Process Safety and Efciency in Pharma

Big Data Solutions for Patient Recruitment

Drug Solubility in pharmaceutical excipients

Quality & Design in Logistics

GLOBAL MEDIA, MARKETING & BRANDING PLATFORM Vol. 2 Issue 1 April 2017
Not for sale, Circulation only on request. To subscribe, e-mail us at: support@worldpharmatoday.com

SIMPLIFYING
PHARMA PROCESSes
 Foreward
Dear Readers,

In the thrust of reducing cost and time along with enhancing the quality of output Pharma
companies today are focusing on process driven approach like never before. Whether it is about
reducing the time required for a new drug development or management of logistics and human
resource requirements, the industry is enhancing its abilities by simplifying processes and
integrating technologies.

Another vital factor that is inuencing on the present Pharma Industry challenge is personalized
EDITORIAL DEPARTMENT medication development to bring a new hope for the patients

Kathryn Gomes Thus this edition of World Pharma Today focus on Simplifying Processes falling under various
Yuvraj Sahni streams of the pharmaceutical industry and the varied technology applications that have already
started to build the foundation of a stronger Pharma future.
ART DEPARTMENT Evaluation of Pharmacology during the early stage of drug development especially for liquid
Santosh Kumar Rangampeta formulations is very complicated and time-consuming as it depends on trial and error method.
Exploring the new solutions with various services and views towards current pharma
MARKETING & SALES manufacturing development keeps you reading.
Sunny Roger Dynamic weighing check machines play a vital role in drug development to ensure better
Soumya V productivity with high quality. It is explored well in the magazine to understand the things in
depth.
PROJECT ASSOCIATE Michael Naimark, Director of Business development, CBSET Inc shared his view on cell-based
Venkateshwarlu Lakum therapy and gave an FDA review. The article covers majorly about the regenerative and cell-
Sanjay K Waghchaure based therapies and other exciting biological approaches towards the therapeutics were
Abijitha Borra explored in an exciting way and shared the experience on cell-based therapies and the future
developments.
ACCOUNT MANAGERS Clinerions PRS system A revolutionized solution for acceleration of clinical trials. The author
Abijitha Borra raised the curiosity in Pharma Industry business providers by introducing the best solution for
balancing the clinical trials with the business needs. Many companies are failed to get
PROJECT HEAD successful in clinical trials due to lack of efcient patient recruitment system and management,
with the help of big data technologies the problem can be resolve during the patient recruiting
Sushma Kandula
into clinical trials. The step by step analysis and the key benets are scripted in an interesting
way to our readers.
CONTACT FOR ENQUIRIES &
ADVERTISING There are several major challenges in managing the site payments for CROs. The improvement
in the latest technology was able to provide better management of budgets and streamlining the
process in more simplied way. The GreenPhires solutions and the way of managing the
Sunny Roger
payments will be more interesting for the CROs and project managers.
M: +91 88268 49084
Drug deliverability and packaging was revolutionized with new standards that overcome the
E: sunny@worldpharmatoday.com
challenges with the high barrier containers in the Pharma Industry packing system. Protection of
the pharmaceuticals with packaging has described by Greg Rosati, Healthcare Marketing
Director for Amcor with its new Ultra AmLite stability solutions. The article scripted well about
Published by: the stability solutions and challenges in the packaging the pharmaceuticals.

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World Pharma Today Magazine is a free of charge
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Leo Marcom Pvt Ltd. All rights reserved.
The commodities of Pharma companies in packaging and shipping need good understanding of
logistics and other process equipment. The Quality by design is what pharma manufacturing
industry will focus as main. It is a clear picture for the pharma savvys about the best packaging
solutions which can enhance the products.
The importance of the personalized medicine supply chain and its maintenance was scripted
well by Scott Ohanesian, Senior VP commercial operations of QuickSTAT Global Life science
Logistics. The article described how seamless the communication and connectivity must be
designed and integrated to support supply chain and leverage support to the gene and
immunotherapy. The commercialization of the clinical trials and drug development and supply
chain capabilities are very interesting for the pharma savvys and logistics specialists.
Accessible and effective Pharma remains top priority at the moment. And with the increase use
of the new technology and processes along with the adoption of innovations we look forward for
a Pharmaceutical Reform.

Leo Marcom Pvt Ltd. Until we meet again!!

Suit # 301, Manbhum Jade Tower's,
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T: +91 40 42030405 . Yuvraj Sahni
Editorial Department
 CONTENT

08
ESTABLISHING
A HIGH
THROUGHPUT
SCREEN OF DRUG
SOLUBILITY IN
PHARMACEUTICAL
EXCIPIENTS

14 20
ENHANCING CELL-BASED
PROCESS SAFETY THERAPY
AND EFFICIENCY AND
IN THE PHARMA FDA REVIEW
 OVERCOMING

26 34
THE CHALLENGES A SCAPEGOAT
OF CLINICAL TRIAL FOR SITE
RECRUITMENT PAYMENT
USING BIG DATA CHALLENGES
TECHNOLOGIES

38
HIGH BARRIER
CONTAINERS MEET
NEW STANDARDS
IN HEALTHCARE
PACKAGING

OVERCOMING THE

44 48
THE ARRIVAL CHALLENGES AND
OF QUALITY BY COMPLEXITIES OF
DESIGN IN THE PERSONALIZED
LOGISTICS MEDICINE
SUPPLY CHAIN
 ESTABLISHING A HIGH
THROUGHPUT SCREEN
OF DRUG SOLUBILITY IN
PHARMACEUTICAL
EXCIPIENTS
Amjad is a formulation scientist at Recipharms
development facility in Uppsala, Sweden. He is
responsible for developing solutions for complex
formulation challenges for both newly discovered
compounds and existing drugs, along with nding
new, cost-eective approaches for formulation
design. He has specic expertise in the development
of liquid formulations through crystallisation, solid-
state characterisation and solid form screening and
selection. He also delivers lectures at Uppsala
University on the formulation of poorly soluble
compounds.

An active member of several professional bodies

including the Controlled Release Society, the
American Association of Pharmaceutical Science and
the Swedish Association of Pharmaceutical Science,
Dr. Amjad Alhalaweh Ph.D., Amjad is also a registered pharmacist with the Syrian
Pharmaceutical Association.
Formulation scientist, Recipharm

At the discovery and early stages of drug development, the aim is to evaluate the
pharmacology, pharmacokinetics and toxicology of a compound using a simple
liquid formulation. During this process, drugs must dissolve at a concentration
high enough to allow therapeutic concentrations of the drug to reach its target.
However, low aqueous solubility can prove to be a major obstacle in the
development of liquid formulations.
 Approaches to enhance solubility

Methods to improve solubility can be categorised into a

number of different techniques. These include chemical
modications (prodrug, salt formation), physical
modications (cocrystal, solid dispersions, nanocrystals),
carrier systems (liposomes, emulsions, cyclodextrins)
and solvent modications (pH adjustment, co-solvent,
3/4
wetting agents) . The most appropriate method will
depend on several factors including an APIs chemical
properties, physical state of the formulation, and route of
administration. In the creation of liquid formulations,
solvent modications and carrier systems are most
commonly used because they affect only the solvation
characteristics of a drug rather than its solid-state
properties5.

Despite there being an abundance of techniques available,

trial and error is the most commonly adopted approach in
selecting formulation excipients to solubilize drugs. This
empirical way of doing things is not only time-consuming,
but also requires a large amount of materials to be used.
Although successful in the long-term, for drug developers,
it proves to be an extremely costly approach. A more
rational approach at this stage demands a technology or
methodology that can identify the best possible
formulation in a more efcient way.

1/2
Consequently, compounds need to be formulated with excipients that can solubilise them .
In selecting excipients which are able to solubilise a particular compound, the industry
currently relies on a trial and error-based approach. This presents a prime opportunity
for the application of a more intelligence-based methodology to formulation.
Establishing a high throughput
screen for liquid formulations
To overcome the challenges
associated with traditional
techniques, a new high throughput
screen method has been
developed to provide a more
efcient way of screening an
excipients solubilisation capacity.
From the outset of the project, the
aim was to establish a
methodology that would use
minimal amounts of API, while
providing a cost effective and
efcient way to achieve results. It
was also vital that the platform
could provide conclusive
information about a compounds
stability in varying solvents and
excipients.
In establishing the methodology,
several experiments were
performed to optimise the
approach and achieve the ultimate
objective of creating a robust,
automatic platform. After the
method had been optimised, the
screening list involved a diverse
range of excipients with different
solubilising mechanisms, for
instance6 : water-soluble organic
solvents, non-ionic surfactants,
water-insoluble lipids, organic
liquids/semi solids, cyclodextrins
and phospholipids
Different excipients will be most
applicable for different delivery
systems. For example, there will be
variance between those which can
be classied for an oral excipient
and those which are most suited to
an injectable. There is also a need Different excipients will
to understand exactly how far a
be most applicable for
concentration can go for each
excipient and each drug delivery different delivery
system. However, this should
systems. For example,
always be within the Generally
Recognized As Safe (GRAS) list of there will be variance
recommended concentrations.
between those which
Selecting the correct excipient, or
mixture of excipients, is important can be classied for an
because for example too high
oral excipient and those
dose could cause pain, hemolysis
and inammation, upon injection. which are most suited
Therefore, insight into drug
to an injectable.
solubility in numerous excipients
could assist in selecting a
formulation that minimises
The method was initially developed
unwanted effects and increases
using six commercially available
patient safety.
drugs with diverse chemical
properties. Testing was conducted
A new methodology
using 30 excipients dispensed in
The newly established high 96 well-plates via a fully automated
throughput screen platform is TECAN-robotic system. The plate
based on identifying the was shaken for at least 48 hours to
solubilisation capacity of each achieve equilibrium.
excipient for a compound to
The solubility results were
rationally select optimum
compared with solubility
excipients to make liquid
measurements performed using a
formulations. It has been designed
manual shake ask method where
to shorten the time necessary to
15mg of powder and 2mL of
identify which excipients can
excipient were added. The
solubilise a drug and which
samples were again shaken for 48
excipients a drug can remain
hours, centrifuged, and then
stable in. Instead of testing every
analysed by high-performance
excipient manually, as is the case
liquid chromatography (HPLC) to
with traditional methods, this
determine the solubility of the
methodology enables multiple
compounds in the excipient and
tests to be undertaken
detect any degradation.
simultaneously.
Findings
Figure 1 shows the solubilisation
extent for each molecule by each
excipient. Though some excipients
show better solubilisation capacity
than others; the trend varies
between the compounds.
Characterising an API based on
these specic molecular properties
enhances the selection of the most
appropriate formulation strategy,
bringing better optimisation for
drug delivery systems.
pH dependent solubility is a very
useful approach for ionisable
compounds, especially if it can be
combined with another solubilising
excipient. The contribution of solid-
state barrier to solubilising a
compound appears to be more
pronounced at a cut-off level of
solid state properties. This has
already been determined to some
extent by previous research
programmes7, and is currently
being investigated using a larger
Figure 1. Solubility of the drugs in the excipients. 15mg/mL was set as the maximum amount,
with degradation of the drug indicated in red.
set of compounds. Before this cut-
off, the solubilisation of the
compound was more compound
specic which creates the need to
also test on a larger set of
excipients.
The results of the high throughput
screen method have demonstrated
that solubility using this technique
is not statistically different (at 95%
condence interval using a t-test)
to that achieved when using a
manual approach. The method can
provide formulation scientists with
detailed information on the
solubilisation capacity of different
excipients for different compounds,
while also offering insight into the
stability of the compound in an
excipient. Additionally, it can
provide greater understanding of
the solubility and stability of a drug
in water, and acidic and basic
buffers.
The high throughput
screen method
overcomes many of the
challenges associated
with manual approaches
by being more cost-
effective and economical
in the use of materials.
The 3-5-day turnaround
time for results (per set
of compounds) is also
signicantly faster than
traditional approaches.
11
Final thought
Screening processes for
potential drug candidates
require liquid formulation
that is suitable for injection.
However, the solubility of
compounds is regarded as
one of the most difcult
obstacles in successful
formulation development.
Establishing a new high
throughput screen platform
has not only created new
potential for reducing
costs, but has opened-up
new possibilities in
improving timelines and the
probability of successful
formulation. By simplifying
formulation design, a faster
and more effective
roadmap for the
development of potential
new drugs can be
achieved.
References
1. Li, P., & Zhao, L. (2007). Developing early
formulations: practice and perspective.
International Journal of Pharmaceutics, 341(1),
1-19.
2. Dahan, A., Beig, A., Lindley, D., & Miller, J. M.
(2016). The solubilitypermeability interplay and
oral drug formulation design: Two heads are
better than one. Advanced drug delivery
reviews, 101, 99-107.
3. Alhalaweh, A., Bergstrm, C. A., & Taylor, L.
S. (2016). Compromised in vitro dissolution and
membrane transport of multidrug amorphous
formulations. Journal of Controlled Release,
229, 172-182.
4. Miyako, Y., Khalef, N., Matsuzaki, K., & Pinal,
R. (2010). Solubility enhancement of
hydrophobic compounds by cosolvents: role of
solute hydrophobicity on the solubilization
effect. International journal of pharmaceutics,
393(1), 48-54.
5. Alhalaweh, A., Roy, L., Rodrguez-Hornedo,
N., & Velaga, S. P. (2012). pH-dependent
solubility of indomethacinsaccharin and
carbamazepinesaccharin cocrystals in
aqueous media. Molecular pharmaceutics, 9(9),
2605-2612
6. Strickley, R. G. (2004). Solubilizing excipients
in oral and injectable formulations.
Pharmaceutical research, 21(2), 201-230
7. Persson, L. C., Porter, C. J., Charman, W. N.,
& Bergstrm, C. A. (2013). Computational
prediction of drug solubility in lipid based
formulation excipients. Pharmaceutical
research, 30(12), 3225-3237.
 Recipharm is a leading Contract Development and Manufacturing
Organisation (CDMO) in the pharmaceutical industry employing around
5000 employees. Recipharm offers manufacturing services of
pharmaceuticals in various dosage forms, production of clinical trial
material and APIs, and pharmaceutical product development.
Recipharm manufactures several hundred different products to
customers ranging from big pharma to smaller research and development companies. Recipharms
turnover is approximately SEK 5.3 billion and the Company operates development and manufacturing
facilities in France, Germany, India, Israel, Italy, Portugal, Spain, Sweden, the UK and the US and is
headquartered in Stockholm, Sweden. The Recipharm B-share (RECI B) is listed on Nasdaq Stockholm.

For more information on Recipharm and our services, please visit www.recipharm.com
ENHANCING PROCESS
SAFETY AND EFFICIENCY
IN THE PHARMACEUTICAL
INDUSTRY WITH CHECK
WEIGHING SOLUTIONS
By
Jana
Meier,
Marketing
Team
Leader
Product

Inspection
&
Head
of
Marketing
Checkweighing,

Mettler-Toledo

Jana Meier
Marketing Team Leader Product
Inspection & Head of Marketing Checkweighing, Mettler-Toledo

Jana Meier is a Marketing Team Leader for Mettler-Toledo

Product Inspection and Head of Marketing
Checkweighing. She is responsible for marketing activities
across all four main product inspection technologies,
including x-ray, metal detection, and checkweighing.

With over thirteen years of experience in the food and

pharmaceutical packaging industry, she coordinates new
product launches to key target markets through various
direct marketing channels and communication tools,
building product awareness and strengthening the
companys brand image. Jana has a degree in Business
Administration with a major in Marketing.
A look at how
pharmaceutical
manufacturers can
benet from the
use of
dynamic
checkweighing
technology to
comply with
international
standards,
increase process
safety, productivity
and process control

15
The need for pharmaceutical manufacturers to rely
on technological advancements has never been
greater. Stringent regulatory requirements with
regard to product safety are evolving constantly, and
with pressure on costs continuing to grow
manufacturers must look to dynamic production
equipment to ensure lines are running optimally and
producing safe, compliant products.
The blockbuster era is drawing to a close and
shorter runs and batch sizes are becoming
commonplace, largely due to growth in emerging
markets and the increased demand which this brings
for a wide range of pharma products. This demand
has shifted the focus somewhat, from production
speeds to the ability to effect fast and efcient
product changeovers and start-ups. One constant
remains, however products entering the supply
chain must be 100% safe for patient use.
Pharmaceutical manufacturers have patient safety in
mind rst and foremost, but they must also focus on
protecting their own brand reputations and the effect
that a negative incident could have on the entire
industry. Unsatisfactory products, such as
incomplete packages for example, should never
reach patients and must therefore be reliably
rejected from the production process. This is where
systems such as check weighers are invaluable. The
industry relies on trust, and to protect that trust
requires manufacturing processes to be safe,
efcient and of course compliant.
Compliance, qualication &
validation
A checkweigher effectively acts as
an inspector on a production line,
seeking out incomplete packages or
packages with open aps, for
example, to help manufacturers to
operate in accordance with
regulatory frameworks such as Good
Manufacturing Practices (GMP).
GMP can be said to dene the rules
for safe and effective manufacturing
of pharmaceutical products, and the
principles of equipment
implementation and validation can
be dened as follows:
Equipment Design Weighing
equipment should be designed for
its intended use, should prevent
contamination of the drug product
and facilitate easy cleaning
Equipment Selection The
manufacturer needs to select the
right equipment with suitable
weighing ranges and accuracy to
meet the dened process tolerance
Equipment Calibration Weighing
equipment should be calibrated
according to written procedures and
established schedules
Qualication and Validation
Weighing systems need to be
qualied and weighing processes
must be validated to document
conformance with dened
specications
 Validation of Computerised
Systems Advanced weighing
systems based on computer
hardware and software need to
comply with specic regulations for
computerised systems.
The responsibility to design the
production process and quality
programs lies rmly with the
manufacturer and non-compliance
can have severe consequences.
The FDA (US Food & Drug
Agency), for example, will rst
inspect a facility and communicate
any concerns it may have in a list
of inspectional observations. If a
manufacturer fails to respond
satisfactorily a warning letter will be
issued from which time the
manufacturer typically has three
weeks to take correctional action.
Should the FDAs concerns still not
be satised after this time, nes
can be levied, operations halted,
batches recalled and, in the most
severe cases, they may prosecute.
(FDS). This details how the
supplier plans to meet all of the
users requirements.
There follows a qualication
process that must offer complete
documentation that follows best
practices. The International Council
for Harmonisation of Technical
Requirements for Pharmaceuticals
for Human Use (IHC) stipulates
that qualication of equipment
should cover design, installation,
operation and performance, to
ensure the checkweigher is entirely
t-for-purpose. The entire process
can then be validated, reducing
the risk of potential nes that may
result from non-compliance.
The responsibility to
design the production
process and quality
programs lies rmly with
the manufacturer and
non-compliance can have
severe consequences.
The FDA (US Food &
Drug Agency), for
example, will rst inspect
a facility and
communicate any
concerns it may have in a
list of inspectional
observations.

For the equipment manufacturer, it

must be able to demonstrate to the
inspecting agency that its
processes have been understood
and quality requirements have
been met. A User Requirement
Specication (URS) must be
prepared by the pharma
manufacturer ahead of equipment
qualication, to identify every
requirement related to the product,
and the supplier responds with a
Functional Design Specication

17
The importance of reliable testing
procedures and the traceability of
process change
As with any system that features
precision components, regular
testing to ensure accuracy is vital.
Many pharmaceutical
manufacturers verify checkweigher
functionality outside of normal
production processes, with the
results recorded manually on a
separate document. This method
of testing has several pitfalls, in
that it is very labour intensive,
causes operational downtime and
relies on operators to test
consistently in order to achieve
reliable results.
Dynamic checkweighers on the
market today are capable of
performing In-Process Tests, which
reduce the risk of errors during
testing procedures. They can be
highly exible in order to adapt to
customer requirements, generate
reports automatically for each test
scenario and most importantly
do not require any shutdown of the
production line. Easy-to-use user
interfaces use screen prompts to
guide operators through the
complete procedure, recording the
results which can then be saved
and printed if necessary.
In order to monitor process
changes, a local audit trail can
operate in the background to
monitor any changes made to the
system. This is in compliance with
21 CFR Part 11 requirements,
which specify that access to
electronic systems is limited to
authorised users, audit trails must the variable being monitored is
be secure, computer-generated measured and recorded. Samples
and time-stamped to record the of the product being produced
date and time of operator entries would be taken and weighed and
and actions that create, modify, or the mean and standard deviation
delete electronic records. No monitored. If control limits are
record changes can be breached, the process is halted
overwritten, and records must be and operators then attempt to
retrievable for a specied period identify and correct the issue.
established for electronic records.
The local audit trail records an Using Statistical Process Control
index for each separate entry, (SPC) allows manufacturers to
which includes date/time stamp, understand when a process should
user-ID, modication area, the be adjusted or left to run. SPC
modied parameter detail name, recognises the importance of
the old and new parameter values controlling variation, rather than
and, if required, an explanation for individual measurements, and
the parameter changes. All accepts the fact that some level of
information can be easily random variation will always exist
integrated into a centralized in a process. SPC is used to
database if required. determine what amount of variation
is common, and uses a control
Optimising process control chart to show whether sample data
falls out of normal range. Upper
In order to optimise process
and lower control limits can be set
control it is possible to use
from assignable variation and the
statistics to improve process
production process monitored to
performance by studying variation
ensure the variation stays within
and its source. By using control
that range. This is known as
charts, manufacturers can detect
process variation. "Assignable
process variation and therefore
causes of variation" is another form
drive process improvements. This
gives them the potential to avoid
production of products that do not
meet requirements satisfactorily.
By making process improvements,
more consistent performance can
be achieved at a lower cost and at
a higher effective capacity.
Monitoring characteristics that
have a continuous scale and can
be measured, such as weight or
volume, is an important element of
control charts for variables. When a
pill bottle is inspected, for example,
of variation, where the cause can therefore rejected by the check Working with an expert partner to
be identied precisely and weigher. Off-centre, or eccentric, ensure your processes are safe,
eliminated. A machine in need of packages as well as products that efcient and compliant is essential
repair is an example of assignable are not spaced correctly can also in the pharmaceutical industry and
variation. transfer differently to the system, check weighers have a very
which can compromise weighing necessary role to play. Achieving
Product Handling performance. Transfer units the correct weight in th is industry
consisting of top and bottom means meeting the legal
In order to maintain process safety
conveyors, side grip belts and requirements for weights and
there are a number of elements
timing worms can assist with measures, for example, while
that must be operating correctly
consistent spacing, which also rejecting products that have
with regard to checkweighing. The
helps to provide smoother missing components could save
way in which products are
transfers to the check weigher. lives. A medical kit could be
transferred to the checkweigher
Ensuring that every package is needed in a time-critical situation,
and then back onto the production
presented to the weigher in the and if a component is missing the
line is a good example, as any
best possible way is vital, so that in ramications could be severe.
unnecessary movement of the
terms of technical challenges 90%
product during weighing will have
of check weighing comes down to The importance of selecting
a direct effect on the accuracy of
good package handling at high competent suppliers cannot be
the measurement. In some
throughput. stressed enough. Ensure your
instances check weighers will need
suppliers are up to the minute in
to be installed away from areas
From a production perspective, the their regulatory knowledge, can
where vibrations or mechanical
checkweigher can also protect demonstrate proven efciency and
shock could occur, as this could
downstream equipment from have the know-how to integrate
also be detrimental.
unnecessary damage. Cartoners systems into existing production
occasionally do not close aps on facilities. By taking the time to
The position of packages is also
packs correctly, which can then select the correct partner your
an important element to consider.
become entangled with guide rails processes can be protected - as
For example, askew packs are
or other hardware, therefore failure well as your reputation and that of
likely to cause product backup in
to ensure process safety has the your clients.
downstream machinery and are
potential to be very costly.

METTLER TOLEDO is a leading global supplier of precision instruments and services. The company has strong leadership
positions in a wide variety of market sectors and holds global number-one market positions in many of them. Specically,
METTLER TOLEDO is the largest provider of weighing and analytical instruments for use in laboratory and in-line
measurement in demanding production processes of industrial and food retailing applications.

The Product Inspection Division of METTLER TOLEDO is a leader in the eld of automated inspection technology. The
Division incorporates the Safeline Metal Detection and X-ray Inspection, Garvens and Hi-Speed Checkweighing and the CI
Vision and PCE Track & Trace brands. The solutions provided by the business increase process efciency for
manufacturers while supporting compliance with industry standards and regulations. Systems also deliver improved
product quality which helps to protect the welfare of consumers and reputation of manufacturers.

For general information on Mettler-Toledo Product Inspection, visit: http://www.mt.com/pi

19
CELL-BASED
THERAPY AND
FDA REVIEW
Partnering
for
Success
at
Your
Pre-IND
Meeting

Michael Naimark is the Director of Business

Michael Naimark
Director of Business Development, CBSET Inc.
Development at Lexington, MA-based CBSET, Inc.,
a leading preclinical CRO providing state-of-the-art
biomedical research services to the pharmaceutical,
medical device and academic research communities.
Michael has more than 16 years of experience in
biomedical and preclinical research as a Study
Director and Project Manager, where he has
overseen the development of novel cell-based
therapies and managed a wide range of preclinical
projects for regulatory submission. He earned an MS
in neurobiology at the University of Tennessee and a
BS in biology/biological sciences at the University
of Mississippi. Michael holds certicates in
Medical Device Regulatory Aairs and Biologics
Regulatory Aairs from Colorado State University,
and is the co-author of several peer-reviewed
scientic papers.
Regenerative and cell-based
therapies have only recently begun to
deliver on the promise they have
portended for years, creating
opportunities to positively impact
patient outcomes and professional
success. In the same way that these
new and exciting biological
approaches have the potential to
revolutionize therapeutics, their very
novelty also poses new challenges
and opportunities for those of us
charged with their development. This
is especially true for individuals and
teams seeking to move toward the
clinic with technology originating
from academic collaborations.
Many of the truly groundbreaking
developments in this still-emerging
eld are originating at a time when
many historic funding mechanisms
are placing greater demands on
entrepreneurship and market-based
opportunities for investigator and
department alike. The rapid growth
and advancement of the
technologies, combined with the
entrance of new players in this
market space, make navigating the
regulatory review process quickly and
efciently more pressing than ever.
If you are a veteran of
traditional small
molecular
pharmaceutical
therapies preparing for
your rst regulatory
marathon with the
agency, you should
familiarize yourself with
some signicant and
valuable differences
between how the
process currently plays
out in this still-
developing area of
regulatory review. Here
are four tips on how to
prepare and use the
meeting to your
advantage.
1) Take a pre-pre! One of the
unique and exciting opportunities
available to your translational cell-
based program is something only
available through the CBER/OCGT
ofces literally a pre-, pre-IND
meeting to give the agency an
opportunity to unofcially review
where you are and where you plan
to go next, in advance of the formal
Type-B pre-IND meeting. The
meeting is informal, generates no
agency minutes, and can be
absolutely invaluable in planning
your project development
milestones well in advance.
Prepare for your pre-pre-IND
meeting as you would for your pre-
IND. In particular, be sure all of
your key scientic and regulatory
partners are able to participate in
the teleconference to make certain
you are able to maximize the value
of this outstanding opportunity to
gain direct guidance and input
from the same organization that
will ultimately decide the success
of your project. A good pre-pre-
IND meeting can familiarize you
with some of the same reviewers
and potential areas of focus you
will encounter again at your pre-
IND meeting and beyond. Some
traditionalists may consider this
interaction with the agency to be a
luxury. You should view it as a
necessity. A few hours of
preparation can save you months
of work. A few well-considered
comments from a reviewer could
save you a fortune in development
efforts.
2) Get the right team involved at
the right time. This is common
sense to veterans of CDER review,
of course; nonetheless, having a
properly built roster of partners
carries additional weight in your
interactions with the agency when
dealing with a eld that evolves as
rapidly as cell-based and
biological therapies. Begin
screening for your ideal CMO and
preclinical CRO partners early in
your project roadmap; these
groups can be powerful partners at
Representatives from your
GMP CMO and preclinical
CRO should be involved in
your preparations for the
earliest possible interaction
with the agency to help
rene your approaches,
anticipate issues, and offer
justications to your
choices.
critical phases in the development
of your therapies. Your CMO and
CRO teams should be able to
bring valuable experience when
operating within the FDAs
regulatory structure and can help
ensure that your developmental
milestones are realistic and
appropriate. Representatives from
your GMP CMO and preclinical
CRO should be involved in your
preparations for the earliest
possible interaction with the
agency to help rene your
approaches, anticipate issues, and
offer justications to your choices.
An experienced regulatory
compliance consultant with
knowledge of CBER/OCTGTs
evolving approaches to cell-based
therapies is always a welcome
participant and strengthens your
position entering into your
interactions with the agency by
properly interpreting the written
and spoken feedback you will get
before, during, and following these
meetings.
3) Manufacturing for the long term.
Anyone who has been through the
pre-IND process with any branch
knows how much emphasis the
agency puts on CMC issues, but
for your cell-based therapies there
is even greater urgency to get an
early grip on your process. With
many cell-based methods it is
almost impossible to avoid animal-
origin excipients (including human-
derived factors required in many
stem cell-based protocols), so of
course you will be doing your due
diligence in sourcing and
compiling all of your CoA and CoO
records. But be aware the
agency wants to see xeno-free
processes sooner rather than later.
Your CMO team may have some
experience in possible alternatives
worth considering as you build
towards your process lockdown.
While the agency is not currently
demanding xeno-free
manufacturing for your cell-based
therapies, do not be surprised if
they ask whether your team is
developing one and how far along
your development is. Be prepared
with an answer.
4) The rules are different here. In
the small-molecule world you
come into your pre-IND meeting
prepared to discuss your plans to
follow the well-worn path the
agency has promoted for decades.
The numbers, the species, the
endpoints all of these critical
study design aspects are largely
rote in most cases. With the cell-
based therapies things are
different. Because of the rapid
evolution of the science, the agency
is more willing than ever to listen to
23
well-founded scientic proposals and
counter-proposals for your critical
studies. Make your CRO and CMO
collaborators key partners in your
process, adding their regulatory and
program experience to your scientic
expertise. If a single species
represents your best in vivo model for
both safety and efcacy, you can make
that case. If you believe you can best
achieve your scientic objectives using
only rodents in the preparation of your
IND, your preclinical partners can help
support your argument in a proposal
that can maximize receptivity. If a well-
dened agency-recommended release entrants create some truly
assay is inferior to one youve unprecedented opportunities for
developed in-house, you will get a fair entrepreneurs and investigators to
hearing to defend the alternative. The make an impact with their novel cell-
term I have heard over and over again based therapies. As the regulatory
regarding these critical meetings with environment continues to evolve
CBER and OCTGT is reasonable. around these advances,
The agency is still in the drivers seat in creating the right development
reviewing your roadmap to the clinic, program with input from the right
but for perhaps the rst time, the support partners can provide a
investigator gets to ride shotgun. translational pathway for your science
that gives you a critical advantage over
The combination of the rapid increase competitors.
in our abilities to harness and modify
cellular mechanisms and the openness
of the commercial market to new
Maximize your impact
by recognizing how
this pathway differs
from the traditional
IND, and seek to
exploit these changes
for the benet of your
product, your team,
and the ultimate
beneciary - the
patient population in
need of novel and
efcacious
technology.

CBSET, Inc. is a leading, non-prot, preclinical research institute located in

Lexington, MA, USA, specializing in the advancement of novel therapies. Our
mission is to advance biomedical science through innovative, high-quality services,
combining top-tier research with operational expertise. Since our inception, CBSET
has pioneered a range of technical and scientic breakthroughs through
collaborative projects in the pharmaceutical, medical device, and academic communities. CBSETs 40,000
square foot, GLP-compliant, AAALAC-accredited facility includes vivaria, procedure rooms,
catheterization/imaging labs, surgical and necropsy suites, histopathology, electron microscopy, and a range of
other technologies. Learn more about CBSETs expert preclinical research services at www.cbset.org.
OVERCOMING
THE CHALLENGES OF
CLINICAL TRIAL
RECRUITMENT USING
BIG DATA
TECHNOLOGIES
Cornelia has 20 years experience in the IT
industry, researching the use of IT in selected
industry verticals. Since 2008, she has specialised
in the international healthcare market. Before then,
her eld of expertise included IT services, public
sector, consumer electronics and
telecommunication end devices. Within healthcare,
she has worked on topics like telehealth and remote
patient monitoring, big data, analytics,
gamication, connected care in the ambulatory and
hospital domains and health insurers move towards
digital therapies. Cornelia holds a Master of
Economics degree from the Johann Wolfgang
Goethe-Universitt Frankfurt (Main), Germany.

CORNELIA WELS-MAUG
Principal Healthcare Analyst, Creative Intellect Consulting
 The problem dened
Any prospective new drug must
successfully pass a succession of three
clinical trials phases, before it can apply
for market approval. These trials
represent a signicant investment for a
pharma company and, as they are prone
to delays and can even fail altogether,
they put immense nancial pressure on
them.
One of the root causes for the failure of
trials is the inability to recruit the specied
number of eligible patients in the foreseen
time span. Delays in the
market launch can amount
to as much as US$8 million
per day for a blockbuster
drug in opportunity costs for
a pharmaceutical company.
Today, eligible patients are
still mostly identied by
manually scanning physicians patient
lists. But this is not only a time
consuming, resource-intensive and
lengthy procedure, it is also far from fool
proof. Many suitable candidates may be
missed.

A viable and effective solution:

automated patient recruitment

The proposed solution takes advantage of an emerging trend to digitise

patient records at hospitals, which means that hospitals have a database
of patient information in more or less real-time. An electronic solution
which can (indirectly) query this data can obviate the above procedural
problems. This results in a more efcient and effective recruitment
process, that takes less time, frees up resources and is rigorous in
matching patients to protocols. All this, ultimately, leads to a faster launch
of new therapies.
Clinerion: A compelling patient
recruitment system provider
Swiss software solutions vendor Clinerions
mission is to improve the efciency and quality of
the traditional patient recruitment process. Its
Patient Recruitment System (PRS) facilitates the
electronic selection of trial sites and the
recruitment of patients, by screening hospital
patient data in real-time. PRS optimises and
accelerates the clinical trial process in modules,
which helps to optimise the study protocol, select
high-potential trials sites and nd more eligible
patients in a shorter time period. On average,
PRS nds 10 to 30 times more patients, faster,
compared to manual screening.
PRS works by screening the electronic health
records (EHRs) of networked partner hospitals
that are located in diverse geographies. In doing
so, it reaches millions of candidate patients in
those institutions. Although each hospitals
database may have a different structure and may
be supplied by a different systems vendor, the
patient records from the multiple sources are
made interoperable by a set of mapping and
semantic methodologies.
A process of patient ID pseudonymisation, the
placement of queried servers within a hospitals
own premises and the use of a distributed cloud
network ensure patient privacy.
As a result of the efciency increase, occasioned
by PRS, and of the higher exposure to Clinerions
international clients, hospitals in the PRS network
have a higher likelihood of participating in
leading-edge sponsored trials, which can
improve their academic reputation and increase
institutional revenues.
Making the
case for PRS:
Balancing clinical
trials with business
needs
Before a new drug can be
launched on the market, it needs
to go through a set of three
consecutive clinical trial phases
that assess the safety and
efcacy of a newly developed
medicine on humans. However,
less than 40% of these trials are
completed successfully.1
A major factor in the success of
a trial is the patient recruitment
process. This is because the
identication of the specied
number of eligible patients who
meet the ever more complex
inclusion and exclusion criteria,
within a given time frame, can be
a considerable hurdle. In Phase
3 trials, where the size of the
study sample is signicantly
larger than in the two previous
stages, having sufciently large
patient numbers is especially
vital.
Assessing the real costs of poor
patient recruitment
An analysis of more than 100 trials established that just
under one-third of them did not meet their recruitment
target and half needed to prolong the recruitment
period to full this target. 2 Delays in recruiting the
required number of patients at an investigator site can
compromise a trials statistical power and scientic
validity. It also means that the availability of potentially
benecial treatments to the public is postponed.
Every day that a drugs launch is delayed comes at a
high cost for a pharma company. Missed sales for a
blockbuster drug can amount to an estimated $8
million (USD) and up to $600,000 (USD) for a less
popular product.3 All of this can add to the overall
development cost for a pharma company.
Clearly, it is in the interest of the pharma companies to
render the clinical trial process more efcient and less
costly. And since patient recruitment represents, on
average, about 30% of the overall time required for
conducting clinical trials, making this area work faster
and more effectively will help achieve this. There are, of
course, other additional costs factors that need to be
tackled, such as regulatory and administrative barriers
and the growing competition for qualied investigators
and sites. However, these are not in the remit of this
paper.
Difculties in patient
recruitment often r
esults in delays and,
in the worst case scenarios,
the actual
cancellation of a trial.
29
Resolving the pitfalls of
recruiting patients into
clinical trials
To enrol patients, there are various
methods of patient screening.
However, the predominant one is
to cooperate with healthcare
providers, especially hospitals.
This allows investigators to tap into
the existing pool of patient data
archives. Nevertheless, if done
manually (still the prevailing mode)
it is highly labour intensive and
time consuming and, therefore,
expensive. Moreover, its results are
not always reliable mainly due to
a lack of medical knowledge and /
or insufcient understanding of the
research protocol, from those who
conduct the scanning.
It is true that the growing
digitisation and consumerisation of
healthcare have helped to
overcome some of the speed and
efciency limitations of traditional,
manual patient recruitment
methods and provided the scale to
reach the wider population.
Examples include the use of social
media, patient networks (e.g.
PatientsLikeMe) and advocacy
groups (e.g. the Multiple Sclerosis
Society), which allow patients to
self-identify themselves within
communities that are potential
recruitment grounds for trials.
Meanwhile, the patient
engagement and retention work of
third-party patient recruitment
service providers (e. g. Acurian,
Synexus) is another means to
render the trials process
more efcient.
But it is the growing
availability of electronic
patient data that,
potentially, has the
biggest positive impact
on patient recruitment. It
paves the way for a more
efcient and scalable
recruitment process, as
well as speeding up the
screening of eligible
candidates.
The adoption of hospital
information systems (HIS)
to capture data,
generated during patient
care, including those from EHRs,
has made the identication of
potential trial subjects signicantly
more efcient, as it allows the pre-
selection of patients for specic
trials, based on their disease
status and individual
characteristics. An automated
notication system can alert study
teams at a hospital when suitable
patients become identied, so that
the team can then retrieve the up-
to-date list of potentially eligible
candidates from the HIS. In a next
step, authorised access to the
patients full EHR can allow the
study team to retrieve additional
information, in order to verify their
eligibility. Once done, a study
physician can then seek consent
from the patient to participate in
the trial.
Having the means to screen, not
just one, but multiple healthcare
institutions even across different
countries for eligible patients
would further shorten the overall
time needed for patient
recruitment. To this end, a platform
is needed that uses real-time data
from EHRs and can access
multiple HIS types. Provided it
complies with privacy and other
relevant governance and security
policies, patient screening can be
done in a fraction of the time
needed for the manual screening
process and with improved
results.


31
These four features constitute a system that can query and aggregate patient information, across multiple local
installations, within a network of hospitals, across different geographies, and without compromising patient
privacy. As more and more hospitals install PRS, the PRS-hospital-network will grow and with it the pool of
suitable candidates.

Once installed, PRS is controlled by a sites own IT department. To ensure privacy and security of patient data, the
latter is pseudonymised and patient IDs can only be re-identied by authorised personnel on a hospitals
premises, via PRSs Patient Finder tool. Each site controls the pseudonymisation, to ensure that no unauthorised
re-identication of patient IDs can be performed. As soon as a patient who matches eligibility criteria is identied,
the respective study team will be notied by SMS text, Instant Messaging or email.
Proven benets for hospitals using PRS
Launched in 2013, PRS has acquired a growing network of partner hospitals that permit real-time access
to their anonymised patient data. The partner hospital network comprises research-heavy hospitals in
Turkey, with a total current patient catchment area of around 30 million. Those hospitals using PRS have
beneted from more efciently run clinical trials, resulting in a signicant reduction in time and resources
needed to conduct clinical studies. Further more, with the assistance of PRS, the hospitals are now in a
position to improve their trial revenues, as well as their academic reputation.
A SCAPEGOAT
FOR SITE PAYMENT
CHALLENGES

Dave Espenshade
Vice President of CRO Partnerships, Greenphire

In his role as Greenphires Vice President of

CRO Partnerships, Dave leads the eorts to
broaden the use of Greenphires solution
suite among global CRO partners.
Greenphire is currently working with eight
of the top 10 global CROs and continues to
see an increased demand for both its
investigator payment solution, eClinicalGPS,
and patient reimbursement solution,
ClinCard, within this sector.
Managing site payments is not an easy task. They are frustrating, burdensome and
a drain of time and resources. CROs, specically project managers, are often
tasked by their sponsor partners to manage the site payment process and
consequently are deemed at fault for any issues that arise, such as late or
inaccurate payments. As a result, project managers often spend hours verifying
payments and elding site inquiries on the status of a payment, causing frustration
and increased employee turnover. These issues and complexities are only
multiplied when dealing with site payments on a global basis as they come with
their own set of regulations and standards.
 For CROs, outsourcing the entire site
payment process to a third party has the
potential to introduce additional
complexities and risks to the process.
Fortunately, technology exists today that
can streamline the site payment process,
and give CROs the tools they need to
more efciently and effectively handle the
site payment process without the
headaches.

Historically, the clinical trial Technology Delivers a Technology Improves the

industry has been known
as being slow to adopt,
with the common fear that
the implementation of a
new solution could
interrupt current workow-
regardless of how
inefcient current
processes are. However,
solutions today are being
strategically built to t
CROs workows without
interruption and confusing
on boarding processes.
Listed below are specic
ways technology can
impact CROs and help
produce better clinical trial
experiences for all.
Better Way to Pay as Trials
Expand Globally
Advanced and evolving technology
in payment solutions eases the
burden on CROs in a number of
ways, such as helping to navigate
payment complexities as trials
expand globally at an increasing
rate. According to Clinicaltrials.gov,
47% of current clinical trials are
conducted outside of the U.S.,
which adds another layer of
complexity due to additional
regulations, languages and
currency types. Choosing a
technology that is proven to handle
global payment regulations can
decrease your risk of failing to
comply with foreign regulations,
and enable your team to be
condent in their process while still
focusing a majority of their efforts
on the research.
CRO Site Relationship
According to the Society of Clinical
Research Sites, 65% of sites have
less than three months operating
cash. This shortage of cash on
hand can threaten the timeline and
ow of the study. This puts
pressure on CROs to ensure sites
are getting paid regularly and on
time. Lack of cash ow can also
put a strain on a sites relationship
with a CRO and lead to questions,
which oftentimes are left
unanswered.
By introducing efciencies, control
and visibility into payments, sites
and CROs are armed with the data
they need to condently answer
tough questions with ease. For
example: when will my payment
arrive? What is this payment for?
Why arent we being paid for x, y,
and z? Centralized nancial
transparency and automated
reconciliation keeps sites operating
at peak performance.
Technology Improves
Financial Transparency
Paying sites on time is important to
the clinical trial process, but when
technology is introduced, CROs
can also benet from insightful
analytics, leading to better
decision-making.
Technology solutions can also
provide long-term predictability
and budget management,
budgeted costs vs. actual
expenditures, accruals
management and cash ow
predictability. The ability to plan,
project, and gain insight into costs
from nancial data can be
extremely benecial for all parties
involved. These are simply not
available for CROs still using Excel
spreadsheets.
A signicant investment is at stake
to complete a single clinical trial,
nancial transparency is key for all
parties involved. Investing in
technology makes it easier to keep
track of payments. Failure to
adhere to clinical trial rules on
compliance and transparency can
lead to compliance misconduct
and fraud, which can include nes,
fees and even jail time, in addition
to lost time and resources on the
trial itself.
Technology Addresses
Increasing Industry
Regulations
Aggregated payment reporting for
health care providers continues to
grow globally, with increasing
requirements for consolidation of
payment data at the healthcare
provider level. Requirements
outside the U.S. are continuing to
develop, at both the country level
and through large inuential
associations.
These reporting requirements
represent another disruption to
traditional practices to the clinical
operations model. Disparate data
sources combined with the manual
processes on which many
organizations rely to track crucial
information make it quite difcult
and labor intensive to collect and
accurately report aggregate spend
data as well as the specic
transparency requirements of each
country and/or associations.
Technology: A Key
Advantage for Sponsors,
CROs and Sites
With such high stakes involved in
completing a clinical trial, the last
thing sponsors CROs and sites
should have to worry about are
payment issues. At the end of the
day, how to advance a new drug or
treatment through the process of
FDA approval (and beyond) should
be where time and resources are
focused. Implementing technology
to automate the process takes the
headaches out of equation all
while improving CROs
relationships with the sponsors
and sites it works with.

Greenphire is the leader in global clinical trial payment solutions.

Greenphires best-in-class solutions optimize clinical trial
performance by simplifying and streamlining payment processes
from sponsors and CROs to sites and patients. Greenphires
ClinCard and eClinicalGPS solutions easily handle any type of trial
design and complexity, resulting in more accurate and compliant
payments globally for both sites and patients. The choice of
industry leaders worldwide, Greenphire provides better
performance and better data, resulting in better trials. Learn more
at www.Greenphire.com.
HIGH BARRIER
CONTAINERS MEET
NEW STANDARDS
IN HEALTHCARE
PACKAGING
Barrier
Solutions
Designed
to
Protect
Pharmaceuticals

Greg Rosati
Healthcare Marketing Director
for Amcor Rigid Plastics

Greg Rosati is currently the Healthcare Marketing

Director for Amcor Rigid Plastics. Amcor is currently a
member of the Healthcare Compliance Packaging
Council (HCPC) and the Active and Intelligent
Packaging Industry Associates (AIPIA). Greg has 24
years of packaging experience including 15 in
Healthcare. He has held various leadership roles in
Product Development, Sales, Marketing and Quality
Systems and holds a Bachelor of Science Degree from
Michigan State University.
Deliver Major Benets for Primary Packaging
Stability
Solution
Today, the chief purpose of primary packaging is product
protection. However this performance capability has
become more challenging in recent years as the
complexity of active pharmaceuticals and their supply
chain increases.

There are many choices when considering material

selection, most of which are driven by
product performance or product compatibility. The
decision is difcult if the standard materials HDPE, PET,
PP) are not capable of meeting the performance
requirements. In addition to standard materials there are a variety of barrier options
including coatings, additives, and multilayer congurations all of which come with a
separate set of considerations including cost, product compatibility, and recyclability.
Amcor Rigid Plastics has a broad portfolio of barrier products ranging from additives and
coatings to engineered resins offering both active and passive options. The
companysStability Solutions is a suite of three products specically designed to
protect pharmaceuticals and extend their shelf life. These barrier alternatives offer
protection from moisture, oxygen, and CO2

Portfolio includes mono-layer

and multilayer congurations

All three barrier options are capable of

being customized to a variety of bottle
sizes and geometries and allow the
customer to control the level of barrier
resistance both optimizing and managing
shelife throughout a products life cycle.
Amcors technical center in Manchester,
Mich. is equipped with the analytical tools
capable of measuring moisture ingress,
oxygen loss, and CO2 loss. The chart demonstrates the remaining moisture absorbing capacity after recovery.
Stability DryTM Incorporates Desiccant
Amcor has developed patent pending technology incorporating desiccant in the product contact layer of bilayer
co-extrusion blow molded containers. The outside layer is formed from high moisture barrier polyethylene or
polypropylene to protect the desiccant from permeating moisture from the environment.

The primary container creates and maintains a dry head space. It regains a dry
head space even after exposure to high relative humidity (RH).The thickness of the
desiccant layer and the outside layer can easily be tailored to optimize package
performance. Stability Dry is covered under both Amcor and the desiccant
suppliers Drug Master File.

Maintains low relative humidity (RH) within sealed

container

u Product contact layer: Moisture Absorption from head

space
u CaO reacts with moisture forming calcium hydroxide
[Ca(OH)2].
u Ca(OH)2 is generally recognized as safe for direct food
contact (CFR 21.184).
u Theoretically 0.32g H2O + 1g CaO = Ca(OH)2

Blend 30% HDPE + 70% CaO Desiccant

Concentrate
3g CaO, 39 mils thickness: Total Mass = 14.6g

4g CaO, 52 mils thickness: Total Mass = 20.8g

5g CaO, 65 mils thickness: Total Mass = 25.4g

Additional Benets
u No lling line canister or sachet equipment
u Eliminates cost and inventory of canisters

Minimize product contamination from dust or

canister/sachet breakage
u No consumer ingestion of canister or sachet

41
Stability UltraTM
New option has provided maximum barrier protection for a leading pharmaceutical
manufacturer since 2013. The package is designed to protect the product from oxygen
degradation by sandwiching a layer of EVOH between two layers of HDPE or PP. The
bottle is produced through a co-extrusion process via extrusion blow molding (EBM)
shuttle technology which allows exibility in the layer structure.

u Three-layer construction:
HDPE + adhesive / EVOH / HDPE + adhesive OR
PP + adhesive / EVOH / PP + adhesive
u Adhesive blended with structural layers
Bonds structural layer with EVOH oxygen barrier layer
Eliminates two specic adhesive layers
u HDPE / EVOH / HDPE - Published patent application
u PP / EVOH / PP patented
u Conforms to FDA direct food contact for packaging dry products with no free fat or oil

Stability LiteTM

Monolayer solution is designed to light weight Key Highlights:

the container by 15-20% without sacricing v 25-40% barrier improvement
oxygen and moisture barrier as well as (MVTR and OTR)
maintaining light protection. This material v Ability to light weight (15-20%)
solution improves the containers dimensional v Improved dimensional stability of
stability, allowing a reduction in gram weight or critical variables
v Permits use of existing tooling
an extension of shelf life at the existing gram
v Instead of light weighting, Stability
weight.
Lite can be used to extend shelf life
by 20-40%, providing a small
Stability Lite is designed for injection blow
extension when needed
molding (IBM) and can be used with existing
tooling thus eliminating the need for additional
capital investment.
Overview: Primary Benets of Stability Solutions TM

u Extendedshelf life and enhanced product protection

u Total cost of ownership
u Sustainability
o Package weight is optimized (e.g. eliminates over packaging)
u Safety
o Desiccant canister/sachets can open and leach into the drug product
o Canisters and sachets are prone to dust
o Sachets and canisters can be a swallowing hazard

Amcor Limited (ASX: AMC; www.amcor.com) is a global leader in responsible

packaging solutions, focusing on a broad range of exible and rigid plastic
packaging that enhances the products consumers use in everyday life, with
95 percent of its sales into the food, beverage, healthcare and tobacco
industries. The company employs more than 31,000 people worldwide,
operating in 40-plus countries and across more than 190 sites.
THE ARRIVAL OF
QUALITY BY
DESIGN IN
LOGISTICS

Mark Sawicki brings 15 years of business development

Mark W. Sawicki Ph.D.
CHIEF COMMERCIAL OFFICER, CRYOPORT
and sales management experience, having consistently
delivered on corporate revenue and market share goals
in the pharmaceutical and biotechnology industries.
Sawicki was most recently the chief business ocer at
AAIPharma Services Corporation/Cambridge Major
Laboratories Inc. Additionally, he has served in senior
business development roles at CMC Biologics and
Albany Molecular Research Inc. (AMRI), where he
increased revenue at rates far outpacing industry
standards. Sawicki holds a bachelors in biochemistry
from the State University of New York at Bualo and a
Ph.D. in biochemistry from the State University of New
York at Bualo, School of Medicine and Biomedical
Sciences. He also received graduate training at the
Hauptman Woodard Medical Research Institute.
Sawicki has authored a dozen scientic publications in
drug discovery with a focus on oncology and
immunology.
Quality by Design (QbD) is a concept that has become mainstream in the pharmaceutical manufacturing
space in recent years. QbD is a science- and risk-based approach to quality that identies, measures and
denes the critical processes that impact quality and provides a pathway to introduce quality and risk
management into the design process. The process begins with a target product prole (TPP) that
describes the intended use, safety and efcacy parameters of the product. Critical quality attributes
(CQAs) such as equipment hold time, nitrogen evaporation rate (for dry vapor liquid nitrogen shippers)
and orientation will need to be identied based on the TPP. By understanding the design space (the sum
total of all variability) and control space (the sum total of all acceptable variability),CQAs can then be
utilized to produce a process supporting the TPP to provide enhanced process controls.

The QbD concept within logistics
cannot be implemented without an
in-depth understanding of the
equipment and processes by
which critical pharmaceutical
commodities are packaged and
shipped.
QbD incorporates modern tools
such as GPS-enabled, real-time
condition monitoring systems to
preemptively understand and
ultimately work to control variation.
The process cannot be
implemented without the ability to
dynamically measure and
understand the variation that exists
in the logistics process by using
historical data, testing and
modeling to help analyze, forecast
and eliminate risk during transport.
Within regenerative therapy
product distribution, for example,
one needs to have the aptitude
and systems to measure and
understand not only the validated
hold time of a cryogenic dry vapor
liquid nitrogen shipper, but also to
understand the inuence on hold
time due to repeated use,
charging, LN2 capacity, orientation
and shock, as well as a myriad of
other external events. Additionally,

Figure 1: Variables impac ng the dynamic hold me of a dry vapor liquid nitrogen shipper

45
this data must be used to manage
the dynamic risk to the product
(Figure 1). The ability to effectively
measure these factors requires
intensive data collection of every
dry vapor shipper in use during
every transit event, providing the
ability to track historical shipper
performance at the unit level.
The key to QbD implementation is
the ability to measure and
preemptively control variation in
real time using modern tools such
as GPS-, cellular- and Wi-Fi-
enabled condition monitoring
systems. Sophisticated condition
monitoring systems can provide
the ability to measure and
understand the in-transit variation
that exists, as well as to collect
critical data to help forecast,
analyze and design process
controls to eliminate the
deleterious effects of the observed
variation, using three basic
activities:
1. Evaluating the actual
performance of the equipment and
in-transit processes
2. Comparing the actual
performance of the equipment and
in-transit processes with goals
3. Acting on any discrepancies
observed during the in-transit
process
If we are to look at an example of
this process in action, one in-
2
transit variable critical to the
transportation of regenerative
therapies is the orientation of the
dry vapor liquid nitrogen shipper
during transit. It is well
documented that a dry vapor liquid
nitrogen shippers orientation
heavily impacts the overall hold
time of the shipper. A dry vapor
liquid nitrogen shipper on its side
or turned upside down can take
hours or even days off its
prescribed hold time, in some
cases reducing its hold time by as
much as 70 percent. In studies
Cryoport conducted using its
SmartPak IITM condition monitoring
systems, we could observe in-
transit misorientation during a
transportation study in 32 of 33
shippers (we looked at both dry
vapor liquid nitrogen shippers as
well as dry ice packaging) with an
average time misoriented between
10 and 30 percent depending on
3
the package type (Figure 2). In
fact, there were multiple examples
of cryo-shippers that spent more
than 75 percent of their in-transit
time misoriented (Figure 3).
The conclusion reached was that
QbD was a critical necessity for the
effective cryogenic transportation
of regenerative therapy materials.
Using static validation studies
alone was insufcient in managing
risk, as the most thoroughly
qualied dry vapor liquid nitrogen
shipper could lose 70 percent of its
validated hold time due to in-transit
handling. Using data captured
dynamically by means of real-time
GPS, cellular and Wi-Fi condition
monitoring systems, one can
develop algorithms that can
dynamically adjust and predict the
hold time of a dry vapor liquid
nitrogen shipper while it is en route
and more effectively manage the
risk to the commodity. This enables the user to humidity and atmospheric pressure to create
understand the in-eld remaining hold time of a dry algorithms that have the capability to track remaining
vapor liquid nitrogen shipper in hours, not days, and hold time of vacuum paneled shippers to a matter of
develop risk mitigation and intervention procedures a few hours and signicantly minimize or even
to prevent product loss before it occurs. eliminate temperature excursions as acceptable risk
factors in the process. This acceptable variance in
Automating the risk management process through temperature
effective use of QbD using real-time informatics is a range is much
critical consideration when contemplating support of tighter in the
a commercial product in the eld of regenerative 2-8C space
medicine. Informatics to capture, interpret and than the
predict, as well as to provide automated alerts cryogenic
and pre-dened escalation protocols based on the space (only 6
nature of the data captured for hundreds if not degrees
thousands of concurrent shipments will be critical in versus the
the effective launch of these therapies. QbD large range, -
processes provide the foundation enabling such an 150C and
approach to be effective. below).
Therefore, the
The QbD process can be extrapolated beyond the ability to
cryogenic transportation space. If we are to look at monitor and
temperature ranges such as 2-8C, one can envision control
augmenting a summer/winter validation protocol with temperature
dynamic remaining hold time calculations that excursions is just as or perhaps even more critical.
account for factors such as external temperature,

Cryoport is the life sciences industry's most trusted global provider of cold
chain logistics solutions for temperature-sensitive life sciences
commodities, serving the biopharmaceutical market with leading-edge
logistics solutions for biologic materials, such as regenerative medicine,
including immunotherapies, stem cells and CAR-T cells. Cryoport's
solutions are used by points-of-care, CROs, central laboratories, pharmaceutical companies, manufacturers,
university researchers et al; as well as the reproductive medicine market, primarily in IVF and surrogacy; and
the animal health market, primarily in the areas of vaccines and reproduction. Cryoport's proprietary Cryoport
Express shippers, Cryoportal logistics management system, leading-edge SmartPak II condition
monitoring system and geo-sensing technology, paired with unparalleled cold chain logistics expertise and
24/7 client support, make Cryoport the end-to-end cold chain logistics partner that the industry trusts.

47
OVERCOMING
THE CHALLENGES AND
COMPLEXITIES OF THE
PERSONALIZED MEDICINE
SUPPLY CHAIN
Scott
Ohanesian,
Senior
VP
Commercial
Operations,

QuickSTAT
Global
Life
Science
Logistics
Scott Ohanesian
Senior VP of Commercial Operations
QuickSTAT, A Quick Company
Scott Ohanesian has held executive roles the past 14
years for Clinical Logistics Organizations and Contract
Manufacturing Organizations, managing global
logistics for Phase I to Phase IV clinical trials.
In his current role, he builds strategic relationships with
pharmaceutical and biotech companies in order to
provide comprehensive solutions for their global supply
chain, ensuring product integrity and patient safety.
Prior to joining QuickSTAT, Scott managed the Asia
Pacic commercial operations for Marken Limited.
He is trained in Good Manufacturing Practices, (GMP)
and has created logistics solutions for numerous new
drug productsfocusing on establishing sound supply
chain models for Direct to Patient trials and
Cell/Gene/CAR-T/Immunotherapy trials through to
commercialization.
 The last decade has seen an increased emphasis on research and
development into personalized medicines, including cell, gene
and immunotherapy treatments a trend that is expected to continue
due to the forecasted 8.74% CAGR of the personalized medicine,
targeted therapeutics, and companion diagnostics market to $149
billion by 2020. These lofty expectations are due in large part
to advancements in science and the availability of more sophisticated
diagnostic tools, which are giving the medical community a better
understanding of the human genome and make it easier to detect
genetic mutations effecting an individual patient.

Specically, 2016 witnessed the
rst ex-vivo stem cell gene therapy
to be approved by the European
Commission to treat patients with
the rare disease ADA-SCID
(Severe Combined
Immunodeciency due to
Adenosine Deaminase deciency).
Martin Andrews, Head of the Rare
Disease Unit at GlaxoSmithKline,
calls the successful approval of
Strimvelis the start of a new
chapter in the treatment of rare
and genetic diseases.
If Strimvelis truly delivers upon its
initial success, it could signal a
signicant increase in the
investment into these treatments,
at both the institutional and
industry level. According to
intelligence rm Informa, the total
nancing in gene and cell therapy
companies in 2015 came to
US$10.8B, which represented a
106% increase over 2014. While
institutional investment into cell
and gene therapies is both
necessary and signicant, having
the knowledge and understanding
of the new technologies,
represented by industry and
corporate investment, gives this
developing technology platform
validity.
Therefore, the increase in
corporate investment from
US$58.9M in 2013 to US$2.432B in
2015, a colossal 4000+% jump
over a two-year period,
demonstrates a belief from large
pharma that cell, gene, and
disruptive new phase in medicine,
immunotherapies can deliver upon
where a one time gene x or
their early promise. This has
treatment replaces a life long
recently been demonstrated in the
dependence on taking a medicine
numerous corporate partnerships
and continuous treatment.
and acquisitions within the cell and
Already, several hundred gene
gene therapy space. Which
therapies are in development with
include Celgenes recent US$1
the hope of providing a true cure
billion investment in a ten-year
for one of the 5,000 rare diseases
collaboration with Juno, Amgens
caused by the error in a single
and Kites combined US$1.1B
gene.
collaboration to advance CAR-T
therapies , and Pzers desire to
The high potential that
become the leader in gene therapy
personalized medicines, including
through their acquisition of
gene and cell therapies, have
Bamboo Therapeutics, Inc. for
demonstrated for curing various
US$150M in August 2016.
types of cancers has led to a
The Personalized
Medicine Supply
Chain: Maintaining
Viability and Safety
While healthcare logistics is
complex for all types of medical
shipments gene, cell and
immunotherapy medicines present
their own special challenges. It
begins at the medical facility where
a patients blood, plasma, white
blood cells, tissue or tumor
samples are harvested, during the
process of apheresis,
leukapheresis, or a biopsy.
Samples are then transported to a
Contract Development and
Manufacturing Organization
(CDMO) or processing facility
where the personalized medicine is
created for a specic patient. Once
the cell, gene, or immunotherapy is
prepared, it is returned to the
medical facility or patient infusion
site for administration.
To ensure adherence to the strict
regulations of the life science
industry, to maintain the integrity of
a therapy in transit, and the overall
safety of a patient, the supply
chain solution developed for both
the clinical development and
commercialization of a
personalized medicine must take
the following into consideration:
Time and Temperature Sensitivity
A Strict and Transparent Chain of
Custody
Connectivity and Communication
Between All Stakeholders
Regulatory Compliance
Scalability to Support
Commercial Growth
Time and Temperature
Sensitivity
Since they can involve the
transport of either cryo frozen or
living cells, CAR-T and
immunotherapy trial logistics are
highly temperature and time
sensitive. For one thing, multiple
temperature proles can exist for
within one trial, with temperature
requirements ranging from -196, -
80, -20, 2-8, to 15-25 Celsius.
That means any supply chain
solution must be exible enough to
accommodate different
temperature requirements to and
from the site, CDMO, or lab.
Time is always an issue where
clinical trials logistics are
concerned, however, many of the
personalized medicines currently
under development have
shortened stability timelines of 6
to 48 hours, which requires their
transport and processing, or
administration to occur within a
highly abbreviated time frame. To
ensure that these cell, gene and
immunotherapy shipments arrive
on time and within the correct
temperature, careful pre-planning
must take place. This includes:
51
 The pre-qualication of
transport routes for every mode of
transportation (air and ground)
The procurement and
conditioning of specialized
packaging, such as Credos or
Liquid Nitrogen Dry Shippers
(LN2) for expedited placement at
the hospital or CDMO
The arrangement of in-transit
storage based on Good
Distribution Practices (GDP)
principles and other best
practices, including access to
temperature-controlled vehicles
The establishment of detailed
contingency plans to be able to
proactively respond to and
overcome potential transportation
interruptions, such as weather,
natural disasters, etc.
The usage of technological
advancements, such as GPS
devices that provide real-time
location data, as well as
temperature, tilt, and other
relevant shipment metrics.
Chain of Custody
In addition to the end-to-end safe
transport between medical
facilities, hospitals and CDMOs
within product specications, it is
critical to the best patient
outcomes that each therapy is
collected from and delivered to
the correct patient, pre- and post-
manufacturing. This involves
using sophisticated technology,
such as QuickSTATs proprietary
IT system QuickTRAC, to track
shipments down to the specic
patient ID number, from the point
of pick-up through to delivery. In
addition, it is critical to leverage
the use of cellular-based GPS
tracking devices with multi-
sensory capabilities, such as real-
time location, tilt, and
temperature monitoring
throughout the entire
predetermined best transit route.
This results in complete control
and visibility into the status of
each shipment milestone and
ensures the strictest chain of
custody, from collection to
customs clearance, and nal
delivery to a specic end user.
Communication and Connectivity
Between All Stakeholders
Robust System & Experienced
Team
The transparency needed to link
the hospitals, CDMOs, doctors,
and patients within a personalized
medicine supply chain requires
seamless connectivity and
communication between all of the
previously mentioned parties.
QuickSTAT has been able to
successfully support cell, gene,
and immunotherapy supply
chains, by leveraging our
proprietary, built-for purpose IT
system, QuickTRAC.
QuickTRAC was designed to
integrate across all electronic
platforms, allowing for real-time
updates to all stakeholders
regarding every milestone a
shipment will encounter in
route to delivery. By utilizing
this technologys ability to set
alarms and alerts based upon
pre-dened rules, QuickTRAC
is able to send instant email
notications and updates to
the relevant stakeholders
regarding events that may
impact a delivery deadline,
including real-time geographic
and temperature data. By
receiving automatic real-time
shipment alerts and constant
oversight from an experienced
logistics team to re-route
shipments requiring alternative
routing, the CDMOs are able to
better schedule their
manufacturing processes and
the sites are able to better
support the administration of a
therapy to a patient.
Regulatory Compliance
Due to the complexity of ever-
changing regulations that vary
from country-to-country for
various types of patient
samples and medications, it is
critical to engage an
experienced and
knowledgeable courier, at both
the clinical and commercial
planning stages, to review the
import/export requirements of
your therapy, as well as VAT,
duties and tax considerations
for all of the countries involved
QuickTRAC was
designed to integrate
across all electronic
platforms, allowing
for real-time updates
to all stakeholders
regarding every
milestone a shipment
will encounter in
route to delivery.
in a program. By having an
experienced team to guide you
through the regulatory and
customs requirements for the
transport of your personalized
medicine, a strong logistics
plan can be developed to set
up robust standard operating
procedures to govern your
global supply chain throughout
the therapies clinical
development and
commercialization.
Scalability for
Commercial Growth
With the commercialization of
a trial or drug product comes a
substantial increase of
patients, sites and
manufacturing facilities
leading to an exponential
growth in expected shipment
volumes. Supply chain
capabilities must be available
to immediately manage the
growing demands resulting
from the varied time and transit
specications needed to
accommodate an expanding
geographical coverage.
Specically, commercialization
requires end-to-end turnkey
capabilities for personnel and
customer service, a robust
global distribution network,
packaging that allows for
universal conditioning
procedures across differing
climates, a robust IT
infrastructure that can
automate much of the supply
53
chains communication, demonstrated contingency
plans with cost effective redundancies, an in-depth
understanding of regulatory and customs
requirements, and seamless connectivity to all
stakeholders involved. By taking all of these
factors into consideration, it will also help a
sponsor to determine a critical piece of its
commercialization strategy, namely the best
location for a manufacturing partner of the therapy
from both a logistics and cost standpoint.

As our industry continues to invest in the

development of cell, gene, immunotherapies and
other personalized medicines, it is crucial that
sponsors leverage the experienced personnel,
state of the art IT systems, and global infrastructure
of a global supply chain provider early on in the
planning process. The best specialist logistics
providers will maximize their knowledge,
experience, and technology to serve as the critical
communication bridge and supply chain network
between the sites, CDMOs, doctors, and patients
that is necessary to deliver successful clinical and
commercial outcomes.

For 36 years, the Quick Group has been serving the
life science and healthcare community worldwide,
providing 24/7 priority logistics and transportation
solutions for time and temperature-sensitive,
mission-critical and life saving needs.
QuickSTAT manages global clinical trial logistics for
all phases of research and drug development, for all
temperature ranges and life science products--from
pre-clinical, to clinical, through to commercialization.
QuickSTAT specializes in end-to-end transport of
clinical research specimens, investigational drugs,
clinical trial supplies and personalized medicine,
helping to bring new drugs to market.
With a global network, QuickSTATs logistics experts
can expedite delivery to anywhere in the world --
even to the most remote locations. They provide
consultation on customs/regulatory compliance,
import/export documentation and Dangerous
Goods, as well as procurement of specialized
packaging for all temperature ranges, ensuring
product integrity and patient safety.
Logistics services include Next Flight Out, Hand
Carry, Global Air Charters and Direct to Patient. Strict
quality control and chain of custody procedures help
to maintain the integrity and security of every
shipment.
Quicks market leading technology, QuickOnlineRX,
provides comprehensive management of your
clinical supply chain logistics, with real-time
shipment tracking and status alerts. QuickOnlineRX
is fully scalable to meet the requirements of newly
commercialized products.

www.quickstat.aero