Help!

My Isolator Is Taking Too Long To

Degas — What Should I Do?
By Herman Bozenhardt and Erich Bozenhardt

Probably one of the most significant developments in sterilization and aseptic

practices in the pharmaceutical business is that of vaporized hydrogen peroxide
(VHP) as a contact or “cold” sterilizing agent. The use of VHP in contained
environments has allowed us to decontaminate working spaces, equipment,
and materials and has led to the development of the reliable isolator. This
application has led to many years of success and provided assurance that
aseptic handling and filling operations are microbial-free. In this article we will
focus on filling isolator systems and equipment. Since the use of this technology
began, we have been singularly focused on sterility by maximizing injection
rates and saturation levels and assuring media fills are successful in
qualification testing.

Another evolution of this technology is the size, complexity, and diversity of

isolators the VHP has been applied to. Originally isolators were “boxes” or
“cylinders” with lots of injection nozzles and a simple HEPA exhaust scheme.
Today the isolators have increased in size so much that the height and width
require more nozzles and greater reach across the fill deck. In addition, we now
have isolators with seven to 13 sections, with multiple right angles to adjacent
sections where each section can be 10 to 20 meters long, and with several
auxiliary docking sections. In all these cases we compensate with more VHP
injection because we need to ensure successful media fills.

New Reality

As this expansion of VHP use and isolator complexity evolves, we have driven
ourselves directly into the newest class of drug products and have “hit the wall.”
We have discovered many new therapies that are classified as “ultra-low”
potency products (in the microgram and nanogram per ml), biologicals that are
sensitive to VHP (and any oxidizer in the vapor phase) and incompatible
products (in some cases there was no prior testing or consideration for VHP
interaction). In these cases, the residual VHP vapor in the isolator interacts with
the open vial of liquid between the dosing nozzles and the capping station and
oxidizes the API in the solution. This becomes a more severe problem with
lyophilized products, where the liquid is exposed from the dosing needle
through the fluted stopper and into the lyophilizer itself. This has had a major
impact on new installations and CMOs as they acquire new business in their
legacy aseptic filling isolators. In some cases, the residual VHP has attenuated
product by 10 to 15 percent potency in standard fills and up to 25 percent
degradation in lyophilized production.

For the CMO, this often violates many of their standard practices and crushes
their high confidence in their VHP cycle and media fill, and they must face the
reality of many isolator changes and potentially reducing their VHP cycles. This
also exposes a flaw: that some isolator VHP residual levels have never been
understood, challenged, or questioned. In many cases with low-potency
products or biologicals, we need to set the residual level from the 100 +/- ppm
levels to as low as 10 ppb. Some may wonder if this achievable, and the answer
is absolutely. However, some practices, equipment, and processes need to
change, and for the better. We will now explore the process of degassing and
removing residual VHP via aeration from the various commercial isolators.

Wrong “Solutions”

As we have dealt with these issues on a global level, we have found folks who
think outside the box and approach the problem with more problems:

• “Let’s just fill with a higher concentration.” This approach of

concentrating the product and letting the degradation take its toll is
foolish. That would require a change to the submission documents and
show a lack of study of the compatibility of VHP with the product. In
addition, the oxidation of the API produces a compound, and now we
would have introduced a new impurity. The FDA would be very
interested in this.
• “Let’s increase the fill volume.” This is equally inappropriate, as the same
issues as above will occur, with a degraded potency and more volume.
The residual generated will be questioned, as will the manufacturing
submission.
• “Let’s just HEPA-ventilate until we get a good reading.” While this is a
compliant solution, it results in a degassing that could take days or weeks
to accomplish. This could have a devastating impact on product delivery
and plant capacity. By using excessive fresh air ventilation, we are also
stretching the service life of the internal HEPA filters while increasing
the operating cost geometrically. The air handling unit (AHU) and
cooling costs will drive up the power load.
• “Let’s see if we can cut back on the validated VHP cycle and see what
happens.” This is a risky approach, since any change to the process would
require a change control and re-execution of media fills. Without any
engineering changes, this is a gamble at best.

The Best Solution

• Recognizing VHP and its residual exist and could impact the product is
the first step in avoiding a problem. It is important to use the product
and run VHP compatibility tests, challenges, and fill trials to gather data
and understand the impact before the fill is tech-transferred into the
isolator site/environment. This should be done in a pilot plant or, at
worst, in a “development” mode with the isolator. This would allow data
to be gathered, a judgement reached on impact, and a rational design
executed before the fill tech-transfer. This would provide parameters for
the residual ppm or ppb of the VHP, the degassing time, and any field-
based modifications needed (options below). The careful design of the
cycles (both VHP and degassing/aeration) and understanding the VHP
levels, temperatures, relative humidity, velocity of aeration, air change
rate (ACR) in the isolator, and point HP values via instrumentation is
 invaluable. A virtual 3D model of the residual VHP generally allows
pinpointing the key VHP source. This proactive approach saves time and
money and allows for the selection of a best economic solution, which is
a tradeoff of engineering technologies and degassing time.

Field-Based Solutions

• One of the most common and overlooked problems is liquid pooling in

certain areas above and below the fill deck. However, you will never see
this at the brief factory acceptance test (FAT), but after several in house
VHP runs a gasket, opening, port, or other point allows moisture
collection and it will contain dissolved HP. A careful study of the unit
during and directly after the VHP routine (of the equipment, the deck,
and below the deck) is usually the first step in troubleshooting.
• The next key area to look for is the elimination of polymer-based
materials inside the isolator, especially all platinum-cured silicon tubing.
All polymer-based material absorbs VHP during the cycle and slowly
expresses it, but at a rate that will continue to thwart the degassing. Some
polymers are significantly worse than others. The focus is to maximize
stainless steel and use Teflon, polyethylene, and polypropylene only
when required. The most detrimental and absorptive polymers are
Delrin, polyurethanes, polyamides, polysulfones, and polystyrenes. You
must look carefully at the materials of construction of your tubing,
filters, seals, gaskets, and other polymer-based components. This also
includes the HEPA filters and mounting systems. The user needs to
understand the materials in the HEPA filter frames particularly. In some
CMOs, the isolators have HEPA filters on the return ducts/plenums.
This is to prevent cross-contamination; these filters (polymers) can be
removed if the product profile does not contain cytotoxics, potent
compounds, or active biologics.
• Along with the polymer-based investigation should be a careful review
of the gloves, glove ports, and other interface seals. First check for
materials of construction, and then make sure the gloves are all extended
(fingers are not together) and have no obscured surfaces or cover a port
of another polymer seal. Polymer surfaces trapped against one another
can also trap and retain VHP and interfere with normal
aeration/degassing.
• The isolators have AHUs that control the air circulating from the isolator
deck-level returns. These AHUs have cooling coils to control the
temperature in the isolator section, which is primarily a cooling function.
The coils are fed chilled plant water internally to cool the air drawn by
the blowers, which pushes the air through the HEPAs back to the isolator
for downward coverage of the vials. Since the AHUs are a major
operating-cost contributor, they have been optimized for cost savings
and minimum circulation and not for degassing. Rethinking design and
orientation are needed to service contemporary product lines.

The coils are cold during normal operations and remain so during the VHP cycle
(even if the chilled water supply valve is shut). The coils are an ideal place for
water to condense, collect, and retain HP (dissolved hydrogen peroxide). Once
pooled in this area, it could take days to evaporate the water and the HP. This
is one of the most prevalent problem areas.

In order for this area not to pool liquid and become the HP reservoir for the
unit, the control system must condition the isolator coils for a post-batch/pre-
VHP cycle. In some designs, there is no temperature control unit (TCU) for
heating and the valves control the chilled water going into a recycle mode and
slowly let the heat from the isolator and machinery warm the air stream. In a
more contemporary design (see AHU scheme), a TCU provides either plant hot
water or electrically heated water to elevate the temperature of the coils and the
internals of the isolator.

In this case, during the normal isolator-filling scheme the programmable logic
controller (PLC) controlling the isolator AHU has a chilled water (CW) set point
CT that has valve VB controlling the chilled water circulating (valves VA and VD
are closed, and VC is open 100 percent). To prepare for the VHP cycle, the PLC
needs to increase the temperature of the coils above the condensing
temperature of the VHP (remember the coils and blower are upstream of the
HEPA filters). This temperature should be 35 degrees Celsius and should be
attained quickly. This will require a TCU to come online with its pump, shut VB
and VC and open VD 100 percent, and control the temperature by actuating
valve VA and putting the TCU mode to heat.

The next step is to run the isolator VHP cycle, knowing the coils are heated.
Once the VHP cycle is completed, the degassing should reinitiate the coil-
heating cycle and drive the temperature of the entire isolator up and accelerate
the degassing, making sure any residual VHP and water/HP evaporates quickly.

As in all of these types of applications, a detailed time-based analysis of the PLC

cycle is critical, as an inadvertent activation of a chilled water line, a wrong set
point for a short period of time, or a valve sequenced incorrectly could be the
root cause of the AHU problems.
 • One of the most worthwhile investments in an isolator is the VHP/HP
absorbing catalyst that can be installed in the AHU. These catalyst
systems are ideal to quickly absorb the VHP from the isolator during
their recirculation mode. The key to efficiency of the isolator is its ability
to recirculate air and only bleed in “make-up” air. The catalyst needs to
be placed by catalyst experts in coordination with the isolator
manufacturer for the correct location, air velocity tests, PLC sequence of
when to engage the catalyst, and overall commissioning of the unit. This
allows the isolator to run in its most efficient (re-circulation) mode and
absorb/destroy VHP. This is ideal if it is done in the design of system. If
this is done as a retrofit, the isolator will be taken out of service and
should be re-commissioned, and re-execution of the media fills would be
required.
• Fan circulation of fresh air and recirculated air is another consideration.
As mentioned above, the isolator typically runs in the mode of
recirculation and reduced power consumption. The blowers are
generally variable frequency drives (VFDs), and the PLC controlling
them may not be programmed properly for maximum exhaust. The
blower-controlling part of the PLC must insure the fans are in sync, not
inhibited by the power management scheme, and able to generate an
exhaust profile that flushes the entire isolator section. It is important to
understand the fluid dynamics in the isolator, not only during the VHP
cycle, but the degassing cycle as well. These are different cycles with
different objectives, and while dwell time and distribution are key for the
VHP injection and downward velocity of .36 to .45 m/s are key for filling,
they do not necessarily work for the degassing/rapid air egress. The only
way to assure ourselves the isolator is being degassed, not leaving “dead
zones” or creating vortices that recirculate the air or another anomaly, is
to perform a computational fluid dynamic (CFD) model of the isolator.
We have too many situations where inadequate air turnover and dead
zones are caused by equipment position, filling deck height, fan location,
and areas not evacuated cleanly. This can also be true of the many
“docking station” options. In the end, your understanding of the air
velocities, aeration profile, and delta pressure across constrictions is key.
• An alternative that is very effective, and also expensive, is the retrofitting
of the filling system with a nitrogen “blow” into the vials, nitrogen
backfill at dispense, and nitrogen blanket up to the stoppering zone. This
does not improve the degassing; however, it protects the product up to a
level. If done at the isolator design, the incremental cost is well
contained. However, if done as a retrofit, it can cost several million
dollars and delay operational use by a year. Another consideration is that
relying on a nitrogen headspace to protect the product will impact the
regulatory filing, as a new ingredient has been introduced.

In summary, troubleshooting of a degassing/aeration problem of an isolator

requires a substantial amount of time, analysis, and patience. To reduce a VHP
level in an isolator from 50 ppm to 50 ppb could take months. That is why
nitrogen backfilling plus isolator CFD analysis, polymer elimination, and
careful temperature control can mean the difference in over a year of startup
time and higher capacity throughput.