.12 98.93 99.48 99.56 99.56 98.38
RSD (%) 0.13 0.10 0.46 0.03 0.15 0.23 0.25
Target % IgG
Dumas (mg/mL)
TP UV (mg/mL)
Concentrations in mg/mL (batch no.) RSD(%)
E0.1%(calc.)Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Mean
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66 BioPharm International www.biopharminternational.com December 2015
BIOLOGICS NEWS PIPELINE
IN THE PIPELINE
Amgen’s Biosimilar BLA for ABP 501 Submitted to FDA
Amgen announced the submission of a biologics
license application (BLA) with the FDA for ABP 501,
a biosimilar candidate to Humira (adalimumab).
This represents Amgen’s first BLA submission using
the 351(k) biosimilar pathway.
ABP 501 is a biosimilar candidate to adalimumab, an
anti-TNF-α-monoclonal antibody, which is approved
in many countries for the treatment of various inflam-
matory diseases. Amgen’s BLA submission includes
analytical, clinical, and pharmacokinetic data. Phase
III comparative efficacy and safety studies were con-
ducted in both moderate-to-severe plaque psoriasis
and moderate-to-severe rheumatoid arthritis.
The Phase III studies met their primary endpoints,
showing clinical equivalence to adalimumab. Safety
and immunogenicity of ABP 501 were also compa-
rable to adalimumab. Data to support the transition of
adalimumab patients to ABP 501 are included in the
submission.
It was initially unclear whether or not Amgen was in
support of the development of biosimilars. The com-
pany previously said minor changes in formulation
may have significant affects on patient safety. During
an Oct. 28, 2015 third-quarter earnings call, Amgen
CEO, Bob Bradway, said the company was preparing
to file clinical trial data with FDA for ABP 501, and
expected legal pushback from AbbVie, the original
developer of Humira.
AbbVie CEO Richard Gonzalez has said the com-
pany plans to aggressively defend its patents for
Humira from biosimilar competitors, many of which
will protect the product until 2022. AbbVie currently
has 70 patents protecting Humira, and the company
expects nearly $18 billion in global sales will come
from Humira alone. Amgen currently has nine biosim-
ilar molecules in development and is expected to
launch ABP 501 in 2017.
Rice University Scientists Develop
Method to Control Infectivity of Viruses
Scientists at Rice University have developed a
method that uses light to control the infectivity of
viruses and gene delivery to the nuclei of target cells.
The method uses two shades of red light to control
the level and spatial distribution of gene expression
in cells via an engineered virus.
The scientists at Rice built custom adeno-associated
virus (AAV) vectors by incorporating proteins that
naturally come together when exposed to red light,
and break apart when exposed to far red. These natu-
rally light-responsive proteins help the viral capsids—
the hard shells that contain genetic payloads—enter
the host cell nuclei.
The protein pair comprises phytochrome B and its
binding partner phytochrome interacting factor 6
(PIF6), found in thale cress. The researchers generated
host cells that express phytochrome B tagged with a
nuclear localization sequence, a small peptide known
to help shuttle proteins into the nucleus more effec-
tively. The smaller PIF6 was then attached to the out-
side surface of the virus capsid. This is the first time
optogenetic proteins have been used to control the
infectivity of viruses.
According to Suh, the platform may be used in
the future to control what cells and tissues express,
and at what level. The strategy could also find use in
tissue-engineering applications like bioscaffolds for
implantation.
Adaptimmune and Universal Cells Collaborate
to Develop Allogenic T-Cell Therapies
Adaptimmune Therapeutics, a clinical-stage biophar-
maceutical company focused on cancer immuno-
therapy products, and Seattle-based Universal Cells,
a genome-editing company developing universal
donor stem cells, have entered into a collaboration
and license agreement for the development of alloge-
neic T-cell therapies.
The enhanced T-cell technology involves the
selective engineering of cell surface proteins (T-Cell
Antigen Receptors) and class I and class II human leu-
kocyte antigen proteins, without the use of nucleases,
to develop universal T-cell products. The companies
are planning to develop off-the-shelf allogeneic affin-
ity-enhanced T-cell therapeutics to treat large patient
populations.
Under the terms of the agreement, Universal Cells
will grant Adaptimmune an exclusive, sub-licens-
able, worldwide license to use, sell, supply, manu-
facture, import, and develop products and services
utilizing Universal Cells’ technology within the
T-cell immunotherapy field. Universal Cells will
receive an upfront license and start-up fee of $5.5
million, and will be eligible for up to $41 million
in milestone payments for certain development
and product milestones. Universal Cells would also
receive a profit-share payment for the first product
and royalties on sales of other products utilizing its
technology.
From R&D to production—
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