HPAI
ERIK T. MICHALSON
High potency active
pharmaceutical ingredients
An overview of safety
and manufacturing concerns
ABSTRACT
Highly potent active pharmaceutical ingredients (HIPO’s)
are increasingly common drug development targets.
Worker safety issues need careful and deliberate
consideration as companies become involved with HIPO’s.
This article is intended to provide an overview of the
concerns associated with high potency API operations.
Some helpful references are also provided for the reader.
INTRODUCTION
It is estimated that more than 25% of clinical API’s
currently in development are high potency (HIPO) actives
(1). A potent compound may be broadly defined as
having a therapeutic dose of 1 mg or less. Occupational
exposure limits are also used to define compound
potency. Steroids, prostaglandins, hormones, retinoids,
cytotoxics and oncology agents such as neuprolide,
abarelix, paclitaxel and camptothecin are examples of
highly potent pharmacologically active compounds.
Concern regarding safe handling of potent drug
substances dates back to the 1970’s. Clearly, special
safety considerations for employee protection and facility
design are required when dealing with highly potent
API’s. Significant capital investments for suitable
engineering controls are needed to address occupational
exposure limits.
OCCUPATIONAL EXPOSURE LIMITS
AND CONTROL BANDS
As noted previously, potent compounds typically have a
Figure 1. Definitions
18 chimica oggi • Chemistry Today • Vol 25 nr 4 • July/August 2007
therapeutic dose of less than 1 mg. For the sake of
comparison, a typical adult dose of aspirin is 325mg. An
Occupational Exposure Limit (OEL) of less than 10
micrograms/ m3/ 8 hr is generally considered to be high
potency. The potency of pharmacologically active
compounds is defined by an understanding of the toxicity,
mode of action, dose, and the no effect level (NOEL).
Occupational Exposure Limits (OEL) and Occupational
Exposure Bands (OEB) are defined in Figure 1. The OEB
is a range of OEL’s within which worker exposure should
be controlled (i.e. mg/m3), and is typically expressed as
an 8 hr time weighted average (TWA). Note that OEB
assignments vary from company to company, with the
number of defined bands ranging from 3 to as many as
6. However, a 4 or 5 band OEL guidance is typically used
by Pharma companies. An OEB guidance example from
Cambrex is shown in Figure 2.
“Control Banding” or assignment of the OEL to potent
compounds is a complex activity requiring industrial
toxicology expertise for accurate hazard assessment.
Attributes such as carcinogenicity, mutagenicity,
sensitization, pharmacologic mode of action, and typical
dose are considered to arrive at the assigned OEL and
OEB values. Professional judgment and safety factors also
figure into OEB assignments. An interesting technical
article for calculation of OEL values may be found on the
Safebridge web site (2). Once an OEB rating has been
assigned for a potent compound, suitable handling
practices must be linked to the OEB assignment. Industrial
hygiene guidance is needed for specific unit operations
according to the OEB rating of the potent compound of
interest.
HIGH POTENCY CONTAINMENT
CONSIDERATIONS
Engineering controls and facility design considerations for
containment of high potency API’s are required.
Fundamental design decisions must be made regarding
the level of containment and engineering controls
required. Facility design decisions will depend on the
targeted OEB capability. Employee exposure must be the
primary concern when designing a facility for potent
compound operations. Reliance on PPE as the primary
worker protection is not acceptable for high potency API
operations. Therefore, design and implementation of
appropriate engineering containment controls are
required. Isolators (or gloveboxes) are standard
 HPAI
containment devices for environmental monitoring.
HIPO facilities. Gravity The practical lower limit for
transfers of highly potent measuring potent compound
compounds may be done levels is about 0.1
using docking mechanisms microgram/m3/ 8hr.
(split butterfly valves) and
intermediate bulk containers
(IBC’s) Figure 3. MILLING AND
It should be noted that MICRONIZING
OSHA has provided a
regulatory guidance for Bioavailability of API’s
HIPO worker protection (3). normally shows dependency
The OSHA guidance on particle size. Small API
provides overview level particles are often desired to
guidance, and generally provide enhanced
leaves the details to be Figure 2. Occupational exposure bands bioavailability. When
sorted out by the company necessary, milling or
engaged in HIPO activities. micronizing potent
compounds presents unique challenges
for product containment due to the
HIPO FACILITY DESIGN dusty nature of the operation. Ball
milling is sometimes a good
Some useful examples of HIPO facility containment option for relatively small
design can be found on web sites of quantities of API. Hammermilling, or
organizations such as International comminution for particle size reduction
Society for Pharmaceutical is a dustier operation, but systems are
Engineering or ISPE (4). Personnel now available with engineered dust
and material flow are particularly controls. Jet milling as a micronization
important considerations in designing process technology is a particularly
a HIPO facility. “Dirty” and “Clean” Figure 3. Transfer of potent compounds – interesting containment challenge.
intermediate bulk containers
zones for personnel movement and Cambrex Charles City has invested in
flow within the facility must be a high potency API micronization
clearly defined, physically containment suite as shown in
separated, and administratively Figure 5. Barrier isolator technology
controlled. Air handling concerns has been employed to provide the
are also paramount. Air flow must engineering containment controls
be carefully designed, staged, and required for this jet milling
maintained to prevent migration of operation.
HIPO powders into “clean” areas.
Sophisticated air handling systems
with air flow monitoring within the MULTI-PURPOSE VS.
facility must be installed and DEDICATED HIGH POTENCY
Figure 4. Barrier isolators for containment
maintained. The air flow must API FACILITY
reliably move away from (“negative
to”) the designated “clean” zones; and the air flow then Dedication of processing equipment to production of a
finally exhausts from the HIPO work area. Dust collection particular highly potent API eliminates or minimizes
considerations and maintenance programs for such concerns about cross contamination. However, this is an
systems are also required. HEPA air filtration systems are expensive option mainly suited for established commercial
commonly used for incoming and exhaust air. high potency API’s. Operation of a multi-purpose high
Architectural and Engineering firms with experience in potency API facility is a much more complicated
HIPO facility design are recommended for HIPO capital undertaking from a cleaning perspective, but allows
projects. greater facility flexibility. Cleaning effectiveness and
Open handling of the highest potency compounds is analytical verification or validation between compounds is
generally not acceptable, except within a containment crucial. Cleaning limits must be calculated, taking into
isolator. Dust is a major hazard associated with HIPO
solids due to inhalation potential and migration of the
material within a facility. Consequently, rigid wall
isolators as engineering control devices are needed to
restrict the area exposed to the HIPO active, and to
provide rugged barrier protection. Isolator designs, sizes
and cost vary tremendously. They may be “off the shelf”
items or custom built (and more expensive) units.

ENVIRONMENTAL MONITORING

Environmental monitoring is used to verify actual levels of

potent compounds present within a potent compound
facility. Analytical method development is required to Figure 5. Contained jet mill micronizer
establish the necessary recovery methods for (Cambrex Charles City).

chimica oggi • Chemistry Today • Vol 25 nr 4 • July/August 2007 19

HPAI
account dosages and equipment surface area. Facility REFERENCES
designs for overall ease of cleaning combined with clean-
1. Pharmaceutical Technology, September 2006
in-place technology are worth consideration. 2. “An Overview of Setting Occupational Exposure Limits (OELs) for
Pharmaceuticals”, Robert H. Ku, www. Safebridge.com
3. U.S. Code of Federal Regulations (CFR) 29 CFR, Occupational
SUMMARY exposure to hazardous chemicals in laboratories. - 1910.1450
4. www.ispe.org

It is clear that potent compound operations comprise a

specialized area of pharmaceutical manufacturing. A
significant capital investment in facility and HIPO
engineering controls is required. Training of operators is ERIK T. MICHALSON
also a vital part of high potency API operations. A system of
SOP’s to govern equipment and facility operations are vital Cambrex Charles City
to support training and administrative control of HIPO Charles City, Iowa
facilities, and the associated cGMP activities. Proper USA
execution of procedures and correct use of specialized HIPO
containment devices is critical to maintaining worker safety.

20 chimica oggi • Chemistry Today • Vol 25 nr 4 • July/August 2007