Industry perspective HPAIs

AMY K. DOANE, ROBIN I. LIVINGSTON

CordenPharma Colorado
2075 55th Street, Boulder, Colorado 80301, USA

Amy K. Doane Robin I. Livingston

Critical aspects of a robust potent

compound containment program
KEYWORDS: Containment, HPAPI, Development, Culture, OEL.

Abstract CordenPharmas Colorado API manufacturing facility has a long history of successfully implementing
innovative solutions to ensure containment of Highly Potent Active Pharmaceutical Ingredients (HPAPI),
designed to protect workers from the unique hazards presented by potent compound handling. While the success of CordenPharmas
programs requires effective Engineering Controls, the critical aspect to a robust containment program is the strength of the softer elements,
including a Containment Culture, Process Development, Occupational Health Pre-Planning, and an ongoing Containment Execution
Cycle. Without these supporting elements, even state-of-the-art containment equipment will not consistently and reliably contain HPAPI.

INTRODUCTION ENGINEERING CONTROLS

CordenPharmas manufacturing facility in Boulder, Colorado Engineering controls represent the hard elements of the
is an Active Pharmaceutical Ingredient (API) contract containment program. CordenPharma Colorado utilizes a
development and manufacturing facility which focuses on the variety of containment systems, including hard-sided and
production of therapeutic peptides, highly potent compounds, flexible isolators, drum containment systems with powder
and complex small molecules. The facility utilizes a full range transfer systems, continuous liners, local exhaust ventilation,
of development and manufacturing equipment covering and others.
all scales, with proven containment systems in laboratory,
mid-scale, and large-scale production areas. CordenPharma Engineering controls are designed according to a
Colorado has over 30 years of experience handling some of Design Exposure Limit (DEL) based on the Occupational
the most potent compounds on the market. As a multi-purpose Exposure Limit (OEL) for the most potent product for all
facility that handles small and large scale production of highly operations less than 2 hours, or 50% of the OEL for the
potent compounds, CordenPharma has encountered and most potent product for operations greater than 2 hours.
solved many containment challenges over the years. The equipment must support not only the manufacturing
process operations, but
In order to ensure a robust system, also decontamination of
CordenPharma utilizes the concept equipment and tools as well as
of a Containment Puzzle, where waste disposal. Additionally,
all of the pieces must align. Not the equipment must be
only does a successful containment ergonomically friendly and
program require the hard elements easy for the operators to use.
of robust containment equipment If a containment device is
and Engineering Controls, but uncomfortable to operate,
equally important are the soft operators are less likely to
elements of the Containment Puzzle: do it properly, risking a loss
a Containment Culture, Process of containment. Whenever
Development, Occupational Health possible, consistent types
Pre-Planning, and an ongoing of containment systems are
Containment Execution Cycle. Figure employed across the plant site
1 displays the key elements of the to ensure that operators can
Containment Puzzle as utilized in Figure 1. Containment Puzzle move throughout the facility and
CordenPharma Colorado. effectively use all systems.

Chimica Oggi - Chemistry Today - vol. 33(5) September/October 2015 71

Engineering control selection and design includes setting
a Design Exposure Limit and benchmarking, while the
qualification process ensures the containment target is met.
A mock-up exercise with input from the full project team
and real-end user is an effective way to ensure all of these
important design considerations are met. In Figure 2 below, a
mock-up technique was used to design a rigid isolator. On
the left is the exterior of the mock-up, in the center is the
inside, where end-users were able to simulate the process
flow and make final detailed design changes, which were
implemented in the design of the final isolator, shown on
the right.
Figure 2. A mock-up exercise performed at CordenPharma Colorado to design this rigid isolator. it inside the isolator as much as possible.
Often existing systems are adaptable and can be modified
to meet the needs of a specific process, and retrofit can
be the most economical and effective means to address a
containment need.
The expansion of containment levels of existing
technology through continuous improvements has
demonstrated that technique and personnel experience
can vastly improve the levels to which equipment can
contain. Once a facility has established and utilized a
successful containment program for many years, their
personnel at all levels (Industrial Hygienists, Engineers,
Operators, Mechanics, etc.) become experts in the
design, installation, verification and use of effective
containment systems. These people are critical to the
success of the program.
CONTAINMENT CULTURE
Soft elements, such as a containment culture, are also
vital to the success of the program. Individuals at all
levels of the organization must understand their personal
roles and responsibilities to safely contain HPAPI. Top
management must also be committed to and lead the
program. This means that the appropriate resources
are provided for containment systems, from design and
ongoing maintenance to monitoring, and that employees
are accountable for themselves and for their co-workers
to ensure that containment systems are used properly.
The end-user operators must also feel empowered to
continuously identify and implement improvements
to containment systems. Supporting this containment
culture is a top-down process, where site-wide goals are
set at the management level to maintain and improve
containment and HPAPI handling capabilities, while at the
operations level safety observations are openly discussed
with management.
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Containment culture is the product of the individual and group
values, attitudes, competencies and patterns of behavior that
determine the commitment to, and the style and proficiency
of, an organizations Industrial Hygiene program.
PROCESS DEVELOPMENT
During process development, essential activities are done
to understand, mitigate, and possibly eliminate the hazards
of the process. This includes selecting the right reagents and
combinations, obtaining chemical hazard data and the
Occupational Exposure Limits, as well as
also designing the process to address
these hazards.
Many approaches can be used to refine
processes during the development phase
to reduce exposure risk. Some examples
include keeping the product in slurry,
ensuring isolation and drying equipment is
coupled, eliminating steps in the process,
and optimizing the process flow to keep
In one process, CordenPharma chemists
and engineers were able to significantly
improve a process reducing the number of chemical steps
from six to two, which eliminated four intermediate isolations
and their associated exposure risk. Additionally, a highly toxic
solvent was eliminated from the process. The developed
process was not only more efficient, but it significantly
reduced the employee exposure potential. While these types
of significant process improvements are not always possible,
they should be considered during the process development
stage when thinking of a commercially safe process.
Process development includes not only obtaining product
hazard data with Occupational Exposure Limits, but also
addressing these hazards. The following data are important to
process development, among others:
Product Hazard data
- Physio-chemical Minimum Ignition Energy (MIE),
reaction calorimetry, flammability, flash point
- Toxicity acute, chronic, mutagenicity, sensitization
- Ecotoxicity biodegradation, toxicity to aquatic life
Product Categorization and Occupational Exposure Limits
(OELs)
All of this information is used in batch record development,
training and hazard communication, to be sure that all hazards
are identified, mitigated, and appropriately communicated.
As a CDMO, CordenPharma Colorado works with
customers to ensure that the most current data is
obtained. The information that is available depends
heavily on the phase at which the product is in the drug
lifecycle. This information is crucial to ensuring that process
hazards are mitigated and containment systems are able
to contain to the appropriate level. Additionally, after a
process is further developed and more data is available,
initial assumptions should be re-assessed and operational
refinements made as necessary.
Chimica Oggi - Chemistry Today - vol. 33(5) September/October 2015
OCCUPATIONAL HEALTH PRE-PLANNING
Occupational health pre-planning is the work done during
process development to ensure that once a containment
system is implemented, ongoing containment can be proven.
This includes the development of the following:
OEL development or placing the product into a control
band (for early-phase products)
Acceptable Surface Limits (ASL)
Industrial Hygiene (IH) sampling and analytical methods
Medical surveillance protocols
Deactivation and/or decontamination methods
Non-routine contingencies
As a CDMO, obtaining this information from customers
can sometimes prove to be difficult due to a number of
reasons. For example, virtual companies with limited
manufacturing experience may have significant process
knowledge but do not have the full understanding of
the information needed to ensure a safe routine process.
Similarly, the disconnect between the manufacturing side
(cGMP) and the clinical side (cGCP) of the organization,
although both sides need information to ensure worker
and patient safety, often creates ineffective lines of
communication between each other to ensure data
is available to those who need it. As a drug progresses
through its lifecycle, more data becomes available. CDMOs
need to be aware of what data is available at each phase.
Table 1 presents the phases of the drug lifecycle and the
correlating information that can be obtained from the data
acquired at each phase of the lifecycle (1):
Table 1. Phases of the drug lifecycle
If the information above is unattainable, information from structurally similar
compounds or parent compound data can be used as a baseline.
CONTAINMENT EXECUTION CYCLE
The containment execution cycle is the on-going work
that continues long after a new manufacturing process
Chimica Oggi - Chemistry Today - vol. 33(5) September/October 2015
has been implemented. It includes aggressive Industrial
Hygiene monitoring to collect enough data to confirm
that containment has been achieved and is maintained.
This includes task observation, equipment and operational
refinement, as well as investigations into deviations from
procedures to foster continuous improvement.
The requirements for success with this piece of the
Containment Puzzle are trained and motivated Industrial
Hygiene staff, availability of monitoring equipment and
instrumentation, and resources for Industrial Hygiene
analytical methods. The Industrial Hygiene staff and
management must ensure that operational procedures
(PJTs and OJTs) and batch records are adhered to, that
consultation is readily available to operations personnel,
and that deviations, departures and digressions are
investigated and mitigated in a timely manner. Without
this critical piece, a containment system that was
qualified upon initial commissioning may develop a loss
of containment that is not identified, putting personnel at
risk for exposure.
At CordenPharma Colorado, all containment systems are
placed on a monitoring schedule whereby observations,
real-time screening, and integrated sampling are performed
to ensure the containment target for the equipment is
continually being met.
CONCLUSION
A robust HPAPI containment program recognizes
that it takes an alignment of all of the pieces of the
Containment Puzzle to ensure continued success,
where there is no such thing as a done stamp on
containment. Once containment is achieved it must
be periodically observed, critiqued and monitored,
because operational qualifications are not just for the
initial installation. Finally, once a system is qualified and
respiratory protection is removed, Industrial Hygiene
monitoring becomes even more critical and should be
completed more often.
The integration of the hard elements of Engineering
Controls and the soft elements of the Containment Puzzle
has proven enhanced and repeatable containment
for specific installations and is vital for the success
of a robust Industrial Hygiene program. Maximizing
engineering control investment success allows continued
alignment to a companys commitment to providing a
workplace free of recognized health and safety hazards.
REFERENCES
1. Drug Discovery and Development Understanding the R&D
Process: http://www.phrma.org/sites/default/files/pdf/rd_
brochure_022307.pdf (last checked on May 29th 2015)
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FINE CHEMICALS
SIMON T. R. MLLER1, AURLIEN MURAT2, PAUL HELLIER2, THOMAS WIRTH1*
*Corresponding author
1. School of Chemistry, Cardiff University, Park Place, Main Building, Cardiff CF10 3AT, United Kingdom
2. Institut de Recherche Pierre Fabre, 81603 Gaillac, France

Thomas Wirth

Safe handling of diazo reagents

through inline analytics and flow chemistry

KEYWORDS: Diazo compounds, flow chemistry, microreactor, inline analytics, ReactIR.

Abstract Through the use of flow chemistry in multistep processes, dangerous but synthetically useful diazo
reagents can be made accessible for large scale applications. The generation, isolation and use of diazo
compounds can be performed continuously, therefore never accumulating large quantities of highly energetic material. The use of
inline analytics via infrared spectroscopy is key in developing these processes.

INTRODUCTION Another major advantage of continuous flow chemistry

Synthetic chemists thrive to develop and use the most
efficient ways to assemble complex molecules. For this
purpose, some functional groups stand out in their ability
to be used flexibly and selectively for target synthesis. One
of the most versatile functional groups is the diazo group,
a highly reactive carbene precursor. Their reactivity stems
from the formation of metal carbenes using catalysis which
undergo a broad range of reactions under high chemo-,
regio-, and stereocontrol. Examples include stereoselective
cyclopropanation (1), C-H insertion(2) and ring expansion
reactions (3). Diazo compounds have been used in the
synthesis of natural products such as (+)-Salvileucalin B (4),
(+)-Lithospermic Acid (5), and (-)-Serotobenine (6). Although
diazo reagents are well studied academically, they are rarely
used industrially due to their energetic properties (7).
is continuous information. Rapid optimization of reactions
can be easily achieved within microreactors and smaller
quantities of expensive reagents are required for optimization
than in typical batch optimizations. It is therefore the perfect
platform for inline analytic techniques (11). However, the high
frequencies of potentially different reaction conditions that
can be performed within a microreactor have to be met
by rapid analytics with in-depth information. Inline infrared
spectroscopy meets these criteria for many reactions and
has been used to detect dangerous residues (12) as well as in
kinetic studies (13).
The outset of this work is to understand how continuous
flow and inline analytics in flow can help in handling highly
reactive diazo reagents safely and in high efficiencies.

Continuous flow chemistry is one of the most promising
techniques for the safe use of hazardous and explosive
reagents (8). Exothermal reactions and unstable compounds
can be problematic in batch reactors because the heat transfer
depends on the surface-to-volume ratio of the reactor used.
When scaling up a reaction from the round bottom flask in the lab
to production scale, the volume of the reactor increases more
rapidly than the surface. Therefore, the heat exchange becomes
less and less efficient. Continuous flow reactors, however, have
a much higher surface-to-volume ratio and are therefore very
effective at heat removal from exothermal reactions. Further,
continuous processing allows limiting the quantities of hazardous
materials formed at any time. Consequently, there are several
useful protocols for using dangerous reagents (9) and highly
exothermal reactions in flow (10).
ACCESS TO UNSTABILIZED DIAZO REAGENTS IN FLOW
Most commonly employed diazo reagents are acceptor,
acceptor/acceptor or donor/acceptor substituted
carbene precursors, due to the relative stability of the
diazo functionality as well as the enhanced reactivity
of the metal carbene. However, in 2009 Barluenga
and coworkers found that unstabilized diazo reagents
such as phenyldiazomethane can react in a reductive
carbon-carbon bond forming reaction under metal-free
conditions with boronic acids (14). The group of Ley recently
developed a highly efficient and adaptable flow protocol
for the formation and the direct use of unstabilized diazo
reagents in sp2-sp3 cross-coupling reactions (15) as well as in
cyclopropanations (16).

74 Chimica Oggi - Chemistry Today - vol. 33(5) September/October 2015