Glass Versus Plastic Ebook PDF

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GLASS VS. PLASTIC
contents
Clash of the Titans: Glass vs. Plastic
page 3
VIDEO: The Future of Blow-Fill-Seal Innovation
page 9
Container Innovations Prairie Home:

Where Catalent Pioneered BFS Packaging for Decades
page 11
Towards a Better Prefilled Syringe
page 16
Integrating Quality by Design for Development

of Prefillable Syringe Components
page 17
Avoiding Unintended Interactions
page 19
Minimizing the Risk of Sterile Manufacturing

Through Automated Aseptic Techniques
page 24
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GLASS VS. PLASTIC
CLASH
OF
THE
By Ste
ve n
Editor E. Kuehn,
in Chie
f
S
N
A
T
I
T
Super-rivals glasS and plastic
square ofF for patient safety
the first synthetic plastic

Bakelite was developed
by Belgian chemist Leo
Baekeland. Advances
came quickly after that
with the likes of BASF,
ICI and Dow bringing
commercial/industrial
ready polymers to market
beginning in the 20s.
As we reach the midpoint
of this centurys second decade,
material scientists continue to
hyper-refine plastics and glass to
enhance positive attributes and mitigate
less-than-desired attributes relative to
Pharma application and commercial/industrial scale
economies. The market for pharmaceutical packaging has
become immense and is showing no signs of slowing down;
leading market research firms predict demand in the U.S.
will grow about 5 percent a year and reach ~ $22 billion
pecifying the best material to serve the primary

packaging requirements for a given pharmaceutical used to be pretty easy, considering there
was virtually only one champion to call on: Glass.
Glass was Pharmas packaging Superman, a hero with
well known virtues; strength, purity and transparency.
For millennia there were few materials out there that
could rival glasss dominance and reputation.
Glass as a material has been around for a long time, but
it wasnt until about the 1st century BC, that glass blowing
was discovered in the Middle East. This advancement
created the industry. Glass vessels could now be mass
produced, and more economically than pottery vessels.
And the rest is history as they say. During the ensuing
millennia, glass as a packaging material came to dominate
the worlds food, beverage and pharmaceutical industries;
there simply were few or no alternatives. That is, until
scientists started uncovering the attributes of organic
polymers found first in naturally occurring substances like
gum and shellac, then later developing chemically modified
materials like galvanized rubber and nitrocellulose. By 1900
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GLASS VS. PLASTIC
by 2018, representing about a third of

the global market which Freedonia
Group pegs at $66 billion by 2017 and
growing at 6.4 percent annually.
Indeed, glass and plastic have
become Pharma packagings
superheroes both working tirelessly
to safely deliver medicines to a world
plagued by evil-doing disease. But as
our heroes pursue this common cause,
packagings dynamic duo have also
become super rivals. However, as far
as superhero-to-superhero conflicts
are concerned, this one only goes so
deep. Suppliers and users understand
that any packaging decision is led
by the formulation of the drug and
ultimately patient safety.
GlasS (shown here) continues to dominate the prefilLed syringe

market, but advanced polycarbonate plastics have great potential.
SCHOtT is manufacturing those as welL to provide its customers
with whatever material suits their neEds best.
GLAsS, THE PROVEN

DEFENDER
In an extensive American Pharmaceutical Review blog titled Pharmaceutical Glass Containers: Proven Solution
for Primary Parenteral Packaging
Gerresheimer Glass Inc.s technical and
quality managers noted that in 2012,
market share for primary packaging of
injectables was approximately 98 percent, representing 23 billion primary
containers for parenterals. According
to Gerresheimer, for the storage of parenterals, borosilicate Type I glass is the
material of choice. Borosilicate glass
was developed to have superior chemical and temperature properties compared to soda-lime glass; it has a stable
matrix that reduces thermal expansion
and resists chemical attack. It is inert,
chemically stable and nonporous.
SCHOTT Pharmaceutical
Packaging, the industrys leading
glass supplier, says it delivers 9
billion containers per year and that
includes ampoules, vials and both
glass and polymer syringes. We are
working in the pharma industry, so
we abide with all regulations, says
Anil Busimi, head of global product
management syringe business at
SCHOTT, which our customers
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like the Pharma companies

have to ensure that their products
are produced as per specifications
and GMP. I think we follow all the
rules. At the same time, says Busimi,
SCHOTT ensures Pharma quality
standards are met by its suppliers.
SCHOTT is a major producer of
glass tubing, [a pre-fabrication form]
which is used for [Pharmas] primary
packaging containers.
The use of glass pharmaceutical
containers remains pervasive,
especially for the thousands of wellknown, broadly administered and
increasingly generic injectable drugs.
Materials and production systems are
well understood, and in the context of
large commercial drug manufacturing
operations, there are hundreds of GMP
compliant and validated fill-and-finish
lines operating out there and a host
of reliable glass container suppliers
with established supply chains. Data
on compatibility and drug/material
interactions are both plentiful and
accessible to all drug developers

and Drug Master Files are kept by
regulators. SCHOTT notes that having
the technological expertise to support
current products when problems
come up helps sustain the company
and glasss dominance in the category.
SCHOTTs scientific advisor Dan
Haines explains that, because most of
our products are components within
other systems, there can be interface
problems. Sometimes there are drug
interaction problems. So having the
technical expertise to help is very
important. SCHOTT provides this
support through its pharma services
group as does Gerresheimer and other
glass container manufacturers. In
the pharmaceutical industry, its a
[relatively] slow evolution from one
drug platform to the next, says Haines,
so theres quite long lead time, which
is good. But on the other hand, you
pretty much have to have rock-solid
solutions when going from the current
generation to the next generation.
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GLASS VS. PLASTIC
DELAMINATION, GLAsSS
KRYPTONITE
The tendency of
delamination to occur with a
pharmaceutical vial made of
tubular glass strongly depends,
says SCHOTT, on how the
process is controlled during
forming. Volatile components
like boron and sodium
evaporate while the bottom
of the glass is being formed.
As the production process
continues, these substances
produce inhomogeneous spots on
the glass surface near the bottom
that are generally more susceptible to
delamination. Active control of this process is possible
if the quality of the glass surface and its tendency
to experience delamination are monitored during
production. According to SCHOTT, this marked
the starting point for a new way to test the risk of
delamination.
For the most part, and over the last

century or so, glass remained impervious to most issues having to do with
compatibility. Most formulators took
it almost for granted. Most compounds
were just fine being contained by glass,
but as newer drugs, including biologics
with aggressive chemistries introduced, manufacturers were confronted with quality issues stemming
from chemical reactions between the glass surface and
the drug chemistry known as delamination. According to
SCHOTT, between 2006 and 2011 some 100 million pharmaceutical vials were recalled due to glass delamination
issues. Delamination became Glasss kryptonite, exposing
its (seemingly) one true vulnerability. At its likely nadir,
2010, glass flakes were discovered in nine different drug
products resulting in immediate recalls; 30 million vials
in one case. Although the phenomenon was recognized as
far back as the 50s, the dramatic uptick in recalls forced
the industry to react. Unfortunately, recalls continue, with
several announced just this year.
The problem with glass delamination, say SCHOTT,
Gerresheimer and others is that it may take years to manifest
itself. The chemistry behind glass attack by water-based
liquids is mainly driven by ion exchange and dissolution.
Gerresheimer says glass delamination is a wellknown phenomenon, recognizing that even upscale
Type I containers are prone to delamination under
certain circumstances. Regardless, glass pharmaceutical
container manufacturers, as well as industry associations
(PDA for example), and regulators all have been
galvanized to act and address this serious problem. Over
the last several years a number of extensive, thorough
studies have been conducted to understand the root
causes of delamination and to find ways to eliminate the
problem. In its 2011 Advisory to Drug Manufacturers:
Formation of Glass Lamellae in Certain Injectable
Drugs, the FDA published that the following conditions
were associated with delamination:
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FIND IT OUT FASTER
SCHOTTs analysts developed a test that allows pharma

glass packaging manufacturers to determine delamination risk within a few hours by applying threshold
values. To start the test, the glass surface is gradually attacked locally. Vials removed from the line are
stressed inside an autoclave at a temperature of 121 C.
In the past, vials were subjected to visual inspections
with a stereomicroscope after autoclaving in steam.
This method, says SCHOTT, has been replaced by more
efficient and effective atomic absorption spectroscopy, a
far easier method that can be performed during routine
production operations. SCHOTT has received a patent for its in-process Delamination Quicktest, which
monitors a threshold value of sodium during manufacturing. To conduct the test, the subject vials are filled
with water so the zone where delamination normally
occurs is covered slightly. Sodium is extracted inside the
autoclave and the amount is determined through atomic
absorption spectroscopy. This level correlates with the
probability that the vial being inspected will experience
delamination eventually.
The bottom line is that SCHOTT and its glass
container-making peers, in association with drug
makers have worked extra hard to eliminate this issue.
Whether through enhanced and refined manufacturing
techniques, coatings or better controlled preparation, filland-finish operations, delamination of glass containers is
becoming less of a threat to operations and supply.
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BEtTER EARLIER THAN LATER
very similar out there, your risk assessment may well

suggest that your other data is sufficient. Personally, I
would probably be a little bit cautious of this part. I would
probably want to have at least some complementary data
there, but I would let the risk assessment guide me.
Pidgeon explains that early packaging risk
assessment may prompt deeper inquiry and
involvement of packaging suppliers so customers
needs can be better met in the name of patient
safety. We would speak to West, for example, says
Pidgeon, tell them that our plant is using this product
with this kind of formulation and then we would work
together to get the client the best service possible.
No surprise that West agrees. Our core business
relates to helping pharmaceutical and biotech
companies select the appropriate packaging materials
for injectable drugs, says Wests vice president of
marketing and innovation, Graham Reynolds. We
are currently participating in some way with all
the top 35 biologics. We work closely with
customers at all levels.
West is also very concerned with
all issues that affect drug safety and
efficacy. This area of extractables
and leachables has probably
become more critical in the
last two years as regulatory
agencies look for more
information on that subject,
says Reynolds. West says they
work with customers to make
sure they have the appropriate
container solutions period.
To get there, says Reynolds,
the first phase [includes] some
element of prescreening work to select
the appropriate materials. That can be
done either by us in our laboratories
we have a pretty extensive laboratory
in-house where we can do that testing
on behalf of customers, notes Reynolds,
adding that many of Wests customers have
that capability internally. It really depends
on the sophistication and the capabilities of
the drug company that we are working with.
Reynolds explains that this prescreening exercise
narrows down the choices, which may include a
glass solution and a plastic solution using Wests
Daikyo Crystal Zenith cyclic olefin polymer:
Often companies will test a CZ solution and a
glass solution.
Tony Pidgeon, applied technology director for finished

dose at Patheon explains that from a contract manufacturers standpoint, their role is to guide primary
packaging choices so that regardless of material choices,
all aspects of packaging risk are managed to foster all
desired outcomes. The first thing we do is determine
what our clients product profile is, in other words what
are they trying to do with their product, says Pidgeon,
explaining that for many customers, the main motivation
is to get the product into its trial in a predetermined time
frame, so speed is essential. Often, he says, that means
trying to piggyback on existing technologies.
For the drug owner, the decision is based on the fact
that glass vials are readily available and for the most
part a no-brainer. People know how to use them, says
Pidgeon. Theres an awful lot of data out there about
them; people tend to [choose] a Type I glass they take
that as being considerable quality and assume that
from a compatibility point of view that that will be
fine. Extractable and leachables to be honest,
even delamination isnt really considered at the
earliest stage. I must say personally I do,
but it depends on the formulations
they are coming to us with.
In talking about
delamination, says Pidgeon
the general rule of thumb
that I tend to follow is that
as long as you dont have
extremes of pH, then youre
normally going to be okay.
Regardless of drug formulation,
at the beginning stages of
the packaging discussion
Pidgeon recommends doing
comprehensive risk assessment
from the very beginning.
That risk assessment will then
dictate or certainly guide
the direction in which you
need to go. In other words, do you need to do the
standard or get involved with the suppliers of the
components themselves? Pidgeon cautions that
just because its been done before, the chemistry
is similar, etc., doesnt mean ones risk associated
with packaging is mitigated. You need to put that
risk assessment in place. I suggest you need to
do at least some work there, which is obviously
unique to your own product, says Pidgeon. But
if its a generic, for example, and theres something
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GLASS VS. PLASTIC
Other fundamentals, like how the product will be filled

and handled, need to be considered, says Reynolds. Is it
in a vial or prefilled syringe? For instance, if a prefilled
syringe is going to go into a mechanical autoinjector, you
want to make sure to take into account the viscosity of
the drug. What forces are going to be necessary? What
speed of injection is needed? At that stage, you need to
really be considering not only the extractable, leachables
and compatibility, but what is the optimal containment
system to give the best result for the final drug delivery?
That opens up a whole new world of do I want
glass? Do I want CZ? Do I want break resistance? Am I
concerned about particles?
Who gets involved in these discussions? At that stage,
there might be multiple people involved, depending on
the complexity of the customer and their approach, says
Reynolds. Typically formulation scientists would be
involved to select the materials. You may have packaging
development people there saying I want it in a vial or
syringe or a cartridge, and what the dose volume would
be, for instance. What were finding now is that even at
that early stage, the device people are involved. Kevin
Cancelliere, Wests marketing director adds, there are a
number of key stakeholders involved in our discussions.
We are also seeing considerable interest from marketing.
A lot of brand managers are very much interested in the
type of primary containers to see if it can get them a
competitive advantage in the marketplace.
For West, both Reynolds and Cancelliere say they are
seeing a stronger trend toward plastic, prefilled syringes.
Its no doubt that the gold standard legacy is glass
containers, but we are seeing a dramatic increase [in the
specification of plastic] because of the emergence of the
new biologics and the costs associated with them, says
Cancelliere. Drug companies are very concerned with
that expensive biologic and how it interacts with primary
containers and components. We are seeing an uptick and
we really think that these trends are going to continue to
grow over time. Part of the challenge says Cancelliere,
is overcoming peoples comfort level with glass. Plastic
containers are still relatively new. I think as people
become more comfortable with them and see the benefits
of plastic, were likely to see an increase in demand.
Prefilled syringes represent one of the fastest-growing
packaging and drug delivery segments in Pharma.
According to a report published by Transparency Market
Research Prefilled Syringes Market (Glass and Plastic)
Global Industry Analysis, Size, Volume, Share, Growth,
Trends and Forecast, 2013-2019, the demand is being
fueled by the advantages associated with prefilled syringes,
including eased administration, reduced risk of cross
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Catalents new aseptic parenteral container

brings advanced plastic Blow/FilL/Seal
technology to one of Pharmas hotTest
categories, injectables.
contamination, less opportunity for overfill, simplified

handling and ultimately better patient outcomes. In 2012,
the global prefilled syringes market, says Transparency
Market Research, was valued at $2.09 billion and is
expected to grow at 13.3 percent from 2013 to 2019,
reaching an estimated value of $4.98 billion in 2019.
Weve actually been manufacturing pre-filled syringes
for many years, says Patheons Pidgeon. This year we are
validating a brand-new state-of-the-art, pre-filled syringe
line at our site in Monza, Italy. Its a big investment for the
company and thats where plastics are going to be coming
in. Pidgeon explains that while hes aware that glass is still
the most popular amongst Patheons clients, plastics and
co-polymers are moving up fast.
SCHOTTs Busimi says his company is working hard to
meet the needs of this market. Definitely we see growth in
the prefilled syringe markets, says Busimi. Having both
products in our portfolio with glass and polymer allows us to
understand our customer needs and requirements, and then
help them try to find the right solution in our portfolio.
PLASTIC IS FANTASTIC
For parenteral, sterile injectables in vials and syringes,

glass remains dominant, but advanced plastic materials like Wests CZ are making real headway; SCHOTTs
move to supply advanced polymer syringes is their hedge.
One market research firm noted that market growth for
plastic prefilled syringe technologies will be double that
of glass from 2013 to 2019. But, as far as the pharmaceutical packagings universe goes, plastic has clearly become
the material of choice across the vast majority of general
pharmaceutical container forms. Think about it; most
solid dose drugs in quantities of 50 or more come in plastic
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injectables as well. Tim Kram, general manager for

rommelag USA noted that worldwide interest in the
technology is growing, fueled by drug shortage fears that
everyone knows are mitigated by high-performing quality
management and risk regimes as well as process excellence
something that BFS sterile, class 100 containment
brings to fill-and-finish lines.
Describing its rising popularity, Kram points out
that in U.S. markets inhalation drugs account for
more than 2 billion units, ophthalmic drugs account
for 1 billion units and IV solution bottles (worldwide)
account for 2.5 billion units. According to Chuck Reed,
marketing director for Weiler Engineering, Weiler has
machines in over 35 countries producing a wide range of
pharmaceutical products which include everything from
generic medicines to vaccines to oral, respiratory therapy,
ophthalmic, nasal, otic and nutraceutical applications,
says Reed. The market, he says, is growing in every sector
due to (among other things) the increasing interest in the
sustainability of the BFS process. Citing its low carbon
footprint, recyclable base material, high utility efficiency,
Reed notes all of these contribute to the success of BFS,
not to mention a large movement away from glass, which
continues to be a driver, he says.
For rommelag, Kram says, customers break out
this way: 40 percent branded, 35 percent CMO and
25 percent Generic, a spread that may indicate that
certain segments are more compelled to adopt the
technologys cost and quality efficiencies than
others, especially those developing sterile,
liquid medicines. Reed notes that the
BFS process provides a significant cost
advantage over glass. A complete BFS
container is typically less than 1/3 the
cost of a similar glass format. Due to
the flexibility in container design, Reed
explains, BFS is becoming a preferred
format for many combination products
due to the changes in device designs.
Additionally, BFS can simplify the
manufacturing steps to make the end
device more cost effective.
Purveyors of our other super
packaging hero, Glass, say their
customers stay with glass because
their processes are validated
and for anything new, there
are tons of data to draw from
to support compliance and riskmanagement regimes. The risks and
costs associated with validating a
bottles with those annoying but necessary child-proof

caps. Most sterile liquids, saline, water for infusion, etc.,
come in plastic bags or bottles, not to mention the bulk
supplies of the same.
SUPER InNOVATION
Drug innovation is driving packaging innovation and

this is most apparent in the area of dispensing/dosing
accuracy, patient compliance and other drug delivery
technologies. Whether its a prefilled multi-dose insulin
injector or a dose-metering and counting COPD therapy
inhaler, plastics are truly the only choice for designers
and engineers fabricating these devices. Whats interesting to note is that for some of these devices the medicine
is contained in a cartridge a market niche that both
plastic and glass are vying for, but a category where
theres a good chance a relative newcomer to the scene,
plastic Blow/Fill/Seal (BFS), may soon come to dominate.
In 1963, Gerhard Hansen invented and built
the first BFS machine; by May of 1964 he founded
rommelag in Switzerland and began to sell his products
internationally. The innovation was profound. In a
single automatic process, BFS creates containers from
thermoplastic granules which are blown into a mold,
then inserts the liquid contents (fill) and then closes and
seals the container.
Among its biggest advantages, BFS technology does
not require the cleaning and sterilization processes
that are essential in other kinds of container
production and fill-and-finish operations.
To provide maximum security in the aseptic
packaging of sterile liquids, creams, ointments
and vaccines, BFS machines can be equipped
with additional modules for quality
assurance and monitoring as well as
aseptic systems for automatic cleaning
and sterilization of lines that come into
contact with products.
Customers throughout the world, say
rommelag, quickly recognized the
advantages of plastic containers, and
other enterprising entrepreneurs
recognized it as well, including
Weiler Engineering who
licensed the technology and
brought it to the U.S. in the
70s. Its origins may soon be
legend because BFS has the
potential to truly dominate;
not only across most sterile
liquids, but for most parenteral
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new product [with glass], says Kram, are better known in

the U.S. than with BFS technology. It is understandable,
he concedes, that people want to stay with the process that
they know. Thus we try to get onto the packaging option
list for new products. We have an extensive knowledge
about compatibility that we can offer to new customers,
along with test containers made from a selection of plastic
resins. Once past compatibility (not guaranteed), the
process for validation is similar. There is no difference in
validating plastic resins in the same application, says Kram,
the difference stems from the different product regulatory
requirements, that is, non-aseptic (preserved) products,
aseptic products and terminally sterilized products.
Pharmaceutical manufacturers are embracing
the technology. For example, says Kram, Nephron
Pharmaceuticals in Columbia, South Carolina, is
expanding into injectable drugs with a BFS ampoule.
An early adopter was AstraZeneca, which began
integrating the BFS process into its nose-drop
production environment, installing a rommelag
machine in the 1980s. By the 1990s the company ramped
up BFS operations in Westborough to support the
commercialization of its Pulmicort asthma medication,
delivered via an ampoule inserted in a nebulizing device.
Both rommelag and Weilers marketing and BFS
technology development spawned companies that at first
demonstrated the technology to potential clients, but
over time evolved to provide BFS contract manufacturing
services. Catalent (formerly ALP with a shared history
with Weiler) offers its customers extensive aseptic, glassfree BFS filling-solution capabilities and capacity with
experience providing development through commercial
scale manufacturing support covering single- and
multi-dose solutions across complex emulsions and
suspensions. Since its inception, the companys owners
have continuously invested in the facility; currently the
500,000 sq. ft. plant encompasses a total of 38 BFS lines.
Catalent says its made significant capital enhancements
in recent years and is about to embark on its next wave
of investment to further expand and improve operations
over the next three years. In September, Ritedose, formerly
rommelags sister business Holopack, announced a $110
million expansion to its Columbia, South Carolina, facility,
planning to add another 80,000 sq. ft. to support enough
capacity to meet growing demand, says the company.
Yes, glass and plastic are Pharma packagings superheroes,
but while they are rivals, they continue to develop their
respective technical and material attributes to cope with the
ever-changing pharmaceutical manufacturing landscape in
an effort to win the hearts and minds of drug makers and
help fight the battle for patient safety.
THE FUTURE
OF BLOW-FILL-SEAL
INNOVATION
Presented by: Megan Johnson,
Nephron Pharmaceuticals Corp.
Recent innovation in Blow-Fill-Seal
technology means exciting new
opportunities in biotech products
and vaccines.
This Fundamentals series includes:

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click here to view the presentation

http://www.brainshark.com/pharmamanufacturing/vu?pi=zHrzr9SVYz9Qtsz0
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GLASS VS. PLASTIC
Visit us at
ISPE Annual Meeting
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Booth 721
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www.rommelag.com
rommelag ag
P.O. Box CH-5033 Buchs, Switzerland
Phone: +41 62 834 55 55 Fax: +41 62 8345500
E-mail: mail@rommelag.ch
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rommelag Kunststoff-Maschinen
Vertriebsgesellschaft mbH
P.O. Box 1611 D-71306 Waiblingen, Germany
Phone: +49 7151 95811-0 Fax: +49 7151 15526
E-mail: mail@rommelag.de
rommelag USA, Inc.

27905 Meadow Drive, Suite 9
Evergreen CO 80439, USA
Phone: +1.303. 674.8333 Fax: +1.303.670.2666
E-Mail: mail@rommelag.com
10
rommelag Trading (Shanghai) Co., Ltd.

Room 1501 Xinyin Building
No. 888 Yishan Road 200233 Shanghai, P.R.China
Phone: +86 21 6432 0166 Fax: +86 21 6432 0266
E-mail: romcn@rommelag.com
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Catalents Woodstock, Illinois, facility has been pioneering

blow-fill-seal aseptic packaging for decades
By Steven E. Kuehn, Editor in Chief
NESTLED OUT on the prairie about 60 miles northwest of Chicago is

Catalents Woodstock, Illinois, home for Blow/Fill/Seal packaging innovation. Regardless of its sylvan setting, Catalents been pioneering efficient,
sterile aseptic blow-fill-seal methodologies and sustaining its development
for more than 25 years and is gearing up for continued success with its
global customers from this central-U.S. location.
LEGACY OF INNOVATION
The Woodstock facility has a long history serving the pharmaceutical industry.
The original company was founded in 1968 as Automatic Liquid Packaging
(ALP) in Elk Grove Village, Illinois. By 1980 ALP headed west to Woodstock,
building a new facility to house four BFS lines intended primarily to demonstrate the efficacy of BFS technology to customers. This eventually created
demand for contract manufacturing services, which the company pursued with
vigor. The facilitys first production runs started in 1982 with approximately
60 employees working three shifts, five days a week to meet the demand. Fast
forward to 1999; Cardinal Health purchases the business, and in 2007 Cardinal
Health PTS becomes Catalent Pharma Solutions.
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11
Shown here: the redundant sterile filtration and

buffer tank that feeds the fill nozzles on the
inside of the BFS machine.
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As of 2014, Catalent offers extensive aseptic, glassfree BFS filling-solution capabilities and capacity with
experience providing development through commercial
scale manufacturing support covering single and
multi-dose solutions across complex emulsions and
suspensions. For more than 30 years here on site, says
David Bricker, Catalents site general manager, Weve
specialized in the hard to do complex molecules
we can do both, but its really the complex molecules
we do well. Bricker explains Catalent has a strong
representation in the ophthalmic, respiratory, topical
and biotech market spaces.
A main focus for Catalent is in the formulation and
development areas. Its not just the straightforward
solutions, but really we are able to simplify the complex
molecules and produce them with the same operational
excellence as the simple solutions, says Natasha Hults,
director of R&D. For example, weve been successfully
producing a biologic in BFS for over 20 years, so we have
a long, proven history of how to handle a wide range of
molecules, including complex and large molecule products.
Since its inception, the companys owners have
continuously invested in the facility and the BFS
technology it encompasses. Currently the plant, at some
500,000 sq. ft., encompasses a total of 38 BFS lines. Since
2011, Catalent has invested a significant amount of capital
and plans to further expand and improve operations
over the next three years. These investments are paying
off especially in the area of quality. Through the
guidance and institutionalization of Catalents Quality
Management System, organization and continuous
attention to operational excellence, the sites regulatory
profile has steadily improved, and in 2013 the company
experienced zero FDA 483 observations. Bricker agrees
that as Catalents organizational methods and processes
were institutionalized the plants quality performance has
improved markedly.
Its obvious wherever you observe Catalent and its production assets, whether its the biotechnologies and biopharmaceuticals, solid dose development or cutting-edge aseptic filling, operational excellence is a priority. For the Woodstock
facility, its excellence culture is being manifested in the first
phase of its planned multi-million-dollar investment. There
are some things we need to do from an infrastructure standpoint, explains Bricker, to provide continuous improvement and continue to meet the current and future cGMP
standards. Characterizing the first phase as a nice project,
Brickers description is apt because very targeted dollars are
supporting some well-defined, high-value operational improvements. Bricker describes it as a refresh with Catalent
better aligning the facility to take advantage, and leverage
the BFS technology for [the] injectable marketplace.
The site has a classic feel, after all, its administrative,
corporate front and original manufacturing and logistic
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12
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GLASS VS. PLASTIC
Inside Catalent BFS: the Parison head, the primary functional component of the process.
spaces were built in 1980. But in

this case classic is relative, more
like a vintage car. With 30 years of
BFS experience within the context
of a nearly continuous history
of expansion and infrastructure
improvement, Catalent knows a
thing or two about leveraging BFS
technology within the ecology of
its operational footprint. But that
doesnt mean opportunities for
improvement have all been exploited.
Upcoming capital spending is
intended, says Bricker, to provide
additional administrative and
operational control that will support
the facilitys ability to support
BFS process flexibility and market
expansion. When you look at the
WPREVIOUS PAGE
BFS technology from a parenteral

manufacturing standpoint, as well as
what has been taking place qualitywise on the traditional glass vial
side, notes Catalents commercial
operations director Eric Feltes, the
automatic, aseptic filling technology
of BFS addresses many of those
root causes of challenges in the
parenterals market. Looking at
it from a technology standpoint,
says Feltes, BFS really has true
advantages, especially in other
market spaces, outside of ophthalmic
and respiratory. So looking at those
advances, particularly in the U.S.
parenteral space, we see as a growth
opportunity for the technology as
well as for us as an organization.
13
PLASTIC AND FANTASTIC
Blow/Fill/Seal technology, pioneered

by Weiler Engineering and operationally perfected by Weilers ALP
and eventually Catalent, offers a
number of specific advantages over
glass injectable drug containers. To
a great degree, the processs automated sterile operations reduce opportunities for contamination and
drive out risk, by orders of magnitude, says Catalent. The elimination
of human intervention and glass
handling prior to fill are huge drivers in this reduction. In particular,
there are several different studies
that support the drastic reduction of
foreign particulates and even a risk
assessment by industry experts that
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GLASS VS. PLASTIC
qualify BFS as 100 times lower risk

than traditional glass vial filling.
This technology really drives out
a lot of the root causes of foreign
particulates even the exposure
time that glass containers have
its minimized; youre controlling or
even eliminating it, says Feltes. He
explains that BFS, through qualityby-design principles and automation, drives out, via the design of
the process, the different variables
that impact quality.
In its pursuit of the sterile
injectables market, Catalent recently
introduced its ADVASEPT advanced
aseptic glass-free delivery solution,
a platform that is directly associated
with the capital investments being
made at the Woodstock facility.
Touting enhanced sterility assurance,
lower risk and greatly reduced
contamination potential of their new
design, ADVASEPT vials integrate
the stopper and a sealing system that
eliminates metal tabs or lids. Catalent
says its container system provides
high performance characteristics
and that the process itself does not
impact biologics negatively or affect
the stability of biologic compounds
tested. Additionally, there is an
ongoing study measuring the
effects on stability of a monoclonal
antibody in glass vs. the ADVASEPT
vial that shows comparable results.
Catalent has performed controlled
extraction studies on ADVASEPT
primary and secondary packaging
components. Six leachables methods
have been validated to cover analysis
of any known extractables in both
water and saline formulations.
Along with the BFS vials, Catalent
offers integrated services that will
accelerate the conversion from glass
to aseptic BFS technology.
OF MOLECULES AND MARKETS
From its role providing flexible BFS

packaging and fill and finish operaWPREVIOUS PAGE
Catalents services include automated back-end operations

to speed production including this inline labeler.
tions to critical phase I, II and III

and commercial scale-up development support, Catalents Woodstock
facility maintains a leadership
role in bringing better operational
methodologies to the pharmaceutical industry. Its customers come to
the organization to help them meet
the challenges they have in bringing
their molecules to market while taking advantage of the design freedom
14
of the primary container closer.

Catalents customers are motivated to
do business with the company for a
variety of reasons, but for many, risk
mitigation is an imperative one
that is served well by depending on
an experienced operational expert
especially if a clients compounds as
well as its customers are better served
by safer, more available and less
expensive medicines.
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GLASS VS. PLASTIC
ITS SAFER INSIDE
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GLASS VS. PLASTIC
TOWARDS A BETTER PREFILLED SYRINGE

West and Vetter look to meet the needs of parenteral manufacturers and regulators demanding safer syringe options.
BY PAUL THOMAS
THE PARENTERAL drug market has long used 1-mL

long glass prefilled syringes. While these syringes have
experienced success, they have been prone to, for example, breakage or production inconsistencies. Increased
regulatory scrutiny of glass syringes, vials, and cartridges, and the way in which they are filled and processed, has
led drug manufacturers to search for alternatives.
A few years ago, syringes of Crystal Zenith, a
proprietary cyclic olefin polymer from Daikyo Seiko,
were introduced. The polymer syringes are said to be not
only more resistant to breakage, but are known to have
improved manufacturing consistency.
West Pharmaceutical Services and Vetter Pharma
partnered to offer 1-mL Crystal Zenith syringes to their
clients. Drug manufacturers have the option to conduct
the syringe filling within their facility, or to outsource
to Vetter. To find out more, we presented questions to
West and Vetter. Responses were provided by Graham
Reynolds, Wests VP for Marketing & Innovation; Mike
Schaefers, Wests VP for Marketing in Europe; and Vetter
Managing Director Thomas Otto.
WPREVIOUS PAGE
PhM: What do drug manufacturers need to know about

the CZ syringes? Are there new manufacturing issues or
validation challenges to consider?
Schaefers: The Crystal Zenith polymer offers many
advantages, including glass-like transparency, which permits visual inspection of the manufactured components
and of the parenteral products that are delivered to the
end user. In addition, the material is highly break-resistant and forms an excellent moisture barrier. Packaging
systems based on Daikyo Crystal Zenith have been used
for many years on marketed drug products. The 1mL long
insert needle syringe system features new enhancements
such as automated cleanroom manufacturing, 100%
vision inspection (including the needle), and an insert
molding process for the needle that eliminates the need
for adhesive or tungsten.
Reynolds: We feel the syringe is ideally suited for biopharmaceutical drug delivery. It is sterile, silicone-oil-free
and the plunger is laminated with Flurotec film, which
16
NEXT PAGE X
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GLASS VS. PLASTIC
Otto: Vetter will apply the same high standards and

systems as used for their filling of glass syringes. In its
European facilities, the company has adapted a cleanroom
especially for filling the Daikyo Crystal Zenith 1mL long
insert needle syringe. Using RABS technology to minimize
contamination risk, the line is operating with two filling
needles. Meeting cGMP specifications, it has a capacity of
up to 3,000 units per hour. All syringes are 100% visual
inspected following the filling process.
helps to lower protein adsorption and serves as a barrier

to leachable substances while enabling effective functionality without the need for silicone oil lubrication. The
materials tight dimensional tolerance and consistency of
syringe functionality can help to make a delivery systems
operation predictable.
PhM: When will commercial-scale filling be available?
Do you expect manufacturers of commercialized products to look to switch syringes?
PhM: How does the prefillable syringe market look

in the years ahead?
Reynolds: Syringe manufacturing capacity is in place today to support customer stability trials and initial activities, which will be required prior to full-scale commercial
launch of a drug. West has sufficient capacity to meet
these requirements, as well as initial scale-up, and has
plans to introduce more capacity within our Scottsdale,
Arizona, facility in the near future. Infrastructure is in
place, and additional manufacturing cells will be added
to ensure customer needs are met. Vetter has installed capacity to meet initial customer needs for technical trials,
stability fills and early-phase clinical fills.
Reynolds: Drug companies are working closely with drug

delivery device manufacturers at an early stage to ensure
that there is efficient development of an overall system
to enable cost-effective drug delivery. The FDA is placing
extra scrutiny on the area of combination products, such as
auto-injector systems that use a prefillable syringe, and there
is uncertainty about how this may impact drug development. Clearly, regulatory factors will continue to have a key
impact on the development of delivery systems.
Schaefers: The prefilled syringe market, estimated at
around 2.5 billion units, is likely to continue to grow
close to 10% per year. Significant growth will continue for therapies to treat chronic conditions such as
autoimmune diseases. Novel systems to enable effective treatment of chronic conditions such as high
cholesterol will also grow. In addition, understanding
the importance of the drug container as it relates to the
integration into the overall drug delivery system will
continue to be a key factor.
PhM: The solution promises automated cleanroom

inspection and 100% vision inspection. Tell us a about
the technology behind this.
Schaefers: West applies 100% vision inspection of the
syringe at various stages, including inspection of the
needle to ensure integrity. Robotic handling in a classified
cleanroom, with minimal operator intervention, contributes to a product of extremely high quality and low
particulate levels.
INTEGRATING
QUALITY BY DESIGN
FOR DEVELOPMENT
OF PREFILLABLE
SYRINGE COMPONENTS
Integrating Quality by Design for

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This presentation will provide details into how significant

advances in quality can be achieved using patients needs as
part of a development strategy for new components, executing
development based on a systematic approach, and driving
continuous improvement of the industrialized product based
on a body of knowledge.
Specifics of the presentation to include:
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Materials and Methods:

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of two or more regulated components, i.e., drug/device,
biologic/device, drug/biologic, or drug/device/biologic that
are physically, chemically, or otherwise combined or mixed
and produced as a single entity2, two regulations apply:
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part of the industrialization of the 1mL long NovaPure plungers
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including a design history file (DHF) and design control were
also incorporated. This was an important distinction to the
development of the NovaPure plunger.
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QTPPs (Quality Target Product Profile)
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i. Six dimensional factors, two elastomer formulations
and multiple coatings
ii. Sixteen design inputs included in finite element
analysis
iii. Thirty unique items in molding experiments,
which included 2 mold tool finishes
2. Product Development
a. Design Verification
b. Validation
3. Industrialization
a. Design Transfer
b. Market introduction
The new plunger design development included two primary

targeted improvements:
Purpose and Hypothesis:
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The development framework utilized for establishing the

new 1mL long plunger design progressed from concept
development to product development to industrialization.
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influenced the progression of this new design. Uncertainty
is reduced through statistical analysis.
Background (Abstract)
Product, process and control understanding based on sound
science and risk management are a Must not a Nice-toHave for primary packaging components used for prefilled
syringes (PFS). Elastomeric closures in combination with
the primary container are a critical element of the total drug
product as delivered to patients and it makes sense that these
components are developed using Quality by Design (QbD)
requirements to minimize risk.
One of the fastest-growing choices for single dose drugs on a

global basis is prefilled syringe systems for use in the vaccine,
pharmaceutical and biopharmaceutical industries (Figure 1).
The market has also begun a trend toward home-use and
patient self-administered delivery of drugs used to treat chronic
conditions (e.g., multiple sclerosis, rheumatoid arthritis and
autoimmune). Prefilled syringe systems are convenient with
fixed dosing and adaptable to automated injection devices,
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patients and the pharma/biotech are realized.
Prior to NovaPure components, plungers that fit 1mL long
staked needle syringes were developed for manual injection
in accordance to standards that apply to disposable syringes,
and were not fully optimized for auto-injector applications.
Pharmaceutical/Biotech manufacturers strive for higher quality
products to meet demands for safe and conveniently administered
medicines. The rising trend for self-injection has helped to
evolve components used in the 1mL long syringe as the
primary choice for drug delivery. To ensure high quality and
component consistency, there was a market need to develop
a next-generation FluroTec film plunger. The new 1mL Long
plunger was developed using a QbD holistic approach.
1. Quality variation of the glass-barrel-to-plunger

interface causing inconsistent breakloose and glide
force can be compensated by the human thumb during a
manual injection. However, for use in auto-injector device
applications, the variability may cause incomplete or
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very consistent breakloose and glide forces for 1mL long
FluroTec plungers.
2. Retain low part-to-part variation for us with commercially
available syringe barrels. Depending on style of fill-finish
PFS machine lines, speed of filling and technique of
plunger placement (vacuum vs. vent tube). The plunger
was designed to reduce the variation due to the nature of
glass material and dimensional differences. The plunger
was developed to achieve optimal fitness for use.
Figure 2
Figure 5
One of the QTPPs the new 1mL Long plunger provides is

for injection time reliability and delivered dose accuracy.
Quality variation of the glass barrel to plunger interface may
cause inconsistent breakloose and glide force, which can
be compensated for by the human thumb during a manual
injection. However, in auto-injector device applications the
variability may cause incomplete injections or stall the plungers
movement, resulting in variable delivered dose.
Figure 7
Figure 8
Results:
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industrialized with a quality product profile of optimized
breakloose and extrusion forces, and low variation from partto-part. The results from the breakloose and extrusion (BLE)
performance evaluations using the steam sterilized ready to
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of the most commonly used, commercially available staked
needle syringe barrels verified that the quality product profile
was achieved. The samples were stored assembled at real-time
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at each of the conditions and within each stored state and
syringe barrel type. The NovaPure plungers showed notably
low BLE forces, and exhibited very consistent, smooth extrusion
force profiles with minimal variation. These results meet the
functionality requirement for plungers contained within prefillable
syringes, and are fit for use with auto-injectors and other medical
delivery devices.
Figure 3
Using QbD philosophy and principles, a new 1mL long plunger

was developed based on patient and practitioner needs.
Specifications and process controls were developed through:
Conclusion:
Using QbD philosophy and principles, a new 1mL long NovaPure
}i{x>>`>i`ì}Vi>
to optimize breakloose and glide force, retain low part-to-part
variability, minimize wrinkling of FluroTec film and provide
the highest quality, including visible and sub-visible particle
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verification for ppm based attributes.
NovaPure plungers are the latest innovation for 1mL long glass
prefillable syringes. The plungers are optimized for manual
injections and auto-injector drug delivery and provide unique
benefits including lower total cost of ownership, quality driven
by patients needs, in-depth product and process understanding and transparency to scientific knowledge.
Bibliography:
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http://www.westpharma.com/en/support/Scientific%20Posters/Integrating%20Quality%20by%20Design%20for%20Development%20of%20Prefillable%20Syringe%20Components.pdf
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WPREVIOUS PAGE
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GLASS VS. PLASTIC
Less is More
EVERYTHING YOU WANT. NOTHING YOU DONT.
The Daikyo Crystal Zenith polymer vial truly delivers an advanced drug containment system. Designed for highvalue molecules, it eliminates glass delamination, while helping to ensure the stability and purity of medications.
For the life of your product. For the lives of your patients.
Daikyo Crystal Zenith:

No risk of glass delamination
High break resistance
Suitable for cold temperature storage
Very low extractables
Used in regulated markets (US, EU, Japan)
www.daikyocrystalzenith.com
(800) 345-9800
West and the diamond logo and By your side for a healthier world are
registered trademarks or trademarks of West Pharmaceutical Services, Inc., in
the United States and other jurisdictions. Daikyo Crystal Zenith is a registered
trademark of Daikyo Seiko, Ltd. Daikyo Crystal Zenith technology is licensed
from Daikyo Seiko, Ltd.
For complete contact information please visit www.westpharma.com.
Copyright 2014 West Pharmaceutical Services, Inc.
WPREVIOUS PAGE
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#8792
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AVOIDING
UNINTENDED
INTERACTIONS
Interactions between drug products
and packaging are better
understood but risks remain
BY THOMAS FEINBERG, PH.D., DIRECTOR,
DEVELOPMENT & CLINICAL SERVICES, CATALENT
IF A drug product is contaminated in any way by a chemical derived from its packaging, this can cause real problems for patients. These leachables have caused real-world
problems ranging from mild and temporary gastrointestinal symptoms to full-blown immunogenic reactions.
At the less severe end of the symptom scale, in 2009
and 2010 various products reached patients that had
a musty smell. This subsequently was identified as 2,
4, 6-tribromoanisole, and eventually traced back to a
breakdown product of a fungicide, with which the wooden
pallets used in storage and distribution were treated.
More dangerous effects occurred in patients taking Eprex
(erythropoietin alpha) after a formulation change. The
solubilizing agent, human serum albumin, was replaced
with the chemically derived alternative, polyethylene
glycol. This change increased the propensity for the new
formulation to leach cross-linking agents from uncoated
syringe elastomer into the product, which then reacted with
the therapeutic protein to cause an antigenic effect.
While such problems are unusual, they do occur, and
thus it is essential that all potential interactions between any
individual component of a drugs formulation and any part
of its packaging are evaluated carefully. Only then can the
manufacturer be assured that the packaging will have no
deleterious impact on the products safety and effectiveness.
During the development and registration of every drug
product, three crucial variables, drug, device and data,
must be considered and understood. By considering each
of these variables as the vertices of a formulation triangle,
every study can be classified as lying within such a figure.
For example, early phase studies of the action of an API
in biological systems lie closest to the side connecting the
WPREVIOUS PAGE
Drug and Data vertices. Device compatibility studies, on

the other hand, lie closest to the side connecting the Drug
and Device vertices. Device performance testing can be
considered to lie between the Device and Data vertices.
The ultimate goal for both the developer and regulatory
authority is to sample the entire space within the triangle.
Only when information is available about all the possible
interactions can a packaged drug product be declared safe
and effective.
Extractables are those substances that can be extracted
from the packaging material in some way, usually
requiring the presence of strong solvents, elevated
temperatures, or both. Leachables are, essentially, a subset
of extractables, and require no unnatural extraction
process to enter a drug product, as they are a natural
interaction phenomenon between a formulation and its
packaging. While both extractables and leachables might
be additives that are deliberately incorporated into the
packaging material, this is not necessarily the case as they
might be low molecular weight fragments of the polymer,
such as cyclic oligomers or even unreacted monomers.
The reactions used to make condensation polymers
such as nylon are, essentially, reversible, and therefore
a condensation polymer backbone can be a source of
an extractable monomer created by the back reaction.
Monomeric extractables are still reactive, and their
free concentrations are usually low. Cyclic oligomers,
such as the dimers and trimers of polybutylene
terephthalate, are commonly observed extractables from
this particular polyester. As long as formulation or any
extraction solvent is not in contact with these materials,
no observation of complete extraction will ever occur.
19
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GLASS VS. PLASTIC
This does not mean that such thermoplastics should be

avoided as the mere presence of these chemicals may not
cause deleterious effects on product quality. In fact it does
illustrate that leachables will always be present in drug
products and anything packaged in plastic.
The extraction process generally occurs at a solid-liquid
interface, although it can occur at a solid-gas interface,
particularly if a volatile organic compound is present in
the packaging material. The rate of extraction depends on
a number of physical and chemical factors, including the
permeability of the solvent into the solid, the solubility
of an extractable into that solvent, and the temperature
and pressure of the system. In the laboratory, there
are numerous ways in which to perform extractions.
Typical techniques include Soxhlet extraction (diffusioncontrolled); boiling point reflux (temperature controlled);
equipment that allows elevated pressures above solvent
boiling points such as accelerated solvent extraction
(temperature controlled); and microwave extraction, to
heat a polarisable or dipolar solvent above boiling points
(temperature controlled).
THE IDENTITY OF EXTRACTABLES AND LEACHABLES
Extractables and leachables fall into various chemical

groups. Polymer additives are a major class of extractables, and differ both within types of polymers and even
grades of the same polymer. They are added to polymers
to impart desirable processing and end-use properties
such as stability, and while they are not by default bad,
there is the potential for them to be extracted or leach
into a drug product. They cover a whole range of different
functionalities, altering the mechanical, chemical or even
electrical properties of the polymer.
Mechanical property modifying additives include
nucleating agents that allow polymers to be processed
at lower temperatures, cross-linkers that give a polymer
mechanical strength and introduce a 3D structure,
and fillers that impart both strength and heft. Fillers
are typically inorganic substances such as clay, heavy
metal oxides or carbon black. Plasticizers, which impart
flexibility and give resistance to cracking, are a major
class of additives, and may include both natural and
synthetic oils, and phthalates. The use of phthalates is
now under particular scrutiny.
Cross-linkers can also be classed as chemical property
modifying additives, as they create supramolecular
structures from the polymer. These larger molecules
do not react or dissolve easily in any solvent, imparting
chemical resistance. Antioxidants are another common
form of chemical additive, and are included if the
WPREVIOUS PAGE
Both small molecule drugs

and biologics have the
potential to be contaminated
by extractables, and the direct
harm a leachable may cause a
patient is the same in either case.
polymer has a high oxidation potential, typically because

it contains many hydrogen atoms. Hindered phenols, or
mixtures of these phenols with phosphine compounds,
are examples of this class of additives. Flame retardants
and clarifiers can also be incorporated into a polymer to
make it less susceptible to high temperature oxidation.
Electrical property modifying additives are typically
surface modifiers to control static build up. These increase
the rate of charge dissipation at surfaces by incorporating
a polar group or fixed charge within the additives
molecular structure. Examples include aliphatic amines,
amides, quaternary amines or polyol compounds.
Usually, leachables are considered to arise from
packaging directly in contact with formulation; i.e.
primary packaging. Additionally, extractables in
secondary packaging; i.e. materials in contact with the
primary packaging, and even from tertiary packaging,
may find their way into a drug product prior to the end
of its shelf life. These may be present in any part of the
entire packaging and delivery system. Examples include
components of printing inks, and chemicals such as flame
retardants or antifungal agents that might be present in
cardboard boxes or shipping containers.
Inorganic compounds can also be found as components
of packaging materials. Many of these chemicals will
fall into a specific additive class such as filler or, in
the case of metal salts of medium chain fatty acids,
plasticizers. While rare, it is possible that residual
heavy metal catalysts may be detectable in plastics.
Fortunately, analytical technology for the detection and
quantitation of heavy metals in drug products is fairly
well understood, and both the European Pharmacopoeia
and the United States Pharmacopeia have well described
methods and limits for these elemental impurities.
THE ORIGINS OF EXTRACTABLES AND LEACHABLES
An extractable or leachable may be introduced at any

point along the packaging supply chain. While a company
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GLASS VS. PLASTIC
packaging, as used for small volume injectables, in cases

of long-term storage, inorganics from glass or organic
compounds from the elastomeric stopper may be found.
If it is packaged in a single-dose pre-filled syringe, there
are more potential source components, including the
thermoplastic barrel, elastomeric plunger, metal needle,
elastomeric needle sleeve, or even the foil pouch or plastic
blister that constitutes the secondary container.
The situation is even more complex for products
designed to be delivered by infusion. There is potential
for long-term storage exposure from the laminate or
multilaminates that make up the bag, as well as inks,
thermoplastic ports and thermoelastomeric connectors.
Further potential sources may come from in-use exposure
during infusion, particularly from thermoplastic
connectors or elastomeric tubing.
Probably the most complex interaction and, historically,
the system of most concern between primary packaging
and formulation is the pressurized metered dose inhaler
(pMDI). A pMDI has many components that could,
conceivably, contribute to the extractables load. These
include the metal canister and spring, the valve body, stem
and metering chamber, the gaskets on the stem and the
valve, and the gathering ring. All of these components will
be continuously bathed in an organic solvent (propellant
and carrier) for as long as the product is viable.
The leaching of extractables into drug product
formulations is inherently a kinetic problem. Intimate
mixture between formulation and the packaging will
increase the rate of leachables formation. The more
similar a formulation is to its primary packaging, the
more care should be taken with the choice of primary
involved in packaging pharmaceutical products will require

full disclosure from their suppliers about their processes and
any extractable that might have been introduced in their
facility, this disclosure requirement does not extend all the
way back through the many links of the supply chain.
A pharmaceutical company will source its packaging
containers and device components from a moulding
shop which converts polymer products, and may add,
for example, lubricants and colorants during moulding.
The converter sources its materials from a masterbatcher,
whose processes could introduce stabilizers, antioxidants,
processing aids or antistatic agents. The masterbatcher
is supplied by a polymer manufacturer, whose products
might contain catalysts, stabilizers, antioxidants
or processing aids. The raw materials for polymer
manufacture are provided by a company that synthesizes
monomers, where bulk chemicals or storage stabilizers
might enter the supply chain.
Quality agreements between pharmaceutical
manufacturers and their suppliers generally do not cover
disclosure beyond the first level supplier. In the US,
pharmaceutical manufacturers also have the advantage
with first level suppliers because those first level suppliers
generally will avail themselves of the Drug Master File
(DMF) system. Having a DMF has become a marketing
tool for first level suppliers and helps them obtain
business from the pharmaceutical industry. The second
level and further level suppliers are so far removed from
the pharmaceutical industry and do not find the size of
the market to be advantageous to their bottom line.
Whatever the form of the packaging, there is always the
potential for leachables. Even for typically clean primary
CONTAINER CLOSURE SYSTEM COMPONENTS

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4FDPOEBSZQBDLBHJOHDPNQPOFOUT XIJDIXJMM
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21
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GLASS VS. PLASTIC
DA
TA
WPREVIOUS PAGE
Another well-known problem arises from vial closures.

In general, most suppliers have switched their elastomeric
closures from natural sulfur-cured latex to other,
synthetic, materials. The older materials can contain
extremely undesirable chemicals such as nitrosamines and
polynuclear aromatic hydrocarbons, which are suspected
(or known) carcinogens. It is therefore advisable to use
modern synthetic elastomeric polymers for safety reasons.
QUANTIFYING THE RISK
UG
Regulators in both the United States and the European

Union have now begun to apply a standard risk level
that manufacturers can pair with their respective benefit
levels for new products. The tolerable risk level for
the genotoxic impurities has been agreed as
an excess negative outcome (cancer) of 1 in
100,000 cases. Derivation of a standard
tolerable risk level for unknown leachables was one of the desired outcomes
of a research project sponsored by the
Product Quality Research Institute
(PQRI). By comparing negative
outcomes from multiple toxicological databases, the toxicologists on the orally Inhaled
and Nasal Drug Product
PQRI working group derived
a common Safety Concern
Threshold (SCT) of 0.15g per
day for any exposure compound.
Below the SCT, the risk of any unknown leachable has been proposed to be
acceptable. This risk can also be understood as an excess
negative outcome of 1 in 1,000,000 cases.
Until these quantitative limits were set, regulators
would routinely request tests right down to the limits of
analytical instrumentation. Analytical capabilities have
been evolving to ever lower levels over the past couple of
decades, and while this has provided an abundance of
information, there is no additional safety margin without
the availability of thresholds such as the SCT. Even with
these thresholds in hand, formulation compatibility must
always be assessed on a case-by-case basis, particularly
for biologics. As new and more potent compounds
and therapies are introduced to patients, there is a real
possibility that lower levels of leachables might cause
problems in a formulation. Fortunately, the introduction
of risk-based thresholds has provided a level of control of
the risks of direct patient exposure that can be measured
and, if necessary, managed.
DR
packaging, and in the design of studies to show its

suitability. While there have been recent examples of
deleterious leachables in solid oral drug products, the rate
of transport of small molecules from packaging onto such
dosage forms is generally low. However, it has happened,
and should be of concern if there is the potential for
volatile chemicals to arise from the primary packaging,
or be transported through the primary packaging. Both
primary and secondary packaging materials should be
screened for volatile organic compounds as part of a
systematic characterization of all packaging components.
Both small molecule drugs and biologics have the
potential to be contaminated by extractables, and the
direct harm a leachable may cause a patient is
the same in either case. There may be some
dependence on site of action, which is still
related to the inherent safety profile of
the contaminant. However, even at high
concentrations in a small molecule drug
preparation, the amount of leachable
will usually be small compared to
the number of molecules of the
drug, and any reactions that
might take place between the
leachable and the active will
not have any appreciable effect
on potency. In contrast, the
number of molecules of large
biologic drugs in a dose is much
lower, so any reactions between
the leachable and the biologic are
much more likely to impact potency.
Another issue with biologics is immunogenicity, which is
very difficult to predict from chemical structure alone.
Different dosage forms of the same molecular entity
will need to be studied separately. It is not possible to
state, without carrying out proper investigations, that
which is safe for an inhalable formulation, for example,
will automatically be safe for an injected drug.
While the identity of extractables or leachables can be
unexpected, some cause well known problems, and thus
are either best avoided or very carefully tested for. For
example, there have been concerns about the migration
of benzophenone from labels into ophthalmic products.
Benzophenone is a common component of UV-active inks,
but is also a potent irritant. Most label suppliers are aware
of this link, and offer benzophenone-free options. However,
while this individual chemical may have been removed,
the irritation potential of the alternative chemicals that are
being used instead has not yet been established.
IC
2O14
DEV
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GLASS VS. PLASTIC
sterile technologies
2014 Catalent Pharma Solutions. All rights reserved.
reduce
the risk of
injectable
filling
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WPREVIOUS PAGE
274-CatalentAd2015-AdvaSept_R6D.indd 6
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10/1/14 4:36 PM
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GLASS VS. PLASTIC
Minimizing the Risk of Sterile

Manufacturing Through
AUTOMATED ASEPTIC
TECHNIQUES
CONTAMINATION EVENTS for aseptic manufacturing have led to product recalls, and even the complete
shutdown of manufacturing plants to remediate the
issues. This has caused companies real economic and
reputational damage. But, fundamentally, the reason why
contamination must be avoided at all costs is the potential
to harm patients. If a case of contamination is not picked
up before the filled product leaves the facility, the risks to
patients are obvious.
In recent years, there have been numerous high
profile recalls and facility shutdowns after the
discovery of contaminated products. Even reading
through the FDAs list of product withdrawals there
are multiple examples of contamination ranging from
glass fragments and other visible particles in vials,
to products that caused immunogenic reactions. The
severity of contamination risk was highlighted in
2012 when formulations for spinal steroid injections
led to hundreds of people becoming infected with
fungal meningitis and caused multiple deaths.1
Many of these could have been avoided had better
manufacturing and control procedures been in place.
Perhaps the biggest challenge to aseptic parenteral
filling is the avoidance of microbial contamination. The
number one source of microbial ingress into a filling
facility is the human operators running the process. If
contact between operator and product can be minimized,
or even eliminated, then a major potential hazard is
instantly reduced, if not removed.
Traditional filling processes offer many opportunities
for microbes to enter the filling line. The primary
container and closure components have to be cleaned
and sterilized ahead of use, but are then exposed to the
atmosphere as they rotate on the filling line or stopper
bowl. This provides plenty of chances for particulates
and other contaminants to be deposited on or in the
otherwise sterile components.
WPREVIOUS PAGE
Human operators within the filling suite still pose the

biggest risk in a traditional filling. They will be physically
monitoring the line, straightening vials on the turntable
and dislodging stoppers that may have become stuck. This
physical contact provides an opportunity for microbe or
pyrogen ingress, and even the fact that there are people
within the filling suite, breathing and moving around,
adds the potential for adventitious contamination.
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GLASS VS. PLASTIC
LEVERAGING ADVANCED ASEPTIC MANUFACTURING TO MINIMIZE CONTAMINATION RISK
An advanced aseptic filling process that leverages blow/

fill/seal, or BFS, technology has the potential to reduce
these risks. The container is made in situ, and filled
in a virtually closed process, with the container being
sealed before it leaves the class A/ISO 4.8 environment.
This technique has been in common use for the manufacturing of sterile products for decades, and is well
established in the filling of parenterals in Europe, South
America and Asia. However, surprisingly, in the United
States traditional filling techniques for parenterals are
essentially exclusive to traditional filling, despite the
significant and documented benefits of BFS filling in
maintaining product sterility.
BFS has been designated as an advanced aseptic
technique by regulators. The FDA has established
requirements that will render a technique advanced
aseptic.2 Essentially, it is a technique where operators
dressed in normal cleanroom garments do not and
cannot interact with open containers of products or
exposed surfaces that come into contact with the product.
The advanced aseptic environment of BFS is automated
and controlled, with rapid product processing, and the
critical control parameters are set and monitored. Other
equipment that can be deemed advanced aseptic includes
restricted access barrier systems and isolators.
BFS is able to meet advanced aseptic demands because
the in situ manufacturing, filling and sealing of the
container requires no human intervention, and the
line is remotely operated and controlled. In addition,
continuous monitoring of parameters, such as the viable
and non-viable air in the fill zone adds a further layer of
security. In all, its features greatly reduce the potential for
microbial and foreign particulate contamination to the
product. The FDA deems the design of the equipment,
process and operational controls to render it advanced
aseptic, with further evidence provided by test results
from numerous microbial challenge experiments that
were designed to push performance to the limit.
SYSTEM DESIGN
At the heart of the advanced aseptic technology of BFS

is the automation and control. The equipment design is
rooted in the principles of Quality by Design. The filling
process takes place in an ISO 4.8, or Class A, environment, and it takes less than 15 seconds from the start
of the container molding process to the final seal being
applied to the container. Both the pathway that brings the
plastic used to make the container and the pathway by
which the product is introduced are virtually closed, with
WPREVIOUS PAGE
no operator intervention required. A further advantage

is the additional level of safety afforded by the high heat
and pressure used to melt and process the plastic resin,
which inactivates any residual or adventitious microbes
or endotoxins that might be present in the plastic.
To make the container, virgin plastic pellets are
fed into an extruder through a vacuum line, where
the pellets will undergo a phase change with high
temperatures and pressures (typically 180 C and 200
atm). The plastic is extruded into parisons, which are
long plastic tubes, into a space that meets ISO 4.8 viable
air standards, where the maximum number of 0.5m
particles per cubic meter is 3,520, and the maximum
for 5.0m particles is 20. The primary container is
shaped via brass and steel 2 stage mold. In the first stage,
the mold closes around the parisons and a vacuum
is pulled to create the container body. The top of the
container is still open and is now ready for filling. Fill
nozzles are then activated to fill the container with drug
product. Once this is complete, the second stage of the
mold closes and seals the product. Again, this entire
automated process takes place in an ISO 4.8, or Class A
space in the matter of seconds.
Control of the quality of the airspace around the nozzle
is maintained and monitored, for both non-viable and
viable air. Should the permitted particulate levels be
exceeded, the filling machine will automatically shut
down to prevent the container and product from being
exposed to potential contamination risks. And, as the
whole process takes just 15 seconds from start to finish,
any risk from exposure to the atmosphere is minimized
as the time the container is open is so short.
The fact that the product pathway is also closed in
BFS provides further surety of safety. In a traditional
filling line, components and equipment are cleaned and
sterilized ahead of time and then stored before being
assembled and aseptically connected, after which they
sit open to the atmosphere within the filling suite. In
contrast, in a BFS line all the cleaning and sterilization
is done in situ, and thus the product is never exposed
to equipment that has been open to the atmosphere or
operators assembling it after it has been sterilized.
The ISO 4.8 space that surrounds the filling nozzle is
not exposed to human operators. In the unlikely event
that an operator does have to enter the closed filling area,
the run is stopped and a full re-clean and sterilization
procedure will be run, prior to restart. This is much less
impactful than in the case of a traditional filling line, as
only minimal amounts of product are ever going to be
exposed, and the containers simply do not exist until they
are extruded.
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GLASS VS. PLASTIC
MICROBIAL CHALLENGE TESTING
It is clear on a qualitative level that vials filled using BFS

are inherently much less likely to be contaminated by microbes or pyrogens. However, at the heart of the advanced
aseptic designations is the microbial challenge data that
supports this designation. Companies such as Advanced
Liquid Packaging (now part of Catalent) ran numerous
tests, in which various parts of the filling process were
exposed to extreme microbial insults.
In order to run these tests, a specific microbial
challenge facility was designed with completely
dedicated HVAC and exhaust systems, to ensure
unplanned contamination was not allowed in, and
none able to escape. Microbial loads could therefore
be carefully measured, the room safely fogged, and
equipment with known amounts of contamination
introduced. Several such challenge tests were carried out
to form the basis of the advanced aseptic nature of BFS.
The three most referenced tests are on the impact of an
extreme microbial challenge on the equipment surfaces,
the virgin plastic pellets used to make the containers,
and the air within the room.
The first of these tests is the equipment surfaces and
components test. All of the BFS surfaces were coated with
varying levels of up to 108 spore suspension of Bacillus
subtilis.3 The filling process was then run under normal
conditions. Even though the surfaces were loaded with
microbial contamination, the only surface that created
a media failure was the fill nozzle that comes in direct
contact with the product. This proves that even if the
equipment itself is extremely contaminated and you
control the fill nozzles, the final product remains safe.
The challenge test on the raw plastic pellets involved
using the loading of up to 108 B. subtilis spore suspension
being fed into the extruder.4 The combination of the
heat and pressures utilized in the process created a 103
reduction in bioburden. Even though the microbial
contamination was far greater than typical resin values,
the data provides the benchmark for the critical control
parameters for the plastic resin. In addition, this process
offers an additional barrier to microbial contamination
based on the extreme heat and pressure needed to convert
the plastic from a solid to molten liquid.
Finally, the airborne challenge study.5 The microbial
challenge facility was fogged with 102 to 108 of an
aerosolized suspension of B. subtilis, with aerosolization
continuing throughout the test. Numerous filling
runs were carried out under different microbial load
conditions, including the activity of the HEPA air
shower in the ISO 4.8 space. The tests showed that the
WPREVIOUS PAGE
contamination fraction was reduced to 103, a substantial

reduction from the levels that had been introduced. This
was directly proportional to the applied microbial load,
as was the number of contamination incidents. Clearly,
the high levels of B. subtilis introduced are significantly
higher than those that are ever likely to be present in
the real world, and these results allowed operating
and environmental conditions under which the BFS
equipment can automatically be guaranteed to meet the
sterility assurance level demanded of products that are
terminally sterilized, which is set at 106.
Now imagine carrying out similar tests in a traditional
filling line. Everything within the filling suite from
equipment to consumables would be covered with
microbial contamination if the room were aerosolized
with a 107 spore suspension. Virtually every single vial
of product would be contaminated in contrast to
those tests leveraging the advanced aseptic process of
BFS. Fundamentally, BFS drastically reduces the risk
of contamination, which is at the heart of its advanced
aseptic designation.
Traditional glass vial filling operations continue to
have challenges with aseptic manufacturing that cultivate
into contamination issues and product recalls that are
leading to drug shortages. It is clear that implementation
of BFS to fill parenteral products would reduce the risk
inherent in the traditional aseptic filling process by
eliminating variables and increasing automation. This
could potentially enhance patient safety and product
availability due to the decreased risk of contamination.
The adage Because thats how weve always done it is not
good manufacturing practice, especially when there are
alternatives that are safer and more reliable.
References
1. Update: Multistate Outbreak of Fungal Infections among Persons
Who Received Injections withContaminated Medication - Distributed via the CDC Health Alert Network
December 20, 2012, 11:55 ET (11:55 AM ET)
CDC HAN-0338-2012-12-20-U-N
2. US FDA: Guidance for Industry: Sterile Drug Products Produced
by Aseptic Processing Current Good Manufacturing Practice
(2004)
3. MCF/2- Effect of Changes in Key BFS Process Variables on Frequency of Vial Contamination. C. Sinclair
4. Sinclair and Tallentire (1993) Predictive Sterility Assurance for
Aseptic Processing. In: Sterilization of Medical Products, Volume
VI, Polyscience Publications, Montreal.
5. Parenteral Science and Technology July/August 1990; Bradley,
Probert, Sinclair and Tallentire
26

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WWW.PHARMAMANUFACTURING.

Innovation & Patient Safety

GLASS VS. PLASTIC

Clash of the Titans: Glass vs. Plastic

VIDEO: The Future of Blow-Fill-Seal Innovation

Container Innovations Prairie Home:

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Integrating Quality by Design for Development

Avoiding Unintended Interactions

Minimizing the Risk of Sterile Manufacturing

GLASS VS. PLASTIC

the first synthetic plastic

pecifying the best material to serve the primary

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by 2018, representing about a third of

GlasS (shown here) continues to dominate the prefilLed syringe

GLAsS, THE PROVEN

like the Pharma companies

accessible to all drug developers

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For the most part, and over the last

FIND IT OUT FASTER

SCHOTTs analysts developed a test that allows pharma

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BEtTER EARLIER THAN LATER

very similar out there, your risk assessment may well

Tony Pidgeon, applied technology director for finished

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Other fundamentals, like how the product will be filled

Catalents new aseptic parenteral container

contamination, less opportunity for overfill, simplified

For parenteral, sterile injectables in vials and syringes,

GLASS VS. PLASTIC

injectables as well. Tim Kram, general manager for

bottles with those annoying but necessary child-proof

Drug innovation is driving packaging innovation and

GLASS VS. PLASTIC

new product [with glass], says Kram, are better known in

This Fundamentals series includes:

click here to view the presentation

GLASS VS. PLASTIC

Advanced aseptic packaging in one operation cycle

rommelag USA, Inc.

rommelag Trading (Shanghai) Co., Ltd.

GLASS VS. PLASTIC

Catalents Woodstock, Illinois, facility has been pioneering

By Steven E. Kuehn, Editor in Chief

NESTLED OUT on the prairie about 60 miles northwest of Chicago is

Shown here: the redundant sterile filtration and

GLASS VS. PLASTIC

t0WFS TRGUPGQSPEVDUJPO MBCPSBUPSZ 3%

Inside the isolator room

OPERATIONAL IMPROVEMENTS ON DECK

GLASS VS. PLASTIC

spaces were built in 1980. But in

BFS technology from a parenteral

PLASTIC AND FANTASTIC

Blow/Fill/Seal technology, pioneered

GLASS VS. PLASTIC

t0WFS TRGUPGQSPEVDUJPO MBCPSBUPSZ 3%