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An introduction to
High-Potent API Classification
David Bormett, Director, Operations
Who is setting the rules?
When dealing with highly potent compounds, it’s
critical that failsafe procedures are in place relating to
their handling, storage and containment. In order to
ensure that the correct procedures are installed and
adhered to, a logical system of classifying the potency
of the High-Potent API (HPAPI) is needed. At present,
there is no official guidance regarding the safe
handling of highly potent APIs. As a result, the industry
has begun self-regulating itself, with standards
developed by SafeBridge® Consultants (http://www.
safebridge.com) being the most widely recognized
classification system.
Origins of the issue
The lack of a single, commonly used system for
classifying HPAPIs can be traced back to the end of
the 1980s, when pharmaceutical companies initially
began discussing the safety issues around HPAPIs and
how they might classify them. One idea considered
at the time was the introduction of a system similar to
the biosafety level approach developed by the Centers
for Disease Control in Atlanta, Georgia. This system
involved a four-level system of pathogenicity, with each
level designated an appropriate level of containment.
This initiative was ultimately unsuccessful and the
idea of developing and implementing a united, single
system for classifying HPAPIs across the entire
pharmaceutical industry lost impetus, primarily due to
the significant variations in areas of therapeutic interest
and manufacturing procedures among the companies.
What emerged instead was the general concept of
HPAPI classification (or banding), which was, in turn,
adopted and customized by individual companies
to meet its own specific requirements. The upshot
- the current diverse range of classification models
witnessed today.
Potency classification scheme
Category I
Occupational exposure limit (µg/m3) >500
Toxicity and potency Low
Source: SafeBridge Consultants
www.safcpharma.com
In practice, the four-tier system discussed initially by
pharmaceutical companies evolved over time to form
the basis of the SafeBridge system. As mentioned
earlier, this system is now well-established and widely
accepted among CMOs. SafeBridge’s system involves
ranking a compound for potential potency and toxicity
on a scale of I to IV. Category I covers low-irritant
drugs, while Category II, currently the largest, includes
drugs that can cause organ toxicity. Category III is the
first tier of potent drugs that cause genetic effects,
plus organ toxicity, and finally, a tier Category IV, of the
most potent compounds. According to SafeBridge, an
increasing number of new drugs under development
fall into the latter two categories.
The following are attributes that may be considered for
each category of compound:
Category 1: Low potency, higher dosage levels,
minimal reversible acute/chronic health effects, good
warning properties, no “genic” effects, not a sensitizer,
slow absorption, no medical intervention required
following exposure.
Category 2: Moderate acute/chronic toxicity, reversible
effects, weak sensitizer, fair warning properties,
moderate absorption rate, no “genic” effects, may
require medical intervention.
Category 3: Elevated potency, high acute/chronic
toxicity, effects may not be reversible, moderate
sensitizer, poor or no warning properties, quick
absorption rate, suspected or known “genic” effects,
moderate to immediate medical intervention required.
Category 4: High potency, extreme acute and chronic
toxicity, irreversible effects, strong sensitizer, poor or
no warning properties, quick absorption rate, known
“genic” effects, higher degree of medical intervention
required, may affect sensitive subpopulations.
Category II Category III Category IV
10-500 0.03-10 <0.03
Moderate Potent Highly Potent
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The SafeBridge four-tiered system is not the only
model used. Some pharmaceutical companies
employ a five-tier system, while some may use
HPAPI categorization systems with tiers ranging
anywhere from three to six categories. With different
companies using different classification systems,
this can prove problematic when, for example, a
pharmaceutical company is seeking to outsource the
manufacture of HPAPI compounds to a CMO. In the
existing framework, the CMO will carry out its own
research and evaluation in order to assess potency,
then classify the HPAPI compound under whatever
system it uses to determine the level of containment
requirements. The system used to do this, therefore,
needs to be well defined, as any confusion or mistakes
at this stage could have a significantly detrimental
effect on safety. One issue facing CMOs now is to find
out how the various other models and systems used by
pharmaceutical companies translate into the accepted
SafeBridge model, and if that model can be widened
out as the single system used across the industry to
classify HPAPI compounds.
Looking ahead...
So far, the only regulatory body to have flagged up
the importance of bringing in updated guidance for
safely dealing with HPAPIs is the European Medicines
Agency (EMEA). In early 2005, it published a concept
paper on the subject, although its focus was more
on high potent product segregation than on actual
material categorization systems.
Further discussion is needed, with CMOs,
pharmaceutical companies and regulators pooling
their knowledge and working together to bring
everyone into line behind a single unified HPAPI
classification standard. Until this happens, there
remains the potential for problems relating to safety
and, as further potent compounds are developed and
the number of CMOs entering the flourishing HPAPI
market increases, the situation will only become
more complex.
While the high potency market undoubtedly
offers major opportunities for CMOs and research
organizations in the Life Sciences sector, the barriers
to market are high and should not be underestimated.
The fact that there are still relatively few companies
producing HPAPIs at commercial scale is testament to
the levels of investment, expertise, infrastructure and
technology that are required to achieve sustainable
market share.
www.safcpharma.com
How SAFC is addressing the issues
With regards to HPAPIs, as a contract manufacturer,
SAFC evaluates all new projects for potential
toxicity, potency and hazards (in addition to the
usual chemistry/capabilities review) to get as much
information as possible on safety and toxicology from
the customer. SAFC has three facilities specifically
designed for potent compound handling.
These include:
• Madison (WI, USA): Over 18 years of small
molecule potent compound experience in both
process development and cGMP manufacturing.
• St. Louis (MO, USA): High potency conjugation -
combining over 30 years of conjugation experience
and large molecule processing.
• Jerusalem (Israel): A high-potency fermentation
facility that will focus production on secondary
metabolites (antibiotic-like molecules), cytotoxins
and large-molecule proteins.
SAFC is set to complete a $30 million expansion
plan to its Madison facility in early 2010 which
will significantly increase its capacity to produce
commercial scale HPAPIs. The expansion included
the purchase of 15 acres of green space in Verona,
WI near its existing HPAPI production site, where the
company is building a new 51,000 sq. ft. manufacturing
facility that will house commercial scale reactors
capable of producing HPAPI batch sizes up to 4,000
liters. The new facility design maximizes efficiencies
and safe handling in high potency manufacturing
while adhering to Category IV engineering standards
and includes a 150 liter mini-processing plant and two
large-scale cGMP manufacturing suites with reactors
up to 4,000 liters.
Learn more about SAFC High-Potent API
capabilities - Click Here
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SAFC®, SAFC Pharma® and Sigma-Aldrich® are registered
trademarks of Sigma-Aldrich Biotechnology L.P. and Sigma-Aldrich Co.
SafeBridge® is a registered trademark of SafeBridge Consultants, Inc.
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