Providing high containment for multiple mills Manufacturing Chemist

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PROCESSING
April 2013 manufacturing chemist vii
Milling any compound is a challenge, but having to mill
high potent or cytotoxic materials creates more of a problem.
When milling a compound of any type, there is never a common
mill that is used to gain the correct particle size: not only do
manufacturers have to mill different compounds, they also have
to use multiple types of milling equipment.
Some milling equipment is used very infrequently but still
requires the complexity of applying high containment. Seeking
to contain each type of mill, however, could run up costs well
into millions of dollars. So to provide high containment for
milling requirements companies should first identify what mills
are used and how often. Quantities of compounds and container
sizes also need to be evaluated. This then becomes the directive
on what approach a company needs to take to develop a
solution.
Another area to consider is the operator exposure level that is
required. Some compounds need containment but not to the
nanogram-level. If companies have newly developed compounds
that do not have a toxicity yet assigned, then they have to
default to the nanogram levels. By taking this approach
companies can get a clear vision of what they need to
accomplish.
Match valves with process requirements
There are many types of high containment valve in the
marketplace. The choice really depends on the process and how
much handling is going to be required. Different valves types
also suit various containment requirements and process needs
and include Ezi Flow, EZi Dock or Buck valve, to name a few.
Where a company is planning to mill large quantities of
compounds and use one mill type, it can use high containment
valves on the inlet and outlet of the mill. This is dependent on
the size of the equipment, however. Where companies have one
compound that is rarely handled and it requires high
containment, a closed system is created by fitting the active half
of the valve on the inlet of the feeder (volumetric if required)
and another active half on the outlet of the mill, hence
achieving the containment. If a material has a containment
level that is not that stringent, it can be off-loaded by using a
continuous liner system (see Figure 1). This type of system can
have extraction provision added.
By using a feeder companies can provide a constant feed rate,
which helps eliminate any bridging of the product. This is
important as the system now is closed through the utilisation of
the valves. The feeder and mill will require a nitrogen purge to
eliminate any dust explosion risk. An added benefit of a
completely closed system is that the nitrogen environment has a
relative humidity of less than 1%, which is beneficial for
compounds that are hygroscopic.
Containment valves (depending on the type chosen) can be
good clean-in-place (CIP) systems that can clean down the
whole process train. If there are any breaks in the system, these
need to be evaluated and the required gasket material chosen to
ensure that there are no breaches of the system.
Selecting the right glovebox technology
If smaller mills are required for high containment compounds,
pharmaceutical producers can either contain each mill, which
can come with a million dollar price tag, or have the flexibility
to use one glovebox that is versatile enough to accommodate
many different types of mills.
Some designs require the mill to be mounted on individual
skids with plug and play control. Only the mill itself would be
presented to the interior of the glovebox. Any drive would be
kept external. This provides the added benefit of being able to
repair a mill easily if it shuts down during a milling operation,
as the drive and motor are external to the process end of the
With more potent drugs gaining market
approval,Michelle Frisch of Powder Systems
Ltd (PSL) looks at the issues of containment
when milling and offers some solutions
Providinghigh
containment for
multiplemills
Fig. 1: Continuous liner systems and loading table
Fig. 2:A full-scale mock-
up of a glove box isolator
Never purchase
a glovebox
without first
having a
full-scale
mock-up created
and placed on
site”
“
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PROCESSING
viii manufacturing chemist April 2013
Never purchase a glovebox without having a full-scale mock-up
created and placed on site. This provides the opportunity to
evaluate the functions and compound sizes that need to be
accommodated. Technicians can ‘mock up’ the milling activities
inside the glovebox. If any issues or concerns arise they can be
addressed and the design can be changed.
Off-loading the milled compound can be achieved through a
variety of methods: using high containment valves, rapid
transport systems (RTPs) and continuous liner systems, or
directly into the next piece of process
equipment.
If traditional technology suits – use it
Even ‘old’ technology (i.e. full suites)
should be considered for milling large
quantities or for one-time events. If large
quantities of material need to be milled on
older equipment or equipment that is not
suitable for containment, it is neither cost
effective nor productive to try and contain
it. Cleaning these systems can prove to be
a challenge as disassembly in a glovebox is
impossible. If a glovebox manufacturer
claims they can do it, arrange to see a
system that is working and speak with
technicians first. It is possible, but very
unlikely, that a system of this type would
achieve what is required. Something will
be compromised.
However, the operation can be
evaluated to see where improvements can
be made to reduce the dust or compound
scatter that can occur. Particular
attention can be paid to the off-loading
activity and some containment systems
can be applied.
In summary, by careful analysis of the
essential factors (listed below) an effective
strategy can be developed that
accommodates the requirements for
achieving high containment milling
without spending a million dollars.
CONTACT
Michelle Frisch MBA
Senior Manager Global Technical Systems
(Member of the AGS Standards Committee)
PSL USA
Cliffside Research Park, 3944 N.
Mountain View Drive, STE 100
Boise, Idaho 83704
US
T +1 208 376 7008
michelle.frisch@powdersystems.com
www.powdersystems.com
Key elements to consider
1 Operator exposure limit to be accommodated
2 Container or drum sizes to be handled
3 Mill type required for each compound
4 Off loading containers
5 Ergonomics
6 Cleaning requirements
Fig. 3: Below: Milling glove box with interchangeable
mills; above right, various mill options
mill. What this means is that with one glovebox system, a
company can install and remove many different mills, thus
providing optimum flexibility for the milling of high potent
compounds or cytotoxics (see Figure 3). However, if the
pharmaceutical manufacturer has a product that is required in
large quantities and needs nanogram containment, it might be
worth having a dedicated glovebox system.
The glovebox offers the advantages of a nitrogen-purged
environment, nanogram containment and the added benefits of
a small area to clean along with better control
over cross-contamination if using different
compounds on the same mill.
Gloveboxes have built in clean-in-place (CIP)
systems that can be validated. Cleaning and
disassembly of the mills is a critical component
and attention needs to be paid to how the mill is
assembled and disassembled. Such tasks have to
be accommodated through gloveports and
gloves. This can prove to be difficult and
modification of the mill might be needed.
Good design is critical, and attention to the
pressures of each mill needs to be considered.
Control for each mill needs to be ‘plug and play’
and relates to the pressure requirements.
If using multiple mills in one glovebox,important things to consider are the ergonomics
and the workability of the glovebox design.
The glovebox offers the advantages of a
nitrogen-purged environment, nanogram
containment, a small area to clean and
better control over cross-contamination”
“
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