Critical considerations

for HPAPI manufacturing

at a CMO
Paul Doherty of Ferro Pfanstiehl Laboratories looks at the critical
aspects of potent compound manufacturing at a CMO
 High potency APIs
Critical considerations for HPAPI
manufacturing at a CMO
Paul Doherty of Ferro Pfanstiehl Laboratories looks at the critical aspects of potent compound manufacturing
at a CMO
H
igh potency API (HPAPI) compound
manufacture is growing every year, primarily
due to the ever increasing potency and
cytotoxicity of oncology drugs. To service this
demand, companies must decide whether to invest
in the infrastructure to manufacture these drugs or
to consider outsourcing. As several suppliers,
including Ferro Pfanstiehl, have years of experience
behind them, the decision to outsource has
become more popular and easier, especially when
one considers the number of criteria that must be
met in order to manufacture a potent compound
safely.
This article will address the critical factors to be
considered with HPAPI manufacturing in a
regulated environment at a contract research or
manufacturing organisation (CRO/CMO). These
include the Occupational Exposure Limit (OEL)
assessment of the compound, EHS monitoring of
the operators and cleaning verification
considerations. The Containment Sphere of Safety
(Figure 1) illustrates the fact that the overlap
between the critical factors and highlights that the
operational safe zone occurs within the overlap of
all the factors combined.
Commercial considerations
The key difference between HPAPI production at a
CMO against elsewhere is the inclusion of client
input and interests into the considerations of how
to process the compound safely and the expense
associated with safe processing. It is not
uncommon for a CMOs clients to have great
expertise in clinical trials or the efficacy of the API
to be manufactured but little with the issues
associated with potent compounds.
Figure 1 - Containment Sphere of Safety
Reprinted from Speciality Chemicals Magazine January 2012
It is important that the client understand upfront
the ramifications of potent compound handling.
The optimal time to discuss the potency of a
compound is in the initial stages of the commercial
relationship. The client needs to have a full
understanding of the steps and costs involved so as
to make an informed decision on how best to
proceed with the development of the compound.
Pharmaceutical compounds are classified by their
toxicity and potency as well as their OEL.
SafeBridge Consultants have developed an
exposure control banding system to categorise the
containment necessary for compound handling.
Many companies, including Ferro Pfanstiehl,
employ the SafeBridge four-band system.
However, several other potent compound
banding systems are used in the pharmaceuticals
industry that differ from SafeBridge in the number
of bands and the limits of each band expressed in
g/m3. It is important to communicate the
referenced banding system when dealing with a
new client. The potency of a compound should
preferably be discussed in terms of g/m3 to
eliminate any ambiguity.
For many novel compounds, the actual potency
has not yet been determined. In these
circumstances, it is important to evaluate the
compound and establish an estimate of its
potency so that preliminary guidance can be
provided to personnel on how to handle the
material safely in areas ranging from laboratories
to shipping departments. It is a recommended
practice that all compounds be assessed for their
potency category before being handled in any way
and a containment strategy established
beforehand for each.
Once the preliminary potency category of a new
compound is established, it will be handled
seamlessly as per the existing site containment
strategy for the selected category. This strategy
should be documented in a site policy or procedure
that establishes the operational practices and the
engineering and administrative controls associated
with each category. Estimates of potency can be
developed by comparison to similar compounds,
NOEL or LOEL data and other means. Guidance
documents exist for this purpose and firms such as
SafeBridge can be employed to develop a
professional opinion of the compounds potency.1,2
As the new product development continues, its
actual toxicological properties will need to be
established at some point. Typical practice is to rely
upon an estimate of potency during the initial
work on a compound, such as drug discovery and
small-scale laboratory synthesis.
The typical time to switch from an estimated to
a measured determination of potency is when a
product moves from pre-clinical to clinical
development. If an evaluation reveals that a
compound falls within one of the potent
categories, additional time and expense will be
incurred in order to handle it properly and safely.
The actual amount of additional time that
should be allotted for the handling of a potent
versus a non-potent compound can vary widely,
depending upon the degree of potency and
quantity of unit operations - and thus the extent of
handling steps involved. Therefore, the usual
ballpark estimate of a 33% increase in time for
potent over non-potent compound handling
should only be employed conceptually, when
specific data are lacking or processing and handling
plans have not yet been developed.
Processing and handling times increase in both
laboratory and plant production, as well as in
analytical laboratories, due to additional
precautions to avoid exposure. These consume
resources and add time including, for example,
gowning and degowning, additional cleaning,
setting up containment equipment and the fact
that handling of materials in an isolator or glove
bag is usually more cumbersome and more time-
consuming than the same operation outside a
contained environment.
Cross-contamination
Another important item that ought to be
considered early in a commercial relationship
involving a potent compound at a CRO or CMO is
the best means to avoid cross-contamination. For
small-scale or early stage work, the best solution is
either to use disposable equipment or to dedicate
equipment such as lab flasks, filters, dryer trays and
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other relatively low cost items to the production in
order to avoid extensive cleaning for reuse on
another project.
The additional cost of dedicating equipment
needs to be considered upfront. As the scale of the
operation increases or the expense of the
equipment involved increases, the client and the
CRO or CMO should both evaluate the need to
develop cleaning procedures and cleaning
verification test methods for shared equipment.
Both cleaning and testing can be more
expensive for potent than non-potent compounds
because the potent compound must be neutralised
and reduced to a negligible amount. The most
typical approach is to employ disposable items
initially where possible and dedicate lab equipment
to a potent compound, then switch to cleaning
verification and/or validation when the product
scale advances to a kilo lab or plant operation.
However, each compound and process differs.
The best practice is if the client and CRO/CMO
discuss the overall long term goals of the project
and estimate the costs associated with preventing
cross-contamination at each stage of development.
Both parties ought to confirm which approach is
the most cost-effective means of addressing the
cross-contamination concern at each stage. This
approach allows for proper planning of the project
and avoids delays arising due to the need to
develop a cleaning procedure and associated
analytical methods or while ordering long lead time
equipment.
The consideration of the potency of a
compound during the initial commercial discussions
is particularly important if a request for proposal
involves a fixed cost bid. A responsible CRO or
CMO ought to broach the subject of a compounds
potency and the potential consequences to cost
and timeline with the client in the initial stages of
the commercial relationship. When the potency is
uncertain, this stage of the commercial relationship
can also be uncertain, which is why it is frequently
advisable to conduct activities on a time and
material basis for very early stage work until the
compound potency is established.
Process hazard analysis & validation
Before proceeding with laboratory- or plant-scale
efforts, a process hazard analysis (PHA) should be
conducted. The complexity of the PHA should be
adjustable based on the scale of the operation and
degree of hazard associated with a particular
process step.
The measured or estimated potency of the
compounds to be handled must be established first
as the presence of a potent compound can
materially affect operational practices and
equipment choices and these also have to be
established for a PHA to be effective. Ideally, a
single PHA would be conducted for each scale of
operation. In practice, some iteration can often
creep into the analysis to optimise the requirements
for product quality, process safety and potent
compound containment
In order to conduct an initial assessment of a
project, all available data regarding the compounds
toxicity and chemical effect should be assessed.
Potent compounds are defined as substances that
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Kilo lab containment at Ferro Pfanstiehl
are effective at doses of 1 mg/kg, and/or have
mutagenic or carcinogenic indications, reproductive
toxicity and poor or no warning properties. This
feasibility study must be done prior to the
manufacturing stage. The information will dictate
the degree to which engineering controls must be
in place.
The information used to make the assessment
include safety data sheets, product use, OEL, short-
term exposure limits, odour threshold, IH
monitoring method and analysis, irritant or
sensitiser, toxicological data, primary toxic effect,
route/mechanism of exposure, warning signs of
exposure, warning signs of exposure, treatment for
exposure, cleaning procedures, acceptable surface
residual levels, deactivation procedures,
flammability/combustibility, applicability of
transportation regulations, waste disposal
consideration and other regulatory impacts. The
key item prior to any manufacturing taking place is
to have an OEL established.
For projects intended to be commercialised, the
need to confirm the potency of the compound in
the early stages is paramount. In general, the
critical process parameters ought to be established
by a risk-based analysis as soon as the process is
sufficiently developed to allow for a reasonable
review. This analysis may need to be repeated if a
compound proves to be potent or more potent
than previously thought and thus enters a more
stringent potency category.
The need for adequate containment and other
issues associated with a potent compound can
affect operational practices and equipment
selection. Critical process parameters and process
validation in general must be established with the
full knowledge of the operational practices and
equipment involved in order to be effective.
Equipment selection
The equipment options available for handling a
potent compound should be dictated by a site
policy or procedure that establishes the
containment strategy associated with each potent
category. For example, a policy of no open
Reprinted from Speciality Chemicals Magazine January 2012
High potency APIs
handling of dry powders with a potency of
Category 3 or higher determines the choice of
contained pressure filter dryer with a continuous
liner for product isolation during discharge over a
centrifuge which discharges wet cake into an open
container.
Another common example is where a standard
lab hood is suitable for a Category 1 compound
but one specially designed for potent compounds
is required for a Category 3 compound. The latter
will have design measures such as a lower face
velocity of 18-24 metres/minute with air introduced
in a non-turbulent fashion, as well as other
measures, to ensure better containment.
A wide variety of potent compound handling
equipment is available, depending on the intended
use and the manufacturer. Most has an advertised
containment level down to 1 g/m3. Specialised
items designed to handle much more potent
compounds, such as isolators, will go lower still.
The containment levels manufacturers advertise are
typically conservative, in our experience, but can be
used as guides for effective containment in the
preliminary stages of process review.
The testing of containment levels with the use of
a surrogate, typically lactose or naproxen sodium,
or with the potent compound itself will usually
reveal a greater degree of containment than the
manufacturer claims. Personal experience indicates
that naproxen sodium can pose a more rigorous
test of containment than lactose. Monitoring
containment with the potent compound itself is
preferred, but this option is not always available
because a compound is new and analytical
methods suitable for industrial hygiene samples
may not yet have been developed.
Demonstrating a statistically significant
containment level requires at least six sampling
events. In practice, it is not always possible to
accomplish this in one session and these
measurements may need to be spread out further.
In this case, a safety factor should be applied to the
measured containment levels to account for the
wider statistical variation associated with a limited
number of samples. It is recommended that more
than one operator be involved in the testing to
account for variations in technique.
It is important to note that these measured
enhanced containment levels are highly dependent
on operational practices. Actual measurements of
containment levels involve both the piece of
equipment and the operational practices. In many
cases, the operational practices can have more
impact than the choice of equipment. For example,
containment booths often demonstrate extremely
low exposures during an operation inside them but
exposures may then increase depending upon how
an operator removes his gloves from the booth or
how degowning is accomplished.
The point is that the established equipment
manufacturers have done a fine job in designing
the equipment to contain potent compounds and
the operational details will probably dictate the
containment levels you experience. Therefore,
extreme caution is recommended in applying a
containment level demonstrated on one potent
compound in a piece of equipment to another,
unless the operational practices and the
 High potency APIs
characteristics of the second potent compound are
essentially identical. Testing with the new
compound is strongly recommended.
Controls
The engineering controls to be employed when
handling a potent compound should be dictated
by a site policy or procedure that establishes the
containment strategy associated with each potent
category. Traditional engineering control
approaches begin with the ventilation, ensuring
that an engineered local exhaust system is effective
to 100 g/m3. Laminar flow hoods may be
effective at 50-100 g/m3, directionalised laminar
flow booths to 50 g/m3.
Closed in-line sampling systems, continuous bag
systems, isolator/glove box technology, split
butterfly valves and rapid transfer ports all ensure a
properly contained system. The greatest risk of
exposure occurs when a high potency compound is
in the solid dry powder form; therefore a lot of
attention is paid to the charging system and drying.
The most commonly overlooked area for exposure
risk is associated with degowning practices.
The administrative controls to be employed
when handling a potent compound, identifying
items such as required personal protective
equipment, gowning and degowning
requirements, cleaning requirements and
procedures, etc., should likewise be dictated by a
site policy or procedure. The point is to have a well
established practice on how to handle a potent
compound and avoid having to make decisions on
a case by case basis. For example, the decision on
how the analytical laboratory handles a 100 ml
sample of a 0.1% solution of a compound is
dictated by the potency category of the
compound.
The use of engineering controls, administrative
controls, and personal protective equipment are
the first line of defence against exposure. Proper
monitoring of the employee and the environment
through industrial hygiene (IH) controls are the
next steps. Whether through direct skin contact
transferred from an exposed surface or from an
airborne particulate or aerosol, a robust IH
programme is critical for protecting employees.
For new equipment, containment capabilities
may be established by IH monitoring using a
surrogate compound and anticipated unit
operations. Once a product considered to be
potent reaches commercial standing, however,
actual IH monitoring of the normal handling of the
material should be established. Then, an IH study
plan will be created, using the actual procedure,
expected step durations and the limit of
quantification determined for the IH cartridges.
Once that plan has been approved by the review
committee, actual monitoring will take place
during the next available production window. An
occupational physician and an industrial hygienist
should be involved in the development and/or
review of the plan.
At least once every three years, the capability
and robustness of the handling procedures for
each potent compound should be challenged by IH
testing and must still meet the maximum threshold
values established for the equipment used
Reprinted from Speciality Chemicals Magazine January 2012
either the incoming or outgoing product for a
given equipment component.
Personal protective equipment used in a down
flow laminar hood
according to a periodic verification programme. If
the procedures do not meet the established limits,
the review committee must conduct a re-evaluation
of the process/product.
As a verification of the effectiveness of IH
controls, a medical monitoring programme is
strongly recommended. A baseline health
assessment is conducted before personnel are
involved with processing potent compounds.
Routine medical exams at least once per year are
conducted to monitor for shifts in health status in
general and to look specifically at potential side
effects associated with the potent compounds
being handled. No evidence of side effects should
exist if the containment practices are adequate.
Cleaning validations
A hallmark component of a proper high potency
manufacturing operations is a proper cleaning
validation programme. Another salient issue that is
discussed in high potency circles is whether or not
to use the same equipment train for potent versus
non-potent compounds.
A proper cleaning validation will consist of
accumulating data from the sampling and analysis
of residues on the wetted surfaces of the
manufacturing equipment. Three consecutive trials
demonstrating acceptable cleanliness is the
minimum standard required to demonstrate
effectiveness of the method for the specified
compound in the specified equipment. The overall
accumulated data from these will be reviewed to
ascertain if the product residue, cleaning agent
residue and microbial levels were consistently
reduced to the appropriate levels.
The first - and all subsequent - cleaning
validation trials will include visual inspection, rinse
residue, residual swab and microbial assessments,
dirty equipment hold time and verifications of
calibration, analytical methods and training records.
The results may suggest that additional measures
are required for subsequent cleaning trials to be
consistently successful. In this event, adding
additional cleaning/rinse cycles, modifying the
solvent system or increasing solvent volumes,
heating the cleaning streams to increase product
solubility, implementing manual scrubbing during
COSA clean-in-place cycles and re-considering the
dedication of equipment components to the
process may be necessary.
The acceptance criteria for visual inspection is
straightforward but the assessment must be
strengthened with adequate lighting and trained
operators, while the acceptable residue swab and
rinse levels for each piece of equipment are
predetermined via maximum allowable carry-over
(MACO) calculations. These can be derived via the
general limit MACO calculation method., which is
used in relation to HPAPIs in which the dosage and
toxicological data have not been developed for
The microbial limit justification involves
examining the specification for the product being
manufactured, the chemistry for a given process
and the effect of microbial contamination on
individual portions of the process equipment. Rinse
residue should be at or below the MACO limit and
the residual swab samples are equal to or less than
the acceptable swab residual target concentrations
established in the MACO calculations.
Calibration verification requires the use of
calibrated instruments. The dirty equipment hold
time can have other implications, tying up
equipment trains that could be used on other
projects. Once a cleaning validation has been
completed, the CRO or CMO could consider
reduced cleaning requirements with periodic
verification of full validation methodologies.
However, reducing routine cleaning requirements
may be too great a risk.
Summary
Potent API manufacturing is not a simple
endeavour and proper consideration to the safety
sphere of containment is prudent. An OEL
assessment is the foundation of a sound
programme, particularly for a CMO, in order to
determine effectively and efficiently the proper
engineering and administrative controls, policies
and procedures and cleaning verifications. Verifying
the effectiveness of the containment control
strategy by an IH monitoring of employees is an
absolute essential ingredient to ensuring a safe
environment for all those involved in the handling
of potent or cytotoxic compounds.

References
1. R.H. Ku, Chemical Health & Safety, Jan-Feb 2000
2. A.W. Adder, R.G. Busman, T.A. Kimmel & R.H. Ku,
Procedures for Determining an Acceptable Daily
Exposure Under Risk-MaPP, Safe Bridge Consultants,
October 2010

Contact
Paul Doherty
Plant Manager
Ferro Pfanstiehl Laboratories
1219 Glen Rock Avenue
Waukegan
IL 60085.
USA
Tel: +1 847 599 5187
Email: dohertyp@ferro.com
Website: www.ferro.com
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