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Modern aseptic performance demands new flexibility in
both mindset and technology
Regulatory approval of the first aseptically spray-dried drug
validates this newer technology
AD INDEX Catalent 18
in the lobby of a pharmaceutical
company: “Be stubborn about your
goals, and flexible about your methods.”
The pressing need to take advantage of
new technologies and explore new ways of
addressing process control and efficiency
is ubiquitous to all areas of pharmaceuti-
cal manufacturing.
targeted approaches to treatment that
are resulting in small-batch aseptic prod-
ucts, proving more difficult to sterilize
and handle, and requiring faster speeds
to market - add further emphasis to this
industry-wide need.
the effects of genomics-based tools and
genetics understanding, that’s all having an
effect on making much more specific and
smaller patient population therapies. And
the effect is that we are not all going to
take a blockbuster - we are going to take
a very specific therapy for our condition,
which will most likely be a smaller batch
injectable with a higher price tag,” says
Chris Procyshyn, aseptic subject matter
expert and CEO at Vanrx, a company at the
cutting-edge of aseptic filling.
manufacturers are now able to recognize
previously unattainable value in small-vol-
ume aseptic processing. With this shift not
Contorting Convention Modern aseptic performance demands new flexibility in both mindset and technology
By Karen Langhauser, Chief Content Director
eBOOK: Aseptic Processing Trends 3
refocus on available technologies.
aseptic design and process control that
were geared toward mass production may
not be optimal, or in some case even fea-
sible, with some of the new therapies we
are seeing,” says Hal Baseman, chief oper-
ations officer, ValSource. “Rather than take
needs of these new therapies and try to fit
them into the ideas and approaches that
have worked for large-scale manufacturing,
maybe we should be looking at this a differ-
ent way, instead asking what are the new
approaches that we should be considering
that would better fit these new therapies.”
THE DEMANDS OF SMALLER BATCHES Smaller batch sizes mean that manufactur-
ers are looking at facilities very differently,
and re-assessing capex spending.
products being manufactured in each
facility, and a lot more specific process
requirements. This is a different scenario
for drug manufacturing - one that is really
demanding a rethink on how facilities
are put together and where priorities are
placed,” says Procyshyn.
heavy investments in large manufacturing
facilities and equipment, but this may not
be the case with modern aseptic process-
ing. Some biologics manufacturers are even
using their clinical manufacturing facilities
to launch, enabling them to determine how
well the product performs before making
bigger investments into manufacturing
and principal consultant, parenteral manu-
facturing, for DPS Engineering.
than ever before, which means facilities
of the future need to be operational a lot
faster than facilities of the past. Equipment
standardization is a great enabler when
it comes to bringing products to market
quickly. Conventional, custom-built fill-finish
than before, which means facilities
of the future need to be operational
faster than facilities of the past.
lines are expensive and time-consuming to
build and offer limited flexibility. Equipment
leaders, such as Vanrx, are recognizing this
new challenge.
where ‘custom’ used to be the rule. But
today’s drug manufacturers don’t have time
to be the guinea pigs for what’s never been
tested before. Customers are looking for
something that is predictable. At Vanrx, we
build very consistent, standardized offer-
ings, and consequently we can develop
and refine and test at a very deep level,”
says Procyshyn.
ing lines. Aseptic component designs also
can benefit from standardization.
ponents to flow through. Standardizing
component offerings would be an important
move forward for the industry. If you get
too many different component designs it
becomes difficult to design machines that
can be everything to everybody. If the goal
is maximizing flexibility while minimizing
costs, the implementation of standardized,
ready-to-use components allows for more
flexible facilities, capable of handling a
wide variety of products in a single facility,”
says Starkman.
gies as, “Technology with the potential to
modernize the body of knowledge associ-
ated with pharmaceutical development to
support more robust, predictable, and/or
cost-effective processes or novel products
and with which the FDA has limited review
or inspection experiences, due to its rela-
tive novelty.”
The industry’s migration away from
standard cleanroom filling in favor of
Vanrx’s SA25 Aseptic Filling Workcell is the first gloveless robotic isolator for making sterile injectables. The machine is designed for flexible production of multi-therapy portfolios, with new technologies that provide superior aseptic assurance and process repeatability.
isolators (close to 30 years ago) brought
with it dramatically improved product
safety and environmental compliance. This,
according to Starkman, helped open the
industry’s eyes to the incredible benefits
of emerging technologies. “There was an
increase in willingness to look at the data
and make changes accordingly,” notes
Starkman. “And I’m hoping this continues,
because acceptance of new technologies
is the only way the industry is going to
move forward.”
indeed changed the industry and markedly
reduced contamination risks for ster-
ile products.
want, but ultimately there needs to be a lot
more consorting and collaboration between
equipment manufacturers, end-users and
is still a ways to go,” says Starkman.
An often-used reason for the drug indus-
try’s reticence when it comes to the use
of new, emerging technologies in the drug
manufacturing process is regulatory hur-
dles. And yet, most experts agree that
regulatory agencies are no longer impeding
progress when it comes to technology.
“We are in a really interesting time. Global
health authorities are recognizing that these
new therapies don’t quite fit large-scale
manufacturing methods, and consequently,
changes,” says Baseman. Baseman is also
the committee co-chair of PDA’s Manufac-
turing Science and Operations Program,
which, among numerous goals, seeks to
identify and encourage use of new manu-
facturing technology and methods.
cal Quality (OPQ) established its Emerging
Technology Team (ETT) to serve as a pri-
mary point of contact for companies that are
interested in implementing emerging manu-
facturing technology in the manufacture of
their drug products. The group is focused on
establishing open communication between
introduce modernizing technologies. Par-
company a face-to-face meeting with the
FDA as well as an onsite meeting at the par-
ticipant’s plant in order to show the Agency
the technology in action.
year that aseptic innovations were one
of the dominating submission types for
participation in the FDA emerging technol-
ogy program.
cuss the company’s gloveless isolator
technology, reports that the team is very
positive and ready to work with industry.
“Ultimately, regulators have the obligation
to make sure there is a supply of safe and
effective medication. They are pushing for
technology advancements. Keep in mind
that they see everyone’s filing and every-
one’s plant, so they know what best-in-class
looks like. Consequently, they push for
advances once they see what’s possible,”
notes Procyshyn.
RISE OF RISK-BASED APPROACH Regulator’s shifting attitude in terms of
emerging technologies can partially be
attributed to the adoption of a risk-based
approach to manufacturing.
involves drug manufacturers defining the
quality attributes of their products, and
how to best assure those quality attri-
butes are established and maintained.
As a result of this reverse engineering
approach, manufacturers can look at each
step along the way and determine the risk
of failure.
pharma can better articulate its processes
to regulators. Having good data and ana-
lyzing that data means manufacturers can
better understand - and articulate - the
risk of failure.
differently. With manufacturers now able
to demonstrate that they understand the
critical quality attributes of their products
and what drives them in terms of critical
process parameters, it is much easier for
regulators to say with confidence that man-
ufacturers truly understand their process,”
says Starkman.
ages a more proactive view of emerging
technologies, enabling drug manufacturers
to take a hard look at the needs of a partic-
ular process and design technologies that
meet those specific needs.
to process design/process control
involves manufacturers defining the
“Adoption of a true risk-based approach
means manufacturers can ask them-
selves what equipment they really need
to establish process control and then
design technologies around that need - as
opposed to designing a process around
technologies that happen to be available,”
notes Baseman.
come of a more risk-based approach is the
introduction of new industry guidance in
the area of aseptic processing.
“The guidances we have are geared toward
larger scale aseptic production. There
needs to be some work put into chang-
ing guidances or adding new guidances
and approaches. It’s important to consider
that maybe the tried and true, traditional
approaches aren’t fitting as well with the
manufacturing needs of new therapies,”
says Baseman.
lation of best practices in the industry, it
would follow that if the industry’s approach
to best-practice in aseptic processing was
to shift, new guidance highlighting these
changes should follow.
THE NEED FOR CHANGING MINDSETS In addition to next-generation technolo-
gies, next-generation aseptic processing
be said that the pharmaceutical industry is
dominated by a generation of people who
don’t necessarily have a lot of experience
managing industry-wide change. “There is
a very different level of technical under-
standing necessary for managing change,”
notes Procyshyn.
“If you step backward, one of the challenges
with our industry is that it’s a lot slower and
more glacial than people might think - but
even if you look at glaciers these days, they
change, too. It may be a slow wave that
goes through industry, but every sign is
there that major changes are well under-
way,” continues Procyshyn.
ing gained the bulk of their experience in
large-scale processing, and are now being
challenged to apply that knowledge to
aseptic processing on a much smaller scale,
notes Baseman.
cess fit what they know from large-scale
manufacturing, or they take a fresh look.
They can take the easier way, or they can
take a way that will have more long-term
benefits. Taking an honest, risk-based think-
ing approach will create a process that can
give the industry high levels of assurance
that is unquestioned by regulators and will
allow new levels of production efficiencies,”
concludes Baseman.
When isolators were introduced
into the pharmaceutical indus-
with some degree of skepticism. The early
designs were relatively crude in appearance
and certainly lacked sophistication. With a
few years of technology development and
successful operational experience it seemed
that the isolator would change the way in
which sterile products were made across
the world.
demise of manned cleanrooms as the highly
capable isolator proved its superiority both
operationally and financially.1 The isolator
was expected to be the paradigm changer
that the pharmaceutical industry needed
to attain the next level of performance and
product safety. The virtual elimination of
contamination compounded with expected
paradise. A number of unanticipated
changes to isolator designs occurred on
the way to that rosy future that has dra-
matically lessened the expected impact.
This article will review the ways in which
the vision of the future envisioned in 1995
has been diminished and outline changes to
current practices in isolator and barrier that
would enable the industry to fully realize
the potential in isolation technology.
The essential difference between isolators
and manned aseptic processing area is the
absence of personnel from the operating
environment. The operator is universally
recognized to be the largest contributor
to microbial contamination in conventional
aseptic processing. First, the operator
Paradise Lost Misdirection in the implementation of isolation technology
By James Agalloco, Agalloco & Associates
eBOOK: Aseptic Processing Trends 9
these microorganisms must be somehow
contained within their gowning materials.
Third, microorganisms from the operator
are continuously dispersed into the environ-
ment because their gowning materials and
methods are not absolute.
Manned aseptic environments - espe-
required presence. The predominant design
elements used to control manned environ-
ments include:
ile materials.
to avoid potential air turbulence that
might disrupt the desired unidirec-
tional flow.
quence of the expected air velocity.
• Monitoring of pressure differentials – to
assure that the air flows in the direction
away from the critical environments
where sterile materials are handled.
• Decontamination of the environment –
the non-product contact surfaces of the
equipment and cleanroom.
part of the expected norms when using
manned aseptic processing. These design
components are all intended to reduce the
adverse impact of microbes and particles
derived from the operating personnel who
are the acknowledged primary contamina-
tion source.
designed to exclude personnel from the
environment in which sterile materials are
exposed, and it is appropriate to question
whether measures intended for use with
aseptically gowned personnel are neces-
sary in an environment in which they are
not present. The first isolators used in this
industry demonstrated superior perfor-
design components commonly associated
with those manned environments:
through HEPA filter cartridges remote from
the isolator chamber (unidirectional flow is
used in cleanrooms to mitigate the impact
of the personnel).
the isolator chambers (floor level returns
are used in cleanrooms to prevent re-en-
trainment of potential contaminants at
work height).
The absence of these and other cleanroom
design features in these early isolators
had no adverse effect on their operational
performance.2 The expected operational
cessing projected at that time were not
contingent on any refinement of the basic
designs. The first isolator-based aseptic fill
lines installed evidenced perfor-
manned cleanroom, yet they did
not include any of the accou-
trements of manned aseptic
nology was superior aseptic
processing performance at a
traditional manned operations.
isolator systems also suggested easy fabri-
cation, short lead times, lower facility costs
and a comparatively easy qualification/val-
idation. The future for isolation technology
appeared to be near limitless.
PARADISE LOST – COMPLICATIONS ENSUED AND OPPORTUNITY MISSED Regrettably, the expected “paradise” of iso-
lators for aseptic processing was never fully
realized. Despite evidence that compara-
tively simple isolator designs were capable
of outstanding performance aspects of
cleanroom design began to appear in 2nd
generation isolators. The wrong-headed
than a small cleanroom requiring all of the
accoutrements of cleanroom design.i Uni-
directional (also called laminar flow) air is a
requirement in manned cleanrooms of ISO
5 and better classification that serves to
reduce the dispersion of personnel derived
contamination into critical locales by mini-
mizing the formation of eddies and moving
contaminated air to low wall returns. Unidi-
rectional flow patterns are rarely absolute
even in the best cleanrooms. Horizontal
surfaces of process equipment and the
presence of gowned personnel preclude
anything truly resembling unidirectional
nation source, the human operator, when
using isolation technology largely mitigates
the contamination risk without the need
for a specific air direction. Sterility test
isolators (which only rarely employ unidi-
rectional air flow) and the 1st generation
One of the main advantages
of isolation technology is
the ability to decontaminate
the interior surfaces by
isolators demonstrated environmental per-
complex isolator designs that include uni-
directional flow. Particle generation from
equipment operation and component han-
dling with modern filling and stoppering
equipment is a lesser concern and can be
readily controlled by means other than air-
flow direction.
are myriad as it had a negative ripple effect
on the design of isolator systems: the seem-
ingly simple introduction of unidirectional
airflow into isolation technology required
substantial physical changes with unfortu-
nate adverse consequences.
larger and more complex to move addi-
tional air - increasing both initial and
routine operational costs; with fabrication,
qualification and validation efforts becom-
ing more extensive as well.
Limited access for cleaning because of
the larger size of the overall system made
extended operation more difficult and
increased changeover times between prod-
ucts by extending both decontamination
and aeration cycle times.
of return air ducts at or near the floor of
the room to avoid turbulence at the level
of exposed sterile materials. These are
difficult to clean locations without opening
of the isolator.
grew to a size that allowed for final
installation only at the operating system
eliminating pre-shipment FAT testing,
and costs.
completion of the batch for cleaning /
changeover as portions of the isolator
internals were no longer easily accessi-
ble. This resulted in increased changeover
and cleaning periods and restricted cam-
paign operations.
FPM (0.45 m/s) ±20% air flow velocity at
the HEPA filter face was often instituted.
The exactness of the expectation belies
its arbitrary nature, obscure origin and
unknown utility as an environmental control
measure. Unidirectional flow is possible at
velocities above and below this range. The
consequences of it and its lack of utility of
in isolators are the identical to those for uni-
directional air.
technology is the ability to decontaminate
the interior surfaces by automated
means. This practice replaces the manual
disinfection procedures that are prevalent
in manned cleanrooms and is more
effective as it virtually eliminates human
error or oversight in execution. Automated
systems for decontamination provides
the availability of an automated capability,
some early practitioners endeavored to
‘sterilize’ rather than decontaminate them.
That such a measure was never possible,
nor, necessary in manned cleanrooms for
successful usage was not considered. The
closed design of isolators and the availability
of a reliable means for antimicrobial
treatment perhaps encouraged this
addition would provide a measurable (or
necessary) improvement in environmental
considered. More treatment was believed
to be better than less. This unnecessary
raising of the performance bar appears
benign, but triggered added complications
in both validation process execution and
routine operation.
adverse effect due to positive results largely
associated with difficulties in preparation of
biological indicators.3
population, there was a commensurate
increase in the duration of the decontami-
nation dwell time to destroy them.
Increases in the exposure period meant that
items exposed to the process would have
greater exposure to the principal decon-
taminating agent - H2O2.
sure led to extended aeration times
post-exposure due to increased H2O2
adsorption by some materials.
life of polymeric materials used in
As the primary purpose of most isolators is
separative aseptic operation, their designs
were often sub-optimal for decontamination,
resulting in lengthy decontamination cycles.
isolator construction was shortened due to
repeated extended exposure to H2O2.
As the primary purpose of most iso-
lators is separative aseptic operation,
their designs were often sub-optimal for
decontamination, resulting in lengthy
industry recommendations with respect
PIC/S, USP, PDA and others had all issued
guidance documents that recommended a
lesser treatment using a lower population
on the biological indicators.4,5,6,7
the decontamination of isolators and their
closed configuration during the process
led to concerns relative to the integrity of
the system. The intent of leak testing is to
confirm minimal operator exposure to H2O2
during the decontamination process. Here
too, a seemingly useful consideration has
been elevated to extremes. Initially a qual-
itative test, leak testing quickly became a
quantitative metric that was both increas-
ingly complex and overly rigorous. While
it is readily acknowledged that aseptic
cleanrooms continuously leak air to their
surroundings, and aseptically gowned per-
sonnel are ‘the’ source of contamination,
the idea that an isolator system should leak
at all became problematic. The futility of
leak testing was perhaps best addressed
by Staerk and Sigwarth, who evaluated
a variety of leak test methods on isolator
gloves and showed that the level of detec-
tion for all was orders of magnitude larger
than the typical microorganism.8 Never-
theless frequent glove leak testing is a de
facto requirement for present day fill isola-
tors. The following adverse consequences
have resulted from this largely unneces-
sary precaution:
of leaks.
and routine operation to check for leaks,
and remediate them where possible.
• Increased cost for the purchase, cali-
bration and maintenance of glove leak
testing equipment.
the isolator.
importantly, the need for adherence to
proper aseptic technique inside an isolator
should always be respected. This measure is
sufficient to maintain asepsis in cleanrooms
where operator routinely shed significantly
more microorganisms than could ever be
present in an isolator, and their glove/
gown integrity has never been consid-
ered absolute.
eBOOK: Aseptic Processing Trends 14
PARADISE DELAYED – HAVING YOUR CAKE AND EATING IT TOO! In the early 1980s, the author encountered
isolators and became a strong proponent of
the technology. I believed that the physical
separation of personnel from the critical
aseptic environment would revolutionize
tion from proximity to sterile materials an
unmatched level of performance would be
realized. When isolators were still a novelty
there were a myriad of design options, and
isolator systems were implemented without
major difficulty. As the cleanroom relevant
concerns were added to isolator designs
implementation began to slow. I heard
statements such as, “It’s taken XYZ more
than 3 years to validate their filling isolator.
What makes you think we can do it at all?”
The over-specification of isolator system
designs caused by the unnecessary impo-
sition of clean room concepts resulted
in a surprising outcome. A less capable
technology was touted as an acceptable
substitute. Restricted Access Barrier Sys-
tems (RABS) were introduced as the best
of both worlds. They would deliver isola-
tor like performance with the simplicity
of a cleanroom. RABS are actually highly
evolved cleanroom designs that rely on
some isolator like design elements, but
eliminates those believed to be particularly
challenging such as unidirectional air, auto-
mated decontamination, and leak testing.
RABS advocates were often employed at
firms that had experienced iso-
lator technology implementation
were frequently heard. RABS
installations vary in sophistication
evolved designs that are little more than
gloves installed on a partial barrier.
As a full-time consultant, I have visited
many different aseptic filling installations.
To those that have implemented RABS in
the best possible manner I must acknowl-
edge their proficiency. To those that
operate less capable RABS systems I must
question the technology decision. With-
out extreme diligence in system design,
RABS can be disappointing in reality. I
have observed many RABS designs that
Many RABS designs are
only marginally better than
the cleanrooms they were
are only marginally better than the clean-
rooms they were intended to displace. That
these firms have invested in a technology
that is decidedly second place in aseptic
capability when done less than perfectly is
most disappointing.
PARADISE FOUND – KEEP IT SIMPLE An oft quoted adage is the KISS principle
or “Keep it simple, stupid.” This is perhaps
the best approach to undertake with any
aseptic processing. The acknowledged
contamination derived from the human
operator. The simplest means to prevent
adventitious contamination from personnel
ical zone. This was understood more than
50 years ago before the advent of HEPA
filters when gloveboxes were used for the
manual filling/assembly of sterile prod-
ucts. These systems operated without air
filtration, automated decontamination and
the separative divide. They were successful
in spite of operational limitations of today
because they removed the major source
of contamination from proximity to sterile
materials and surfaces. They could not be
cleanrooms (something that was yet to be
invented) and yet these gloveboxes were
‘best available technology’ for their time.
In considering isolator designs, our indus-
try must carefully weigh forcing cleanroom
design elements upon them. The very first
aseptic isolators were operationally suc-
cessful and had more in common with the
gloveboxes of 1940 than a contemporary
cleanroom. These early isolators may have
looked primitive and unsophisticated to
today’s industry, but their performance
was nothing less than stellar and led to the
isolators of today. I continually encounter
individuals and firms that cite the ‘isolator
problems’ as justification for use of less
capable systems. The message to these is
to design an isolator system that separates
the operator first, and then weigh the addi-
tion of cleanroom design features with the
understanding that adding features adds
complexity, size, cost and time to the proj-
ect and likely has no impact on isolator
performance. No regulator has mandated
that isolators be designed to cleanroom
In considering isolator designs, our
industry must carefully weigh forcing
cleanroom design elements upon them.
standards, and the more we devoid our-
selves of that misdirection the easier will be
the implementation of what should be the
globally acknowledged superior technology
interpreted as “Honey, I shrunk the
belief that a 106 biological indicator
population is required to demonstrate
sterilization. See USP <1229> Steril-
ization of Compendial Articles for the
correct understanding of biological indi-
cators in sterilization.
Technology”, PDA Journal of Pharma-
ceutical Science and Technology, Vol.
49, No. 5, p. 244-248, 1995.
2. Martin, P., “Isolator Technology for
Aseptic Filling of Anti-Cancer Drugs”,
chapter in Advanced Aseptic Processing,
Technology, ed. By Agalloco, J. & Akers,
J., InformaUSA, New York, 2011.
3. Agalloco, J. & Akers, J., “Overcoming
Limitations of Vaporized Hydrogen Per-
oxide”, Pharmaceutical Technology, Vol.
4. FDA, Guidance for Industry: Sterile Drug
Products Produced by Aseptic Process-
ing, (Rockville, MD, Sept., 2004).
5. PIC/S, “Isolators Used For Aseptic Pro-
cessing And Sterility Testing,” PI 014-2
(Geneva, Switzerland, 2004).
Testing—Validation Of Isolator Systems“
(US Pharmacopeial Convention, Rock-
Isolator Systems for the Manufacturing
and Testing of Health Care Products,”
(Bethesda, MD, 2001).
Gloves for Isolators”, PDA Journal of
Pharmaceutical Science and Technol-
new chemical entities (NCEs) are insuffi-
ciently soluble, resulting in low bioavailability
and decreased efficacy, according to spray
drying services provider, Upperton.1 Spray
drying can be an enabling technology when
it comes to bioavailability and solubility.
As particle characteristics like size and mor-
phology can be controlled accurately, the
resulting solubility and bioavailability char-
acteristics can be influenced in a controlled
manner. For example, in API manufacturing,
spray drying can create stable crystalline
constructs that increase API bioavail-
ability by increasing the solubility of the
active ingredient. Spray drying can be
used for coating and microencapsulation
of a pharma product to not only enhance
bioavailability but also to create controlled-
or delay-release products.
established in industrial manufacturing of
food and chemicals, it took decades to gain
acceptance in the pharmaceutical industry,
says Michael Levis, Ph.D., principal scien-
tist, particle technologies at Siegfried Ltd.
“The availability of spray drying plants for
pharmaceutical use — which are able to
handle flammable solvents on a plant scale
and comply with the cGMP requirements
— were the supposition to transform spray
drying from an exotic academic method to
a widely applied strategy to make insoluble
APIs soluble,” he says.
and chemical industry is mostly performed
Spray Drying Enhances Solubility and Bioavailability Regulatory approval of the first aseptically spray-dried drug validates this newer technology
By Guy Tiene, strategic content director, Nice Insight/That’s Nice LLC
eBOOK: Aseptic Processing Trends 19
uct, the pharmaceutical
industry requires multipur-
used flexibly for different
the technology available
from the financial expendi-
spray drying equipment
phases or even toxicology
studies,” says Levis. Just
Pharmaceutical Equipment
service provider.”
in its amorphous form via
spray drying. “The amor-
phous material is many
crystalline form, thus making
solution to avoid recrys-
tallization during shelf life,
amorphous dispersion within
a customized polymer
loop spray dryer promises
opens the widest choice for
the combination of API and
polymer properties.”
has enhanced the demand
to spray dry amorphous
dispersions with the goal
of overcoming issues with
Outsourcing Survey, 23 per-
CROs for such bioavailabil-
that is gaining more
convert a liquid formulation
for parenteral applications
nal sterilization. The aseptic
into different presentations,
possible to aseptically spray dry products
for up to five days continuously, manufac-
turing large, kilogram quantities of powder.
Efficiencies can be gained using either
traditional or aseptic spray drying
by co-processing APIs with solubility
enhancers or stabilizers, which may not
be possible with lyophilization, says Sam
de Costa, stabilization project manager at
Nova Laboratories. Consider the dissolution
times for monoclonal antibodies (mAbs).
Usually, mAbs can take a long time to dis-
solve, ~ 20 minutes in some instances. de
Costa says this can greatly be improved
by applying spray drying compared to
a lyophilized product (see Figure 1 on p.
20). Nova’s patented aseptic spray drying
technology, Aerospheres, manipulates the
solve the product instantly.
of APIs,” says de Costa. “The difference is
traditional spray drying is carried out under
a low bioburden manufacturing environ-
ment whereas aseptic spray drying is done
under cGMP sterile conditions. This allows
you to manufacture a product to injectable
grade, allowing it to be used as a paren-
teral product.”
no difference between spray drying and
aseptic spray drying,” says Levis. “How-
ever, aseptic spray dryers have to be built
and qualified to comply with regulations
for aseptic manufacturing. For example,
steam sterilization of the equipment is
required and aseptic conditions must be
applied and documented to avoid any
microbiological contamination in the spray
drying process.”
product is atomized into a controlled drop-
let size spray using an atomizer/nozzle.
The droplet starts to dry rapidly within the
drying chamber in contact with drying air.
The resulting powder is collected within a
cyclone separator. For aseptic spray drying,
all of the above steps are carried out in a
Grade-A manufacturing environment. Nova
Laboratories uses gassed-isolator technol-
environment. The CMO has pioneered
aseptic spray drying technology and has
been offering this as a service for the last
eight years using what de Costa says is
the world’s first cGMP, aseptic, apyrogenic
spray drying facility.
at Siegfried, which are used for cGMP man-
ufacturing, are very well suited to keep
the microbiologic burden of a product at
a minimum, says Levis. “Our spray drying
is performed within a closed system, with
only minimum contact to the environ-
ment. The equipment can be effectively
chemically sanitized and both inlet and
outlet nitrogen are HEPA filtered. A polish
filtration is a typical GMP standard; upon
request, the solutions can be sterile fil-
tered to remove any potential bacteria.
In addition, secondary drying to reduce
water activity and residual solvent content,
combined with a reliable cooling chain for
storage and transport, minimize the risk
of microbiological growth on spray dried
material. Any open handling is performed
in a controlled environment with periodic
microbiological controls.”
A MILESTONE IN ASEPTIC SPRAY DRYING Despite the advantages of aseptic spray
drying on improving bioavailability and sol-
ubility, de Costa says the pharmaceutical
community has not readily adopted aseptic
spray drying “because the industry is rather
conservative and reluctant to apply a novel
technology like aseptic spray drying as
opposed to lyophilization, which is the more
established method of drying.”
been a significant shift in this mentality in
recent years evidenced by the success-
ful application of aseptic spray drying to
several products. For instance, Nova Lab-
oratories received approval from the FDA
and EMA’s for Raplixa from ProFibrix BV,
a wholly owned subsidiary of Mallinckrodt
Pharmaceuticals. Raplixa is the world’s
first aseptically spray dried biologic and
is manufactured at Nova Laboratories’
sterile manufacturing facilities. Raplixa is
comprised of spray-dried thrombin and
spray-dried fibrinogen, which are blended
and filled aseptically.3
director of the FDA’s Center for Biologics
Evaluation and Research, described the
breakthrough, explaining “This approval
option to help control bleeding during sur-
gery when needed.” She continued,“The
spray-drying process used to manufacture
Raplixa produces dried powders that can be
Spray drying allows pharmaceutical products
to be manufactured to previously
unattainable molecular characteristics,
combined into a single vial. This eliminates
the need to combine the fibrinogen and
thrombin before use and allows the product
to be stored at room temperature.”3
“Other companies exploring aseptic spray
drying as a manufacturing option will see
the FDA verdict as a regulatory milestone
and a vote of confidence in this enabling
stabilization technology,” says de Costa.
“Acceptance by the regulatory authori-
ties as a viable manufacturing method has
gained attention of Big Pharma.”
Nova continues to support this product
by manufacturing commercial supplies on
behalf of Mallinckrodt Pharmaceuticals. He
says: “This achievement in pharmaceutical
manufacturing has raised a lot of interest in
applying aseptic spray drying technology to
a range of biologics, including monoclonal
antibodies, therapeutic proteins, peptides
MORE STABLE PRODUCTS Spray drying allows pharmaceutical products
to be manufactured to previously unattain-
able molecular characteristics, opening up
opportunities for novel delivery methods.
“The major benefits of spray drying — con-
tinuous processing, particle engineering
— will enable us to create product that is
versatile and stable,” says deCosta. “We
expect continuing interest in the applica-
tion of aseptic spray drying technology,
especially for biologics. To substantiate this
growing demand, Nova is currently expand-
ing its aseptic spray drying and powder
filling capabilities to support projects from
proof-of-concept to commercial-scale
tic spray drying facility.”
REFERENCES 1. Upperton,
Equipment Annual Survey http://www.
bleeding during surgery, April 30, 2015,
Modern aseptic performance demands new flexibility in both mindset and technology
Paradise Lost
Spray Drying Enhances Solubility and Bioavailability
Regulatory approval of the first aseptically spray-dried drug validates this newer technology
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