1000 µg/m3 (see below), are basically considered
nuisance dust - not harmful, not irritating and
with low pharmacological activity. As OEL value
decrease and approach 1 µg/m3 and below this is
when compounds are considered highly potent as
they exhibit extreme toxicity and potency, which
will require much greater levels of control.
CONTAINMENT TECHNOLOGIES REVIEW
One of the outcomes of banding is that containment should be achieved through the use of
Engineering Control Measures, not just procedures
and personnel protective equipment. Exposure
control banding sets the framework to select technologies and procedures to be applied with a predictable and repeatable outcome. What technologies can be employed to bring
these potent compounds under control in your manufacturing process?
Before deciding on containment strategies, it is important to review
the type of physical activity planned for each production step. For
example, a milling step, which is a high energy operation with the
potential to generate significant levels of dust, would certainly require a
different containment approach than a low energy sampling activity. It
is important to understand that the performance of any chosen technology is a function of the process with which it is integrated.
CONTAINMENT TECHNOLOGIES AND ANTICIPATED
The following is intended to provide a high level overview of the
basic containment technologies in common use within the pharmaceutical industry. In general, containment technologies fall into one of two
types: one that leverages airflow and the other which provides a physical barrier to isolate.
Local Exhaust Ventilation (LEV)
The objective of Local Exhaust Ventilation (LEV) is to extract particles before they make it into the general processing area or into an
operator’s breathing zone. This is critical not only for the operators, but
in situations where there is multi-product processing or batch segregation, the LEV technology can help to ensure control over cross contamination. Within the performance range of this technology, this might be
appropriate for Bin Charging, Hopper Charging type activities.
One caution worth mentioning is that there is often a temptation to
over-design the removal device but be cautious, because if the system
works too well you could be removing ingredients and impacting the
Air Flow Technology [AFT]
Air flow technologies are based on a similar principle to LEV. The
idea is to sweep air away from operators breathing zone and away from
the emission source by utilizing uni-directional air.
Designed to mitigate the most hazardous situations, Isolation
Technology provides a physical barrier between the emission source
and the operator/environment. There are two basic approaches when
considering system containment. The first and most commonly used
is the applied isolator scenario in which an isolator is “bolted-on” to
the system to be contained. The other approach is to select a system
that has been engineered to be contained from
the outset. One of the biggest challenges faced
with any isolated system is how to introduce
and remove items from the system. This requires
an in-depth analysis to identify all routine and
foreseen processing steps and interventions to
assure that the system has a means to accommo-
date these requirements while still maintaining
containment. In addition, consideration must be
paid to how cleaning and maintenance will be
SCALEUP VERSUS SCALE-OUT: A CONCEPT
There are many reasons to consider scale-out ver-
sus scale-up when moving from pilot plant to manufacturing.
Scale-Up is traditionally used to achieve a batch size as defined by a
manufacturing company as large enough to meet the anticipated market
Scale-Out is the use of multiple smaller and more flexible batches to
achieve commercialization - using sizes traditionally aligned with ‘pilot
scale’ and still meet the quantities necessary to meet market demand.
One definition of the “scale-out” concept combines a hybrid scale-out and ‘batch unit’ approach, and attempts to limit some of the business hazards as well as the more tangible hazardous and potent materials discussed throughout this article. Certain aspects of containment,
fire and explosion, handled carefully in a pilot plant, become a greater
challenge when moving into manufacturing.
Clearly, scale-up of a successful pilot scale Phase II or III product
involves more than just concerns about potent compound safety.
Marketing, sales, engineering, manufacturing, finance, procurement &
supply chain make the question “how much product will be needed?” a
complex one, as Phases II and III come to a close.
The organization should carefully review the scale of the proposed
operation. Bigger may not be better, especially when it comes to potent
and hazardous materials in many of solid dosage form applications.
The world of potent compound hazards boils down to a simple fundamental - do everything you can to understand the compounds your process
is dealing with, in the lab, at the pilot stage and in commercial manufacturing. Understand material data sheets, flammability, and combustibility.
• Limit quantities when possible to below exempt amounts by scaling
out instead of up
• Checking all the codes and regulations
• Do a hazard evaluation in the earliest stages of the process and then
repeat it, challenging it at each stage of the design process
• Look at different mediation solutions - not just one, put them on
paper, get two options, challenge it, do the pro-con analysis.
• Challenge your engineering team and your engineering firm.
• Select and implement procedures and the chosen technologies
• Do a performance verification
• Monitor as often and as thoroughly as the risks indicate
• Re-evaluate and adjust to changes
26 FEBRUARY 2014 ◗ pharmpro.com
ORAL SOLID DOSAGE TECHNOLOGIES
• Technique driven performance
• 10 (probably better at < 20) to 100
• Potentially remove actives
• Barrier added to increase performance
• Cost $$
Positives: Good cost: performance ratios
Negatives: Difficult to truly reach 10