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Aseptic Processing Trends

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TABLE OF CONTENTSContorting Convention 3

Modern aseptic performance demands new flexibility in

both mindset and technology

Paradise Lost 9

Misdirection in the implementation of isolation technology

Spray Drying Enhances Solubility and Bioavailability 19

Regulatory approval of the first aseptically spray-dried drug

validates this newer technology

AD INDEXCatalent 18

Catalent Advertorial 24

eBOOK: Aseptic Processing Trends 2

www.PharmaManufacturing.com

There’s a quote I once saw framed

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.

However, today’s modern therapies - new,

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.

“If you look at where we are today with

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.

This shift in market demand means that

manufacturers are now able to recognize

previously unattainable value in small-vol-

ume aseptic processing. With this shift not

Contorting ConventionModern aseptic performance demands new flexibility in both mindset and technology

By Karen Langhauser, Chief Content Director



only comes the opportunity, but the need to

refocus on available technologies.

“Traditional methods and approaches to

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 BATCHESSmaller batch sizes mean that manufactur-

ers are looking at facilities very differently,

and re-assessing capex spending.

“The industry is starting to see a lot more

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.

Drug manufacturing of the past required

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

technology, points out Barry Starkman, a

30-year veteran in biopharma facility design

and principal consultant, parenteral manu-

facturing, for DPS Engineering.

Speed to market is also more important

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

Speed to market is more important

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.

“We are talking about an equipment market

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.

Standardization needs aren’t limited to fill-

ing lines. Aseptic component designs also

can benefit from standardization.

“The machine is just a vector for the com-

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.

EMBRACING EMERGING TECHNOLOGYThe U.S. FDA defines emerging technolo-

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.”

Recent emerging technologies in aseptic

processing, such as advanced isolators,

robotics and increased automation, have

indeed changed the industry and markedly

reduced contamination risks for ster-

ile products.

“Equipment manufacturers are definitely

moving in the right direction and end-users

are getting better at defining what they

want, but ultimately there needs to be a lot

more consorting and collaboration between

equipment manufacturers, end-users and

regulators. We are getting there, but there

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,

I believe they are open to considering

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.

In late 2015, CDER’s Office of Pharmaceuti-

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

the FDA and drug companies who want to

introduce modernizing technologies. Par-

ticipating in this program will grant a drug

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.

Encouragingly, the Agency noted last

year that aseptic innovations were one

of the dominating submission types for

participation in the FDA emerging technol-

ogy program.

Vanrx, who has met with the ETT to dis-

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 APPROACHRegulator’s shifting attitude in terms of

emerging technologies can partially be

attributed to the adoption of a risk-based

approach to manufacturing.

Adoption of a true risk-based approach

to process design and process control

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.

Taking a risk-based approach means

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.

“The idea of the risk-based approach has

really driven regulators to look at things

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.

Additionally, a risk-based approach encour-

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.

Adoption of a true risk-based approach

to process design/process control

involves manufacturers defining the

quality attributes of their products.



“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.

Another added bonus that could potentially

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.

If you were to view guidances as a compi-

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 MINDSETSIn addition to next-generation technolo-

gies, next-generation aseptic processing

requires next-generation thinking. It can

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.

In addition, most experts in aseptic process-

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.

“Manufacturers are going to hit this fork in

the road where they either make the pro-

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-

try they were properly viewed

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.

I was bold enough to predict the rapid

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

lower costs would create an operational

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 LostMisdirection in the implementation of isolation technology

By James Agalloco, Agalloco & Associates



carries on/in them a population of microor-

ganisms of greater than 1014 CFU. Second,

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-

cially those locales where exposed sterile

items are handled - have been specifically

designed to address the microbial contami-

nation threat associated with the operators

required presence. The predominant design

elements used to control manned environ-

ments include:

• Unidirectional (laminar) airflow – to

provide a sweeping action and avoid

re-circulation of air over the ster-

ile materials.

• A defined air velocity (90 FPM ± 20%) –

to avoid potential air turbulence that

might disrupt the desired unidirec-

tional flow.

• A large number of air changes – a conse-

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 –

post-batch and periodic sanitization of

the non-product contact surfaces of the

equipment and cleanroom.

The design features and monitoring prac-

tices outlined above are a substantial

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.

However, aseptic isolators were specifically

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-

mance when compared to manned aseptic

environments yet they lacked two primary

design components commonly associated

with those manned environments:

They employed turbulent airflow delivered

through HEPA filter cartridges remote from

the isolator chamber (unidirectional flow is

used in cleanrooms to mitigate the impact

of the personnel).

Air returns were located in the ceiling of

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

advantages of isolators in aseptic pro-

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-

mance far exceeding that of any

manned cleanroom, yet they did

not include any of the accou-

trements of manned aseptic

filling operations!

The promise of isolation tech-

nology was superior aseptic

processing performance at a

fraction of the operating cost of

traditional manned operations.

The simplicity of these early

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 MISSEDRegrettably, 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

notion that an isolator was little more

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

air. The absence of the primary contami-

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

automated means.



isolators demonstrated environmental per-

formance equivalent to that of the more

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.

The consequences of this perceptual error

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.

The isolator HVAC system became both

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.

Adding unidirectional flow required the use

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.

The isolator and its air-handling system

grew to a size that allowed for final

installation only at the operating system

eliminating pre-shipment FAT testing,

and increased overall facility dimensions

and costs.

Required opening of the isolator at the

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.

In parallel with the unidirectional flow

designs cited above, maintenance of 90

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.

One of the main advantages of isolation

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

for the treatment of surfaces and objects

that are not readily accessible. Given the

closed design of most early isolators, and

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

excessive practice. Whether this procedural

addition would provide a measurable (or

necessary) improvement in environmental

control or patient safety was not

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.

In order to accomplish “sterilization,” the

number of biological indicators placed and

the population of each biological indicator

were increased.ii The increase in biologi-

cal indicator population had the greatest

adverse effect due to positive results largely

associated with difficulties in preparation of

biological indicators.3

Due to the increased biological indicator

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.

Increased exposure of items in the enclo-

sure led to extended aeration times

post-exposure due to increased H2O2

adsorption by some materials.

In some instances the operational

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

decontamination cycles.

The greatest failing in decontamination was

the complete rejection of regulatory and

industry recommendations with respect

to the expected process objective. FDA,

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 use of a potent sporicidal compound in

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:

• Increased cost of fabrication for the isola-

tor system to eliminate even the smallest

of leaks.

• Extended times during initial qualification

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.

• Increased downtime between operat-

ing runs spent in leak testing gloves on

the isolator.

That cleanrooms operate successfully with

continual leakage has apparently never

been given adequate consideration. More

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.



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

aseptic processing. By removing the major

source of viable and non-viable contamina-

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

difficulties, while others were

those without actual isolator

experience that were swayed

by the isolator “war stories” that

were frequently heard. RABS

lack a singular description and

installations vary in sophistication

from those that certainly match

isolator performance to less well

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

intended to displace.



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 SIMPLEAn 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

weakness in aseptic processing is the

contamination derived from the human

operator. The simplest means to prevent

adventitious contamination from personnel

is separation of the operator from the crit-

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

means for easy transfer of materials across

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

of isolation.

REFERENCESi. This attitude could be humorously

interpreted as “Honey, I shrunk the

cleanroom.”

ii. There is a widespread and erroneous

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.

1. Agalloco, J., “Opportunities and Obsta-

cles in the Implementation of Barrier

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.

37, No. 9, pp 60-70, 2013.

4. FDA, Guidance for Industry: Sterile Drug

Products Produced by Aseptic Process-

ing, (Rockville, MD, Sept., 2004).

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cessing And Sterility Testing,” PI 014-2

(Geneva, Switzerland, 2004).

6. USP General Chapter <1208>, “Sterility

Testing—Validation Of Isolator Systems“

(US Pharmacopeial Convention, Rock-

ville, MD, 2011).

7. PDA, “TR #34, Design and Validation of

Isolator Systems for the Manufacturing

and Testing of Health Care Products,”

(Bethesda, MD, 2001).

8. Gessler,A., Stärk, A., Sigwarth, V., et

al.. “How Risky Are Pinholes in Gloves?

A Rational Appeal for the Integrity of

Gloves for Isolators”, PDA Journal of

Pharmaceutical Science and Technol-

ogy, Volume 65, No.3, pp 227-241, 2011.



http://www.catalent.com/advasept

It is estimated that at least 40 percent —

and possibly as high as 90 percent — of

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.

Although spray drying has been widely

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.

While industrial spray drying in the food

and chemical industry is mostly performed

Spray Drying Enhances Solubility and BioavailabilityRegulatory approval of the first aseptically spray-dried drug validates this newer technology

By Guy Tiene, strategic content director, Nice Insight/That’s Nice LLC



in huge mono plants

designed for just one prod-

uct, the pharmaceutical

industry requires multipur-

pose equipment that can be

used flexibly for different

APIs. “Contract manufactur-

ers that offer spray drying

in their portfolio have made

the technology available

and accessible to compa-

nies that would shrink back

from the financial expendi-

ture or lead time to install

spray drying equipment

they would need for clinical

phases or even toxicology

studies,” says Levis. Just

one-third of respondents

to the 2016 Nice Insight

Pharmaceutical Equipment

Annual Survey use spray

drying equipment.2 “Using

a contract manufacturer,

API substances with poor

bioavailability can be tested

quickly and relatively cost

effectively with the benefit

of the operational excel-

lence and knowledge of the

service provider.”

According to Levis, the

best strategy for improving

bioavailability of a poorly

soluble API is to isolate it

in its amorphous form via

spray drying. “The amor-

phous material is many

times more soluble than a

crystalline form, thus making

the product bioavailable,”

he explains. “Polymers have

to be added to the spray

solution to avoid recrys-

tallization during shelf life,

downstream processes or

application. Therefore, the

best solution is to make an

amorphous dispersion within

a customized polymer

matrix. Spray drying from

organic solvents in a closed

loop spray dryer promises

the best success rate as it

opens the widest choice for

the combination of API and

polymer properties.”

Combining this with com-

petent CROs that develop

solutions on a lab scale

has enhanced the demand

to spray dry amorphous

dispersions with the goal

of overcoming issues with

bioavailability. According to

the 2016 Nice Insight CRO

Outsourcing Survey, 23 per-

cent of respondents rely on

CROs for such bioavailabil-

ity services.

ASEPTIC VS. TRADITIONAL SPRAY DRYINGOne type of spray drying

that is gaining more

attention for improving

bioavailability is aseptic

spray drying. Aseptic spray

drying uses a hot gas to

convert a liquid formulation

into a dry powder suitable

for parenteral applications

without the need for termi-

nal sterilization. The aseptic

powder can then be filled

into different presentations,

such as vials. Currently, it is



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

surface area of the powder spheres to dis-

solve the product instantly.

“Pharmaceutical spray drying has been well

established within the pharma sector for

many years, especially in the manufacture

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.”

“From a technical point of view, there is

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.”

With spray drying, the pharmaceutical

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-

ogy to achieve the Grade-A manufacturing

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.

Nevertheless, even standard spray dryers

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 DRYINGDespite 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.”

He points out, however, that there has

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

In a press release, Karen Midthun, M.D.,

director of the FDA’s Center for Biologics

Evaluation and Research, described the

breakthrough, explaining “This approval

provides surgeons with an additional

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,

opening up opportunities for

novel delivery methods.



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

and specialty APIs for parenteral use.”

MORE STABLE PRODUCTSSpray 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

ability, flowable powder and gentle drying

— 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

supply within our new state-of-the-art asep-

tic spray drying facility.”

REFERENCES1. Upperton, http://www.upperton.com/

applications.

2. The 2016 Nice Insight Pharmaceutical

Equipment Annual Survey http://www.

niceinsightpharmaequipment.com/buy-

ing-trends.aspx.

3. FDA approves Raplixa to help control

bleeding during surgery, April 30, 2015,

http://www.fda.gov/newsevents/news-

room/pressannouncements/

ucm445247.htm.



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