Cardinal Health BSLS Script 5: Bioassay Development
[ Look and Feel notes: Follow CAH guidelines.
Concept Notes: This eBrochure reprises the opening graphics from the Overview eBrochure, and
continues the forward motion (left to right) theme. See specific suggestions in copy below. ]
[ Header: The Science of Success ]
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The Sterile and Biotechnology Development business of Cardinal Health brings people, capabilities,
facilities, and integrated technology and healthcare systems together to help speed your product
through the development process, from discovery to commercialization.
[ Briefly reprise the illustration/animation from the overview eBrochure to help tie all of the
eBrochures together. (The department name change should apply also to the three existing
eBrochures and the two remaining ones under development.)
]
[ Header: Bioassay Development ]
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[ Continue timeline image animation until Bioassay Development Icon appears. ]
[ Header: Bioassay Development: Large Molecules and Biologics ]
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Assaying large molecules and biologicals includes more complex assays and analysis of the
data to determine not only structure, but also . . .
[ Show these bullet points on screen . . .
Flexible Approach
 Specialized Capabilities
 Serve as Virtual Department
 Manage Entire Program
Specialized Capabilities
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[ Header: Bioassay Development: Function | Behavior | Safety ]
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. . . the function and behaviors and safety of the drug compound in vivo—whether it
proliferates or at which point it causes death, expansion of antigens, or other behavior—how
a drug compound interacts with the body.
[ Show these bullet points.
Preclinical Studies
 Potency
o LD50 of dose curve
o Lot Equivalency
o Rate of release over time
o Stability at differing temperatures and environments. ]
[ Header: Bioassay Development: Complex Assays and Analysis ]
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Assays
Indicate what a compound does in vitro: whether it proliferates or at which point it causes
death, expansion of antigens, etc.—generally, how a drug compound interacts with the body.
Perform cultures to prove purity and density and other characteristics of a drug material
Also perform Aseptic Testing—this is done to show that no external contaminants such as
microorganisms in vials when assays begin.
Characterization Studies—banked cell lines
[ Show these bullet points.
Large Molecules and Biologics
 Structural Analysis
 In Vitro Assays required by FDA
 Enzymatic Assays
 Immunoassays
o ELISA (Enzyme-Linked ImmunoSorbent Assays)
o RIA (Radioimmunoassays)
o Neutralizing Assays Contaminants
 Flow Cytometry
 Cellular Assays
o Mammalian Cells
o Bacteria
o Viruses
Animate this illustration:
Pharmacokinetics & Pharmacodynamics (PK PD) Studies
Measuring drug products in blood, urine or other fluid over time.
Time
1
Sample
2
Sample
3
Sample
4
Sample
5
Sample
--------------------------------- Analysis -----------------------------Quantity
Quantity
Quantity
Quantity
Quantity
--------------- Results to Dose Response Curve -----------------]
[ Header: Bioassay Development: Quality | Validity ]
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Our lab is GMP Compliant and routinely performs work according to GMPs or GLPs.
[
GMP Compliant routinely perform work according to GMPs or GLPs. GMP cell banking
and assays can be done.)
[ Header: Bioassay Development: Biosafety—Dealing with Contaminants ]
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. . . And Biosafety . . . Proving your drug product is pure, assaying for the presence of
contaminants produced by the organisms producing the drug substance itself . . .
All Biopharmaceutical products come from “in vitro” cells in vivo systems (living organisms,
such as cells in or blood). These cells create the potential for contamination.
Biosafety Testing of starting materials such as . . .
Develop testing for cell banks or product protein from cells that show the resulting
compound is
Free from contamination by
[ Show these bullet points.
Proving Product Purity
Viral Safety
 Develop testing for cell banks or product protein from cells that show the resulting
compound is
 Free from contamination by
o Bacteria
o Viruses
o Mycoplasma (bacteria with no cell walls)
o Extra proteins or DNA
 PCR tests (tests for presence of known viruses and microplasma mycoplasmas)
 Other characterization tests
 One type of test demonstrates cell species identity. It’s about proving that a Mouse Cell is
a Mouse Cell
Show images or icons of these contaminants (many available examples of bacteria, viruses,
mycoplasmas, and rogue proteins, here.
[Mycoplasma image from http://webmedia.unmc.edu/biochemistry/2SL31-mycoplasma.jpg
]
[ Header: Bioassay Development: Biosafety—Viral Clearance Studies ]
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Essentially, this means developing a small scale model of relevant steps of the manufacturing
process, spike process intermediate (before processing step) measure virus in process
intermediate after process step. Study must be performed using panels of relevant viruses
(one virus at a time). Virus panel determined with input from regulatory agency and based
on source of product., then reporting the viral clearance study data the way regulatory bodies
like to see it.
. . . proving you have developed an effective process for clearing contaminants and that your process
scales up.
[One of The CAH labs is a Biosafety level 3 (BSL3) lab which means they can handle . . .
Viral clearance studies required for IND
Pre-BLA testing is even more extensive
Re-assays required when form or approved dosages of an approved
commercial drug change
Biosafety Level 3
 Blood derived pathogens,
 HIV,
 West Nile virus,
 Other inhalable serious or potentially lethal disease-causing agents.
]
[ Header: Bioassay Development: Knowledge | Expertise | Experience ]
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Each assay is unique and uses (unique?) qualified reagents.
Each assay, then, is not just a matter of performing the assay properly in the lab, but also of
having the scientific knowledge to analyze the resulting data.
Why working with Biopharmaceuticals requires advanced science and people with PhDs . . .

Every product CAH works with is different:

Has its own assay

Takes more than the simple types of structural analyses non-bio-based drugs require
(usually using an HPLC). These are “simple standardized science.”
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Bioassays are each unique and require more variability and more scientific input to be
meaningful. They show what a product is doing in the body, return relevant potency
values, defined cell lines.
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Understanding mechanism of disease state.
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Not all human cell lines work—so sometimes have to identify and develop a
different appropriate mammalian cell line.
[ Show these bullet points.
Scientific knowledge, expertise, and experience
 Every biopharmaceutical product is unique
 Each bioassay is unique
 Accurate, meaningful analysis requires scientific judgment
o Relevant potency values
o Defined cell lines
o Understanding of disease state
o Knowledge of which mammalian cell lines work
Knowledge Base
 Handling different cells and cell cultures.
 Consistent, repeatable cell culture techniques and methods
 Handling biopharmaceuticals
 Consistent handling and procedures
 Defined methods for
o Cell and sample handling
o Incubator positions
o Many other minute details that collectively make a big difference in accuracy,
repeatability and ruggedness of results ]
[ Header: Bioassay Development: Knowledge | Expertise | Experience ]
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Special Expertise?
This all takes expertise, training, education and experience because there’s a lot of variability
and chance for error in an arena where the stakes are very high.
Expertise in interpreting 4-5 parameter curves—much more complex than “linear” curves
Why PhDs?
Bioassays require PhDs for the reasons cited above, plus to develop and maintain an internal
“knowledge base” through accurate data interpretation, reporting, etc.
CAH has two PhDs with years of experience in cell culture in the bioassay lab who’ve done
much post-doctoral work. (actually three Ph.D.’s, counting Gwen)
Many of the analysts in this lab have BS or MS degrees and many years of experience (All
analysts have a minimum of a BS. A number have advanced degrees (M.S.; Ph.D.))
About 40% Ratio, overall, of PhD to non-PhD personnel. Generally, CAH bioassay group
staff is much more educated, experienced, and qualified than competing labs.
The lab technicians who do the “day-to-day” lab work are all highly experienced and welltrained in lab procedures.
[
GMP Compliant routinely perform work according to GMPs or GLPs. GMP cell banking
and assays can be done.)
[ Header: Bioassay Development: Knowledge | Expertise | Experience ]
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Deep understanding of FDA and other regulatory requirements and —types of reporting, data,
format, etc. Very often competing labs or drug development companies become customers
after they’ve “run into trouble” using their own in-house lab.
Other labs just don’t compare at all with the quality of work produced by CAH.
In many cases, the bioassay group saves a drug development project from “utter disaster”
technically, in regulatory compliance, and financially.
The drug development industry as a whole doesn’t take the science seriously until it’s too
late—once or twice a year, every year, they gain a new client when someone comes to them
“in panic mode” with a stalled project caused by some kind of inadequate science that the
FDA rejects.
[ Show these bullet points . . .
Points of frequent failure in drug development projects
 Executing the “exact science” required to achieve and report results with sufficient
consistency over time
 Reporting accurate, meaningful data analysis.
 Submitting paperwork to FDA in an acceptable manner.
Examples:
Potency:
 FDA looks for parallelism—a “quasi-linear dose-response slope”
 FDA looks for Repeatability and Ruggedness—similar response curve within different
conditions and environments.
Analyzing Data
CAH helps define what the dose response curve should look like from assay results—
defining things like how many points should appear, how spread out they should be (over
time) and the relevant range (bottom and top) of the data. [ Might be good to show an image
of this curve in the eCommercial. ]
Mock 75% of Reference Standard
Mock 50% of Reference Standard
Reference Standard
]
Looking for consistency
[ Show these bullet points.
 Every biopharmaceutical product is unique
 Each bioassay is unique
 Accurate, meaningful analysis requires scientific judgment
o
o
o
o
Relevant potency values
Defined cell lines
Understanding of disease state
Knowledge of which mammalian cell lines work
Knowledge Base
 Handling different cells and cell cultures.
 Consistent, repeatable cell culture techniques and methods
 Handling biopharmaceuticals
 Consistent handling and procedures
 Defined methods for
o Cell and sample handling
o Incubator positions
o Many other minute details that collectively make a big difference in accuracy,
repeatability and ruggedness of results ]
[ Header: Bioassay Development: Integrated services | Strategic approach | Industry experience ]
Integrated services—CAH is a one-stop-shop for bioassay services, clearing, filling, moving
into manufacturing.
Most small development companies don’t understand the overall process or approach
development strategically—like the other groups in the Sterile Biotechnology Development
business of Cardinal Health, the Bioassay Development group adds a consulting aspect to its
services.
Senior people have an amazing amount of industry and “Big Pharma” experience and know
how (including DuPont, Wyeth, Bayer and others) where they’ve “sat face-to-face” with
regulators (which helps in understanding what they want to see).
[ CTA Page ]
[ Header: Cardinal Health: Working together. For Life ]
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At least three scientists from this group (Ana, Kathryn, and Gwen) are highly visible in the
field, presenting at conferences and symposiums, presenting courses, publishing research
papers:
Ana presents a two day course on genetic engineering (she has since sent the flyer for that),
Kathy is presenting a talk on validation at a Viral Safety Validation Technology seminar in
June (brochure attached) and has published a 2500 word paper on Viral Robustness Studies
(Remington KM. 2005. Viral robustness studies for biopharmaceuticals. BioProcess International.
3,7S:24-28.) for on O.O.S notifications for bioassays (I think that Gwen is presenting a talk
on this).
. . . Cardinal Health provides a single seamlessly-integrated source with the people, equipment, and
know-how to support your development efforts from discovery to commercialization.
[ Show established CTA copy. ]
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Original version
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