Aseptic Processing Trends - Pharmaceutical Manufacturing

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TABLE OF CONTENTS Contorting 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

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18

Catalent Advertorial 

24

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Contorting Convention Modern aseptic performance demands new flexibility in both mindset and technology By Karen Langhauser, Chief Content Director

T

here’s a quote I once saw framed

“If you look at where we are today with

in the lobby of a pharmaceutical

the effects of genomics-based tools and

company: “Be stubborn about your

genetics understanding, that’s all having an

goals, and flexible about your methods.”

effect on making much more specific and smaller patient population therapies. And

The pressing need to take advantage of

the effect is that we are not all going to

new technologies and explore new ways of

take a blockbuster - we are going to take

addressing process control and efficiency

a very specific therapy for our condition,

is ubiquitous to all areas of pharmaceuti-

which will most likely be a smaller batch

cal manufacturing.

injectable with a higher price tag,” says Chris Procyshyn, aseptic subject matter

However, today’s modern therapies - new,

expert and CEO at Vanrx, a company at the

targeted approaches to treatment that

cutting-edge of aseptic filling.

are resulting in small-batch aseptic products, proving more difficult to sterilize

This shift in market demand means that

and handle, and requiring faster speeds

manufacturers are now able to recognize

to market - add further emphasis to this

previously unattainable value in small-vol-

industry-wide need.

ume aseptic processing. With this shift not

eBOOK: Aseptic Processing Trends 3

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Speed to market is more important than before, which means facilities of the future need to be operational faster than facilities of the past. only comes the opportunity, but the need to

requirements. This is a different scenario

refocus on available technologies.

for drug manufacturing - one that is really demanding a rethink on how facilities

“Traditional methods and approaches to

are put together and where priorities are

aseptic design and process control that

placed,” says Procyshyn.

were geared toward mass production may not be optimal, or in some case even fea-

Drug manufacturing of the past required

sible, with some of the new therapies we

heavy investments in large manufacturing

are seeing,” says Hal Baseman, chief oper-

facilities and equipment, but this may not

ations officer, ValSource. “Rather than take

be the case with modern aseptic process-

needs of these new therapies and try to fit

ing. Some biologics manufacturers are even

them into the ideas and approaches that

using their clinical manufacturing facilities

have worked for large-scale manufacturing,

to launch, enabling them to determine how

maybe we should be looking at this a differ-

well the product performs before making

ent way, instead asking what are the new

bigger investments into manufacturing

approaches that we should be considering

technology, points out Barry Starkman, a

that would better fit these new therapies.”

30-year veteran in biopharma facility design and principal consultant, parenteral manu-

THE DEMANDS OF SMALLER BATCHES

facturing, for DPS Engineering.

Smaller batch sizes mean that manufactur-

Speed to market is also more important

ers are looking at facilities very differently,

than ever before, which means facilities

and re-assessing capex spending.

of the future need to be operational a lot faster than facilities of the past. Equipment

“The industry is starting to see a lot more

standardization is a great enabler when

products being manufactured in each

it comes to bringing products to market

facility, and a lot more specific process

quickly. Conventional, custom-built fill-finish eBOOK: Aseptic Processing Trends 4

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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.

lines are expensive and time-consuming to

too many different component designs it

build and offer limited flexibility. Equipment

becomes difficult to design machines that

leaders, such as Vanrx, are recognizing this

can be everything to everybody. If the goal

new challenge.

is maximizing flexibility while minimizing costs, the implementation of standardized,

“We are talking about an equipment market

ready-to-use components allows for more

where ‘custom’ used to be the rule. But

flexible facilities, capable of handling a

today’s drug manufacturers don’t have time

wide variety of products in a single facility,”

to be the guinea pigs for what’s never been

says Starkman.

tested before. Customers are looking for build very consistent, standardized offer-

EMBRACING EMERGING TECHNOLOGY

ings, and consequently we can develop

The U.S. FDA defines emerging technolo-

and refine and test at a very deep level,”

gies as, “Technology with the potential to

says Procyshyn.

modernize the body of knowledge associ-

something that is predictable. At Vanrx, we

ated with pharmaceutical development to Standardization needs aren’t limited to fill-

support more robust, predictable, and/or

ing lines. Aseptic component designs also

cost-effective processes or novel products

can benefit from standardization.

and with which the FDA has limited review or inspection experiences, due to its rela-

“The machine is just a vector for the com-

tive novelty.”

ponents to flow through. Standardizing component offerings would be an important

The industry’s migration away from

move forward for the industry. If you get

standard cleanroom filling in favor of eBOOK: Aseptic Processing Trends 5

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isolators (close to 30 years ago) brought

“We are in a really interesting time. Global

with it dramatically improved product

health authorities are recognizing that these

safety and environmental compliance. This,

new therapies don’t quite fit large-scale

according to Starkman, helped open the

manufacturing methods, and consequently,

industry’s eyes to the incredible benefits

I believe they are open to considering

of emerging technologies. “There was an

changes,” says Baseman. Baseman is also

increase in willingness to look at the data

the committee co-chair of PDA’s Manufac-

and make changes accordingly,” notes

turing Science and Operations Program,

Starkman. “And I’m hoping this continues,

which, among numerous goals, seeks to

because acceptance of new technologies

identify and encourage use of new manu-

is the only way the industry is going to

facturing technology and methods.

move forward.” In late 2015, CDER’s Office of PharmaceutiRecent emerging technologies in aseptic

cal Quality (OPQ) established its Emerging

processing, such as advanced isolators,

Technology Team (ETT) to serve as a pri-

robotics and increased automation, have

mary point of contact for companies that are

indeed changed the industry and markedly

interested in implementing emerging manu-

reduced contamination risks for ster-

facturing technology in the manufacture of

ile products.

their drug products. The group is focused on establishing open communication between

“Equipment manufacturers are definitely

the FDA and drug companies who want to

moving in the right direction and end-users

introduce modernizing technologies. Par-

are getting better at defining what they

ticipating in this program will grant a drug

want, but ultimately there needs to be a lot

company a face-to-face meeting with the

more consorting and collaboration between

FDA as well as an onsite meeting at the par-

equipment manufacturers, end-users and

ticipant’s plant in order to show the Agency

regulators. We are getting there, but there

the technology in action.

is still a ways to go,” says Starkman. Encouragingly, the Agency noted last An often-used reason for the drug indus-

year that aseptic innovations were one

try’s reticence when it comes to the use

of the dominating submission types for

of new, emerging technologies in the drug

participation in the FDA emerging technol-

manufacturing process is regulatory hur-

ogy program.

dles. And yet, most experts agree that regulatory agencies are no longer impeding

Vanrx, who has met with the ETT to dis-

progress when it comes to technology.

cuss the company’s gloveless isolator eBOOK: Aseptic Processing Trends 6

www.PharmaManufacturing.com

Adoption of a true risk-based approach to process design/process control involves manufacturers defining the quality attributes of their products. technology, reports that the team is very

step along the way and determine the risk

positive and ready to work with industry.

of failure.

“Ultimately, regulators have the obligation

Taking a risk-based approach means

to make sure there is a supply of safe and

pharma can better articulate its processes

effective medication. They are pushing for

to regulators. Having good data and ana-

technology advancements. Keep in mind

lyzing that data means manufacturers can

that they see everyone’s filing and every-

better understand - and articulate - the

one’s plant, so they know what best-in-class

risk of failure.

looks like. Consequently, they push for advances once they see what’s possible,”

“The idea of the risk-based approach has

notes Procyshyn.

really driven regulators to look at things differently. With manufacturers now able

RISE OF RISK-BASED APPROACH

to demonstrate that they understand the

Regulator’s shifting attitude in terms of

critical quality attributes of their products

emerging technologies can partially be

and what drives them in terms of critical

attributed to the adoption of a risk-based

process parameters, it is much easier for

approach to manufacturing.

regulators to say with confidence that manufacturers truly understand their process,”

Adoption of a true risk-based approach

says Starkman.

to process design and process control involves drug manufacturers defining the

Additionally, a risk-based approach encour-

quality attributes of their products, and

ages a more proactive view of emerging

how to best assure those quality attri-

technologies, enabling drug manufacturers

butes are established and maintained.

to take a hard look at the needs of a partic-

As a result of this reverse engineering

ular process and design technologies that

approach, manufacturers can look at each

meet those specific needs. eBOOK: Aseptic Processing Trends 7

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“Adoption of a true risk-based approach

be said that the pharmaceutical industry is

means manufacturers can ask them-

dominated by a generation of people who

selves what equipment they really need

don’t necessarily have a lot of experience

to establish process control and then

managing industry-wide change. “There is

design technologies around that need - as

a very different level of technical under-

opposed to designing a process around

standing necessary for managing change,”

technologies that happen to be available,”

notes Procyshyn.

notes Baseman. “If you step backward, one of the challenges Another added bonus that could potentially

with our industry is that it’s a lot slower and

come of a more risk-based approach is the

more glacial than people might think - but

introduction of new industry guidance in

even if you look at glaciers these days, they

the area of aseptic processing.

change, too. It may be a slow wave that goes through industry, but every sign is

“The guidances we have are geared toward

there that major changes are well under-

larger scale aseptic production. There

way,” continues Procyshyn.

needs to be some work put into changing guidances or adding new guidances

In addition, most experts in aseptic process-

and approaches. It’s important to consider

ing gained the bulk of their experience in

that maybe the tried and true, traditional

large-scale processing, and are now being

approaches aren’t fitting as well with the

challenged to apply that knowledge to

manufacturing needs of new therapies,”

aseptic processing on a much smaller scale,

says Baseman.

notes Baseman.

If you were to view guidances as a compi-

“Manufacturers are going to hit this fork in

lation of best practices in the industry, it

the road where they either make the pro-

would follow that if the industry’s approach

cess fit what they know from large-scale

to best-practice in aseptic processing was

manufacturing, or they take a fresh look.

to shift, new guidance highlighting these

They can take the easier way, or they can

changes should follow.

take a way that will have more long-term benefits. Taking an honest, risk-based think-

THE NEED FOR CHANGING MINDSETS

ing approach will create a process that can

In addition to next-generation technolo-

that is unquestioned by regulators and will

gies, next-generation aseptic processing

allow new levels of production efficiencies,”

requires next-generation thinking. It can

concludes Baseman.

give the industry high levels of assurance

eBOOK: Aseptic Processing Trends 8

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Paradise Lost Misdirection in the implementation of isolation technology By James Agalloco, Agalloco & Associates

W

hen isolators were introduced

contamination compounded with expected

into the pharmaceutical indus-

lower costs would create an operational

try they were properly viewed

paradise. A number of unanticipated

with some degree of skepticism. The early

changes to isolator designs occurred on

designs were relatively crude in appearance

the way to that rosy future that has dra-

and certainly lacked sophistication. With a

matically lessened the expected impact.

few years of technology development and

This article will review the ways in which

successful operational experience it seemed

the vision of the future envisioned in 1995

that the isolator would change the way in

has been diminished and outline changes to

which sterile products were made across

current practices in isolator and barrier that

the world.

would enable the industry to fully realize the potential in isolation technology.

I was bold enough to predict the rapid demise of manned cleanrooms as the highly

The essential difference between isolators

capable isolator proved its superiority both

and manned aseptic processing area is the

operationally and

financially.1

The isolator

absence of personnel from the operating

was expected to be the paradigm changer

environment. The operator is universally

that the pharmaceutical industry needed

recognized to be the largest contributor

to attain the next level of performance and

to microbial contamination in conventional

product safety. The virtual elimination of

aseptic processing. First, the operator eBOOK: Aseptic Processing Trends 9

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carries on/in them a population of microor-

The design features and monitoring prac-

ganisms of greater than 1014 CFU. Second,

tices outlined above are a substantial

these microorganisms must be somehow

part of the expected norms when using

contained within their gowning materials.

manned aseptic processing. These design

Third, microorganisms from the operator

components are all intended to reduce the

are continuously dispersed into the environ-

adverse impact of microbes and particles

ment because their gowning materials and

derived from the operating personnel who

methods are not absolute.

are the acknowledged primary contamination source.

Manned aseptic environments - especially those locales where exposed sterile

However, aseptic isolators were specifically

items are handled - have been specifically

designed to exclude personnel from the

designed to address the microbial contami-

environment in which sterile materials are

nation threat associated with the operators

exposed, and it is appropriate to question

required presence. The predominant design

whether measures intended for use with

elements used to control manned environ-

aseptically gowned personnel are neces-

ments include:

sary in an environment in which they are

• Unidirectional (laminar) airflow – to

not present. The first isolators used in this

provide a sweeping action and avoid

industry demonstrated superior perfor-

re-circulation of air over the ster-

mance when compared to manned aseptic

ile materials.

environments yet they lacked two primary

• A defined air velocity (90 FPM ± 20%) – to avoid potential air turbulence that

design components commonly associated with those manned environments:

might disrupt the desired unidirectional flow. • A large number of air changes – a consequence of the expected air velocity. • Monitoring of pressure differentials – to assure that the air flows in the direction

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).

away from the critical environments where sterile materials are handled.

Air returns were located in the ceiling of

• Decontamination of the environment –

the isolator chambers (floor level returns

post-batch and periodic sanitization of

are used in cleanrooms to prevent re-en-

the non-product contact surfaces of the

trainment of potential contaminants at

equipment and cleanroom.

work height).

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The absence of these and other cleanroom

generation isolators. The wrong-headed

design features in these early isolators

notion that an isolator was little more

had no adverse effect on their operational

than a small cleanroom requiring all of the

performance.2

accoutrements of cleanroom design.i Uni-

The expected operational

advantages of isolators in aseptic pro-

directional (also called laminar flow) air is a

cessing projected at that time were not

requirement in manned cleanrooms of ISO

contingent on any refinement of the basic

5 and better classification that serves to

designs. The first isolator-based aseptic fill

reduce the dispersion of personnel derived

lines installed evidenced performance far exceeding that of any manned cleanroom, yet they did not include any of the accoutrements of manned aseptic filling operations!

One of the main advantages of isolation technology is the ability to decontaminate

The promise of isolation technology was superior aseptic processing performance at a fraction of the operating cost of

the interior surfaces by automated means.

traditional manned operations. The simplicity of these early isolator systems also suggested easy fabri-

contamination into critical locales by mini-

cation, short lead times, lower facility costs

mizing the formation of eddies and moving

and a comparatively easy qualification/val-

contaminated air to low wall returns. Unidi-

idation. The future for isolation technology

rectional flow patterns are rarely absolute

appeared to be near limitless.

even in the best cleanrooms. Horizontal surfaces of process equipment and the

PARADISE LOST – COMPLICATIONS ENSUED AND OPPORTUNITY MISSED

presence of gowned personnel preclude

Regrettably, the expected “paradise” of iso-

nation source, the human operator, when

lators for aseptic processing was never fully

using isolation technology largely mitigates

realized. Despite evidence that compara-

the contamination risk without the need

tively simple isolator designs were capable

for a specific air direction. Sterility test

of outstanding performance aspects of

isolators (which only rarely employ unidi-

cleanroom design began to appear in 2nd

rectional air flow) and the 1st generation

anything truly resembling unidirectional air. The absence of the primary contami-

eBOOK: Aseptic Processing Trends 11

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isolators demonstrated environmental per-

difficult to clean locations without opening

formance equivalent to that of the more

of the isolator.

complex isolator designs that include unidirectional flow. Particle generation from

The isolator and its air-handling system

equipment operation and component han-

grew to a size that allowed for final

dling with modern filling and stoppering

installation only at the operating system

equipment is a lesser concern and can be

eliminating pre-shipment FAT testing,

readily controlled by means other than air-

and increased overall facility dimensions

flow direction.

and costs.

The consequences of this perceptual error

Required opening of the isolator at the

are myriad as it had a negative ripple effect

completion of the batch for cleaning /

on the design of isolator systems: the seem-

changeover as portions of the isolator

ingly simple introduction of unidirectional

internals were no longer easily accessi-

airflow into isolation technology required

ble. This resulted in increased changeover

substantial physical changes with unfortu-

and cleaning periods and restricted cam-

nate adverse consequences.

paign operations.

The isolator HVAC system became both

In parallel with the unidirectional flow

larger and more complex to move addi-

designs cited above, maintenance of 90

tional air - increasing both initial and

FPM (0.45 m/s) ±20% air flow velocity at

routine operational costs; with fabrication,

the HEPA filter face was often instituted.

qualification and validation efforts becom-

The exactness of the expectation belies

ing more extensive as well.

its arbitrary nature, obscure origin and unknown utility as an environmental control

Limited access for cleaning because of

measure. Unidirectional flow is possible at

the larger size of the overall system made

velocities above and below this range. The

extended operation more difficult and

consequences of it and its lack of utility of

increased changeover times between prod-

in isolators are the identical to those for uni-

ucts by extending both decontamination

directional air.

and aeration cycle times. One of the main advantages of isolation Adding unidirectional flow required the use

technology is the ability to decontaminate

of return air ducts at or near the floor of

the interior surfaces by automated

the room to avoid turbulence at the level

means. This practice replaces the manual

of exposed sterile materials. These are

disinfection procedures that are prevalent eBOOK: Aseptic Processing Trends 12

www.PharmaManufacturing.com

As the primary purpose of most isolators is separative aseptic operation, their designs were often sub-optimal for decontamination, resulting in lengthy decontamination cycles. in manned cleanrooms and is more

In order to accomplish “sterilization,” the

effective as it virtually eliminates human

number of biological indicators placed and

error or oversight in execution. Automated

the population of each biological indicator

systems for decontamination provides

were increased.ii The increase in biologi-

for the treatment of surfaces and objects

cal indicator population had the greatest

that are not readily accessible. Given the

adverse effect due to positive results largely

closed design of most early isolators, and

associated with difficulties in preparation of

the availability of an automated capability,

biological indicators.3

some early practitioners endeavored to ‘sterilize’ rather than decontaminate them.

Due to the increased biological indicator

That such a measure was never possible,

population, there was a commensurate

nor, necessary in manned cleanrooms for

increase in the duration of the decontami-

successful usage was not considered. The

nation dwell time to destroy them.

closed design of isolators and the availability of a reliable means for antimicrobial

Increases in the exposure period meant that

treatment perhaps encouraged this

items exposed to the process would have

excessive practice. Whether this procedural

greater exposure to the principal decon-

addition would provide a measurable (or

taminating agent - H2O2.

necessary) improvement in environmental control or patient safety was not

Increased exposure of items in the enclo-

considered. More treatment was believed

sure led to extended aeration times

to be better than less. This unnecessary

post-exposure due to increased H2O2

raising of the performance bar appears

adsorption by some materials.

benign, but triggered added complications in both validation process execution and

In some instances the operational

routine operation.

life of polymeric materials used in eBOOK: Aseptic Processing Trends 13

www.PharmaManufacturing.com

isolator construction was shortened due to

leak testing was perhaps best addressed

repeated extended exposure to H2O2.

by Staerk and Sigwarth, who evaluated a variety of leak test methods on isolator

As the primary purpose of most iso-

gloves and showed that the level of detec-

lators is separative aseptic operation,

tion for all was orders of magnitude larger

their designs were often sub-optimal for

than the typical microorganism.8 Never-

decontamination, resulting in lengthy

theless frequent glove leak testing is a de

decontamination cycles.

facto requirement for present day fill isolators. The following adverse consequences

The greatest failing in decontamination was

have resulted from this largely unneces-

the complete rejection of regulatory and

sary precaution:

industry recommendations with respect

• Increased cost of fabrication for the isola-

to the expected process objective. FDA,

tor system to eliminate even the smallest

PIC/S, USP, PDA and others had all issued

of leaks.

guidance documents that recommended a

• Extended times during initial qualification

lesser treatment using a lower population

and routine operation to check for leaks,

on the biological indicators.4,5,6,7

and remediate them where possible. • Increased cost for the purchase, cali-

The use of a potent sporicidal compound in

bration and maintenance of glove leak

the decontamination of isolators and their

testing equipment.

closed configuration during the process

• Increased downtime between operat-

led to concerns relative to the integrity of

ing runs spent in leak testing gloves on

the system. The intent of leak testing is to

the isolator.

confirm minimal operator exposure to H2O2 during the decontamination process. Here

That cleanrooms operate successfully with

too, a seemingly useful consideration has

continual leakage has apparently never

been elevated to extremes. Initially a qual-

been given adequate consideration. More

itative test, leak testing quickly became a

importantly, the need for adherence to

quantitative metric that was both increas-

proper aseptic technique inside an isolator

ingly complex and overly rigorous. While

should always be respected. This measure is

it is readily acknowledged that aseptic

sufficient to maintain asepsis in cleanrooms

cleanrooms continuously leak air to their

where operator routinely shed significantly

surroundings, and aseptically gowned per-

more microorganisms than could ever be

sonnel are ‘the’ source of contamination,

present in an isolator, and their glove/

the idea that an isolator system should leak

gown integrity has never been consid-

at all became problematic. The futility of

ered absolute. eBOOK: Aseptic Processing Trends 14

www.PharmaManufacturing.com

PARADISE DELAYED – HAVING YOUR CAKE AND EATING IT TOO!

technology was touted as an acceptable

In the early 1980s, the author encountered

tems (RABS) were introduced as the best

isolators and became a strong proponent of

of both worlds. They would deliver isola-

the technology. I believed that the physical

tor like performance with the simplicity

separation of personnel from the critical

of a cleanroom. RABS are actually highly

aseptic environment would revolutionize

evolved cleanroom designs that rely on

aseptic processing. By removing the major

some isolator like design elements, but

source of viable and non-viable contamina-

eliminates those believed to be particularly

tion from proximity to sterile materials an

challenging such as unidirectional air, auto-

unmatched level of performance would be

mated decontamination, and leak testing.

realized. When isolators were still a novelty

RABS advocates were often employed at

substitute. Restricted Access Barrier Sys-

firms that had experienced isolator technology implementation

Many RABS designs are

difficulties, while others were

only marginally better than

experience that were swayed

the cleanrooms they were

were frequently heard. RABS

intended to displace.

those without actual isolator by the isolator “war stories” that lack a singular description and installations vary in sophistication from those that certainly match isolator performance to less well

there were a myriad of design options, and

evolved designs that are little more than

isolator systems were implemented without

gloves installed on a partial barrier.

major difficulty. As the cleanroom relevant concerns were added to isolator designs

As a full-time consultant, I have visited

implementation began to slow. I heard

many different aseptic filling installations.

statements such as, “It’s taken XYZ more

To those that have implemented RABS in

than 3 years to validate their filling isolator.

the best possible manner I must acknowl-

What makes you think we can do it at all?”

edge their proficiency. To those that operate less capable RABS systems I must

The over-specification of isolator system

question the technology decision. With-

designs caused by the unnecessary impo-

out extreme diligence in system design,

sition of clean room concepts resulted

RABS can be disappointing in reality. I

in a surprising outcome. A less capable

have observed many RABS designs that eBOOK: Aseptic Processing Trends 15

www.PharmaManufacturing.com

In considering isolator designs, our industry must carefully weigh forcing cleanroom design elements upon them. are only marginally better than the clean-

of contamination from proximity to sterile

rooms they were intended to displace. That

materials and surfaces. They could not be

these firms have invested in a technology

cleanrooms (something that was yet to be

that is decidedly second place in aseptic

invented) and yet these gloveboxes were

capability when done less than perfectly is

‘best available technology’ for their time.

most disappointing. In considering isolator designs, our indus-

PARADISE FOUND – KEEP IT SIMPLE

try must carefully weigh forcing cleanroom

An oft quoted adage is the KISS principle

aseptic isolators were operationally suc-

or “Keep it simple, stupid.” This is perhaps

cessful and had more in common with the

the best approach to undertake with any

gloveboxes of 1940 than a contemporary

aseptic processing. The acknowledged

cleanroom. These early isolators may have

weakness in aseptic processing is the

looked primitive and unsophisticated to

contamination derived from the human

today’s industry, but their performance

operator. The simplest means to prevent

was nothing less than stellar and led to the

adventitious contamination from personnel

isolators of today. I continually encounter

is separation of the operator from the crit-

individuals and firms that cite the ‘isolator

ical zone. This was understood more than

problems’ as justification for use of less

50 years ago before the advent of HEPA

capable systems. The message to these is

filters when gloveboxes were used for the

to design an isolator system that separates

manual filling/assembly of sterile prod-

the operator first, and then weigh the addi-

ucts. These systems operated without air

tion of cleanroom design features with the

filtration, automated decontamination and

understanding that adding features adds

means for easy transfer of materials across

complexity, size, cost and time to the proj-

the separative divide. They were successful

ect and likely has no impact on isolator

in spite of operational limitations of today

performance. No regulator has mandated

because they removed the major source

that isolators be designed to cleanroom

design elements upon them. The very first

eBOOK: Aseptic Processing Trends 16

www.PharmaManufacturing.com

standards, and the more we devoid our-

Technology, ed. By Agalloco, J. & Akers,

selves of that misdirection the easier will be

J., InformaUSA, New York, 2011.

the implementation of what should be the

3. Agalloco, J. & Akers, J., “Overcoming

globally acknowledged superior technology

Limitations of Vaporized Hydrogen Per-

of isolation.

oxide”, Pharmaceutical Technology, Vol. 37, No. 9, pp 60-70, 2013.

REFERENCES i. 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

4. FDA, Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing, (Rockville, MD, Sept., 2004). 5. PIC/S, “Isolators Used For Aseptic Processing And Sterility Testing,” PI 014-2 (Geneva, Switzerland, 2004). 6. USP General Chapter , “Sterility

sterilization. See USP Steril-

Testing—Validation Of Isolator Systems“

ization of Compendial Articles for the

(US Pharmacopeial Convention, Rock-

correct understanding of biological indi-

ville, MD, 2011).

cators in sterilization.

7. PDA, “TR #34, Design and Validation of Isolator Systems for the Manufacturing

1. Agalloco, J., “Opportunities and Obstacles in the Implementation of Barrier Technology”, PDA Journal of Pharma-

and Testing of Health Care Products,” (Bethesda, MD, 2001). 8. Gessler,A., Stärk, A., Sigwarth, V., et

ceutical Science and Technology, Vol.

al.. “How Risky Are Pinholes in Gloves?

49, No. 5, p. 244-248, 1995.

A Rational Appeal for the Integrity of

2. Martin, P., “Isolator Technology for

Gloves for Isolators”, PDA Journal of

Aseptic Filling of Anti-Cancer Drugs”,

Pharmaceutical Science and Technol-

chapter in Advanced Aseptic Processing,

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

eBOOK: Aseptic Processing Trends 17

sterile technologies

˝ 2017 Catalent Pharma Solutions. All rights reserved.

advasept® technology

glass-free injectable delivery. automated aseptic. reliably supplied. Our next generation glass-free injectable platform, with advanced aseptic filling technology, has the potential to reduce foreign particulates by more than 95%, increase sterility assurance through automation, and improve supply reliability. Catalent. More products. Better treatments. Reliably supplied.™ us + 1 888 SOLUTION (765-8846) eu + 800 8855 6178 catalent.com/advasept

www.PharmaManufacturing.com

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

I

t is estimated that at least 40 percent —

bioavailability but also to create controlled-

and possibly as high as 90 percent — of

or delay-release products.

new chemical entities (NCEs) are insuffi-

ciently soluble, resulting in low bioavailability

Although spray drying has been widely

and decreased efficacy, according to spray

established in industrial manufacturing of

drying services provider,

Upperton.1

Spray

food and chemicals, it took decades to gain

drying can be an enabling technology when

acceptance in the pharmaceutical industry,

it comes to bioavailability and solubility.

says Michael Levis, Ph.D., principal scientist, particle technologies at Siegfried Ltd.

As particle characteristics like size and mor-

“The availability of spray drying plants for

phology can be controlled accurately, the

pharmaceutical use — which are able to

resulting solubility and bioavailability char-

handle flammable solvents on a plant scale

acteristics can be influenced in a controlled

and comply with the cGMP requirements

manner. For example, in API manufacturing,

— were the supposition to transform spray

spray drying can create stable crystalline

drying from an exotic academic method to

constructs that increase API bioavail-

a widely applied strategy to make insoluble

ability by increasing the solubility of the

APIs soluble,” he says.

active ingredient. Spray drying can be used for coating and microencapsulation

While industrial spray drying in the food

of a pharma product to not only enhance

and chemical industry is mostly performed eBOOK: Aseptic Processing Trends 19

www.PharmaManufacturing.com

in huge mono plants designed for just one product, the pharmaceutical industry requires multipurpose equipment that can be used flexibly for different APIs. “Contract manufacturers that offer spray drying in their portfolio have made the technology available

in its amorphous form via

to spray dry amorphous

and accessible to compa-

spray drying. “The amor-

dispersions with the goal

nies that would shrink back

phous material is many

of overcoming issues with

from the financial expendi-

times more soluble than a

bioavailability. According to

ture or lead time to install

crystalline form, thus making

the 2016 Nice Insight CRO

spray drying equipment

the product bioavailable,”

Outsourcing Survey, 23 per-

they would need for clinical

he explains. “Polymers have

cent of respondents rely on

phases or even toxicology

to be added to the spray

CROs for such bioavailabil-

studies,” says Levis. Just

solution to avoid recrys-

ity services.

one-third of respondents

tallization during shelf life,

to the 2016 Nice Insight

downstream processes or

Pharmaceutical Equipment

application. Therefore, the

Annual Survey use spray

best solution is to make an

ASEPTIC VS. TRADITIONAL SPRAY DRYING

drying equipment.2 “Using

amorphous dispersion within

One type of spray drying

a contract manufacturer,

a customized polymer

that is gaining more

API substances with poor

matrix. Spray drying from

attention for improving

bioavailability can be tested

organic solvents in a closed

bioavailability is aseptic

quickly and relatively cost

loop spray dryer promises

spray drying. Aseptic spray

effectively with the benefit

the best success rate as it

drying uses a hot gas to

of the operational excel-

opens the widest choice for

convert a liquid formulation

lence and knowledge of the

the combination of API and

into a dry powder suitable

service provider.”

polymer properties.”

for parenteral applications without the need for termi-

According to Levis, the

Combining this with com-

nal sterilization. The aseptic

best strategy for improving

petent CROs that develop

powder can then be filled

bioavailability of a poorly

solutions on a lab scale

into different presentations,

soluble API is to isolate it

has enhanced the demand

such as vials. Currently, it is

eBOOK: Aseptic Processing Trends 20

www.PharmaManufacturing.com

possible to aseptically spray dry products

aseptic spray drying,” says Levis. “How-

for up to five days continuously, manufac-

ever, aseptic spray dryers have to be built

turing large, kilogram quantities of powder.

and qualified to comply with regulations for aseptic manufacturing. For example,

Efficiencies can be gained using either

steam sterilization of the equipment is

traditional or aseptic spray drying

required and aseptic conditions must be

by co-processing APIs with solubility

applied and documented to avoid any

enhancers or stabilizers, which may not

microbiological contamination in the spray

be possible with lyophilization, says Sam

drying process.”

de Costa, stabilization project manager at Nova Laboratories. Consider the dissolution

With spray drying, the pharmaceutical

times for monoclonal antibodies (mAbs).

product is atomized into a controlled drop-

Usually, mAbs can take a long time to dis-

let size spray using an atomizer/nozzle.

solve, ~ 20 minutes in some instances. de

The droplet starts to dry rapidly within the

Costa says this can greatly be improved

drying chamber in contact with drying air.

by applying spray drying compared to

The resulting powder is collected within a

a lyophilized product (see Figure 1 on p.

cyclone separator. For aseptic spray drying,

20). Nova’s patented aseptic spray drying

all of the above steps are carried out in a

technology, Aerospheres, manipulates the

Grade-A manufacturing environment. Nova

surface area of the powder spheres to dis-

Laboratories uses gassed-isolator technol-

solve the product instantly.

ogy to achieve the Grade-A manufacturing environment. The CMO has pioneered

“Pharmaceutical spray drying has been well

aseptic spray drying technology and has

established within the pharma sector for

been offering this as a service for the last

many years, especially in the manufacture

eight years using what de Costa says is

of APIs,” says de Costa. “The difference is

the world’s first cGMP, aseptic, apyrogenic

traditional spray drying is carried out under

spray drying facility.

a low bioburden manufacturing environment whereas aseptic spray drying is done

Nevertheless, even standard spray dryers

under cGMP sterile conditions. This allows

at Siegfried, which are used for cGMP man-

you to manufacture a product to injectable

ufacturing, are very well suited to keep

grade, allowing it to be used as a paren-

the microbiologic burden of a product at

teral product.”

a minimum, says Levis. “Our spray drying is performed within a closed system, with

“From a technical point of view, there is

only minimum contact to the environ-

no difference between spray drying and

ment. The equipment can be effectively eBOOK: Aseptic Processing Trends 21

www.PharmaManufacturing.com

chemically sanitized and both inlet and

He points out, however, that there has

outlet nitrogen are HEPA filtered. A polish

been a significant shift in this mentality in

filtration is a typical GMP standard; upon

recent years evidenced by the success-

request, the solutions can be sterile fil-

ful application of aseptic spray drying to

tered to remove any potential bacteria.

several products. For instance, Nova Lab-

In addition, secondary drying to reduce

oratories received approval from the FDA

water activity and residual solvent content,

and EMA’s for Raplixa from ProFibrix BV,

combined with a reliable cooling chain for

a wholly owned subsidiary of Mallinckrodt

storage and transport, minimize the risk

Pharmaceuticals. Raplixa is the world’s

of microbiological growth on spray dried

first aseptically spray dried biologic and

material. Any open handling is performed

is manufactured at Nova Laboratories’

in a controlled environment with periodic

sterile manufacturing facilities. Raplixa is

microbiological controls.”

comprised of spray-dried thrombin and spray-dried fibrinogen, which are blended

A MILESTONE IN ASEPTIC SPRAY DRYING

and filled aseptically.3

Despite the advantages of aseptic spray

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

drying on improving bioavailability and sol-

director of the FDA’s Center for Biologics

ubility, de Costa says the pharmaceutical

Evaluation and Research, described the

community has not readily adopted aseptic

breakthrough, explaining “This approval

spray drying “because the industry is rather

provides surgeons with an additional

conservative and reluctant to apply a novel

option to help control bleeding during sur-

technology like aseptic spray drying as

gery when needed.” She continued,“The

opposed to lyophilization, which is the more

spray-drying process used to manufacture

established method of drying.”

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. eBOOK: Aseptic Processing Trends 22

www.PharmaManufacturing.com

combined into a single vial. This eliminates

opportunities for novel delivery methods.

the need to combine the fibrinogen and

“The major benefits of spray drying — con-

thrombin before use and allows the product

tinuous processing, particle engineering

to be stored at room

temperature.”3

ability, flowable powder and gentle drying — will enable us to create product that is

“Other companies exploring aseptic spray

versatile and stable,” says deCosta. “We

drying as a manufacturing option will see

expect continuing interest in the applica-

the FDA verdict as a regulatory milestone

tion of aseptic spray drying technology,

and a vote of confidence in this enabling

especially for biologics. To substantiate this

stabilization technology,” says de Costa.

growing demand, Nova is currently expand-

“Acceptance by the regulatory authori-

ing its aseptic spray drying and powder

ties as a viable manufacturing method has

filling capabilities to support projects from

gained attention of Big Pharma.”

proof-of-concept to commercial-scale supply within our new state-of-the-art asep-

Nova continues to support this product

tic spray drying facility.”

by manufacturing commercial supplies on behalf of Mallinckrodt Pharmaceuticals. He

REFERENCES

says: “This achievement in pharmaceutical

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

manufacturing has raised a lot of interest in applying aseptic spray drying technology to

applications. 2. The 2016 Nice Insight Pharmaceutical

a range of biologics, including monoclonal

Equipment Annual Survey http://www.

antibodies, therapeutic proteins, peptides

niceinsightpharmaequipment.com/buy-

and specialty APIs for parenteral use.”

ing-trends.aspx. 3. FDA approves Raplixa to help control

MORE STABLE PRODUCTS

bleeding during surgery, April 30, 2015,

Spray drying allows pharmaceutical products

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

to be manufactured to previously unattain-

room/pressannouncements/

able molecular characteristics, opening up

ucm445247.htm.

eBOOK: Aseptic Processing Trends 23

catalent to provide fill & finish services for commercial supply of samsung bioepis’ biosimilar therapy Catalent Pharma Solutions, the leading global provider of advanced

firm commitment to quality, Samsung Bioepis aims to become

delivery technologies and development solutions for drugs,

the world’s leading biopharmaceutical company. Samsung Bioepis

biologics and consumer health products, announced recently that

continues to advance a broad pipeline of 13 biosimilar candidates

it will provide fill-finish production services for the commercial

that include six first-wave candidates that cover the therapeutic

supply of SB4, a biosimilar referencing Enbrel®1 (etanercept), on

areas of immunology, oncology and diabetes. Samsung Bioepis

behalf of the Korea-based biopharmaceutical company Samsung

is a joint venture between Samsung BioLogics and Biogen. For

Bioepis Co., Ltd. The services will be provided at Catalent’s

more information, please visit: www.samsungbioepis.com

flagship sterile pre-filled syringe facility in Brussels, Belgium. Used in the treatment of adults with moderate to severe rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis and plaque psoriasis, SB4 is the first etanercept biosimilar to receive regulatory approval by the European Commission (EC), as Benepali®2. SB4 has also received regulatory approvals from Korea’s Ministry of Food and Drug Safety (MFDS), Australia’s Therapeutic Goods Administration (TGA), and Canada’s Health Canada, as BRENZYS™ 3,4. “We are proud to have partnered with Samsung Bioepis on the launch of this biosimilar therapy, which was the first etanercept biosimilar to receive European Commission approval, and look forward to a continued partnership as we continue to commercial supply,” commented Jonathan Arnold, Vice President & General Manager, Drug Delivery Solutions at Catalent. Catalent’s 265,000 square foot Brussels facility offers the latest in innovative pre-filled syringe fill-finish processing and associated packaging. With experts in technology transfer, scale-up and life-cycle management, its annual

about catalent Catalent is the leading global provider of advanced delivery technologies and development solutions for drugs, biologics and consumer health products. With over 80 years serving the industry, Catalent has proven expertise in bringing more customer products to market faster, enhancing product performance and ensuring reliable clinical and commercial product supply. Catalent employs approximately 9,200 people, including over 1,400 scientists, at more than 30 facilities across five continents, and in fiscal 2016 generated $1.85 billion in annual revenue. Catalent is headquartered in Somerset, New Jersey. For more information, visit: www.catalent.com. For customized manufacturing solutions of your aseptic fill finish products, visit www.catalent.com. Enbrel is a registered trademark of Immunex Corp. Benepali ® is a registered European trademark of Biogen Idec International Holding Ltd. 3 BRENZYS™ has not been approved for the treatment of patients with psoriatic arthritis and plaque psoriasis in Canada. 4 BRENZYS™ is a trademark of Merck Sharp & Dohme Corp. 1

2

syringe filling capacity is more than 200 million units.

about samsung bioepis Established in 2012, Samsung Bioepis is a biopharmaceutical company committed to realizing healthcare that is accessible to everyone. Through innovations in product development and a

Discover more solutions with Catalent. Call: us + 1 877 891 1837 eu + 800 88 55 6178 Email: [email protected] Visit: www.catalent.com