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Preventing cross contamination
Paul Doherty

of potent compounds
Considerations in a multi-product facility

PAUL DOHERTY
Ferro Pfanstiehl Laboratories, 1219 Glen, Rock Avenue, Waukegan, IL 60085, USA

KEYWORDS CONTAMINATION PREVENTION STARTS WITH A

SYSTEM
Potent handling; cross contamination; manufacturing; API.
The key to preventing cross contamination of other products by
ABSTRACT
a potent compound is to establish a robust system for handling
potent compounds before allowing any potent compounds on
This article will touch on the philosophy and methods used
site. Bear in mind that contamination by a potent compound
to prevent cross contamination of a potent compound
could potentially happen throughout the site; from the loading
into other products produced at a multiple product
dock to the production floor to the laboratory. A frequent
facility. The key to preventing cross contamination of
mistake is to focus solely on the production location. Proper
potent compounds into other products is to establish a
measures for handling potent compounds for each area and
site policy and system that establishes the administrative
activity need to be established upfront and communicated to all
and engineering standards, controls and practices for
personnel. The system for handling potent compounds should be
containment of potent compounds. It is important to
22 focus on the entire facility and not just on the production
documented in a site policy or procedure which establishes the
operational practices, engineering controls, and administrative
area when preventing cross contamination. An OEL
controls associated with each potency category. The system
determination or assessment is the foundation of a sound
must be communicated to all site employees and not limited to
program in order to effectively and efficiently determine
only those directly handling potent compounds.
the proper engineering controls, administrative controls,
Pharmaceutical compounds are classified by their toxicity and
policies and procedures and cleaning verifications.
potency as well as their Occupational Exposure Limit (OEL).
Verifying the effectiveness of the containment control
SafeBridge has developed an exposure control banding system
strategy by an Industrial Hygiene monitoring of
to categorize the containment necessary for handling of the
employees is an absolute essential ingredient to ensuring
compound. Many companies, including Ferro Pfanstiehl, employ
a safe environment for all those involved in the handling
of potent or cytotoxic compounds and for verifying that
containment measures are adequate for preventing cross
contamination.

INTRODUCTION

T
he market for high potency Active Pharmaceutical
Ingredient (API) compounds is growing faster than the API
market in general, primarily due to the growth of oncology
drugs.
Because these APIs are in fact potent and a small amount of
compound can have a significant pharmacological impact,
these compounds frequently are produced in very limited annual
volumes.
Therefore, it may be economically impractical to dedicate an
entire facility to the production of a single potent compound
except in cases of unusually high production quantities or in
cases of extremely high potency compounds. In most situations,
potent compounds are manufactured in a facility in which other
compounds are also manufactured.
This article outlines the best means to prevent potent compounds
from contaminating other manufactured compounds.
the SafeBridge four band system.
However, there are several other potent compound banding
systems used in the pharma industry and these differ from the
SafeBridge system in the number of bands and the limits of
each band expressed in g/m3. A category 4 potent denotes a
different level of hazard in different systems.
The site policy on potent compounds should specify the
containment strategy associated with each potency category.
Once a compound is assigned a potency category, the site
policy dictates the engineering controls, administrative controls
and personal protective equipment to be employed when
handling that potent compound. The point of this strategy is to
have a well-established practice on how to handle a potent

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compound and avoid having to make decisions on a case referenced as opposed to simply estimating the cost to clean
by case basis. For example, the decision on how the receiving based on past experience. It is easy to underestimate the cost
department samples an incoming item for Quality Control is to clean equipment after potent manufacturing, particularly
dictated by the potency category of the compound, with a for extreme high potency compounds. The batch size of the
category one compound being treated with fewer precautions product to be manufactured after the potent compound uses
than a category four compound. the equipment can also be critical. The switch from dedicated
For many novel compounds, the actual potency has not yet been equipment should occur only when it is no longer the most
determined. In these circumstances, it is important to evaluate cost effective means of addressing the cross contamination
the compound and establish an estimate of the compound concern. This approach allows for proper planning of the project
potency so that preliminary guidance can be provided to and avoids having project delays due to the need to develop
personnel on how to safely handle the material in areas ranging a cleaning procedure and associated analytical methods or a
from laboratories to shipping departments. It is a recommended delay while ordering long lead time equipment.
practice that all compounds be assessed for potency category Once it is determined that a potent compound will be
before being handled in any way and that a containment manufactured in shared equipment, it is imperative that cleaning
strategy is established beforehand for each potency category. analytical test methods and procedures be developed. At a
Once the preliminary potency category of a new compound is minimum, the analytical methods should be scientifically sound
established, the new compound will be handled seamlessly per or qualified. If the potent compound is a commercial product or
the existing site containment strategy for the selected potency if commercial products are to be produced in the equipment at
category. This strategy should be documented in a site policy any time after the potent compound has used the equipment,
or procedure which establishes the operational practices, the analytical methods used to verify the equipment is clean must
engineering controls, and administrative controls associated with be validated and the cleaning procedures must be validated.
each potency category. Estimates of potency can be developed A proper cleaning validation will consist of accumulating data
from comparison to similar compounds, No Observable Effect obtained from the sampling and analysis of residues on the
Level (NOEL) or Lowest Observable Effect Level (LOEL) data, and wetted surfaces of the manufacturing equipment. At a minimum,
other means. Guidance documents exist (1, 2) for this purpose three consecutive trials demonstrating acceptable cleanliness
and firms such as SafeBridge can be employed to develop a is the standard required to demonstrate effectiveness of the
professional opinion of the compounds potency. As the new method for the specified compound in the specified equipment.
product development continues, the actual toxicological The overall accumulated data of the three cleaning trials will
properties of the compound will need to be established at some be reviewed to ascertain if the product residue, cleaning agent
point. Typical practice is to rely upon an estimate of compound residue, and microbial levels were consistently reduced to the
potency during the initial work on a compound such as drug appropriate levels.
discovery and small scale lab synthesis. The typical time to The first and all subsequent, cleaning validation trials will include:
switch from an estimated to a measured determination of actual visual inspection assessment, rinse residue assessment, residual
compound potency is when a product moves from pre-clinical swab assessment, microbial assessment, dirty equipment hold
to clinical development. time, calibration verification, verification of analytical method 23
validation, and training record verification. Until three consecutive
successful cleaning trials are executed, the cleaning procedure
PREVENTING CROSS CONTAMINATION FROM cannot be considered validated. The results from the first cleaning
SHARED EQUIPMENT trial may suggest that additional measures are required in order
for subsequent cleaning trials to be consistently successful.
For small scale or early stage work with a potent compound, the
best solution is to either consider use of disposable equipment,
or to dedicate equipment such as lab flasks, filters, dryer trays
and other relatively low cost items to the production in order
to avoid extensive cleaning of the equipment and testing to
verify that the equipment is clean enough for reuse on another
project. The additional cost of dedicating this equipment
needs to be considered upfront and compared to the cost of
cleaning and developing test methods to verify the equipment
is adequately cleaned. As the scale of the potent compound
operation increases or the expense of the equipment involved in
potent compound processing increases, the organization should
be evaluating the need to develop cleaning procedures and
cleaning verification test methods for shared equipment.
Both cleaning and testing of potent compounds can be
expensive in comparison to non-potent compounds because
the potent compound must be neutralized and reduced to a
negligible amount. The most typical approach is to initially employ
disposable items where possible and dedicate lab equipment to
a potent compound and 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 organization evaluates the overall long
term goals of the project and estimates the costs associated with
preventing cross contamination at each stage of the products
development. To accurately calculate the costs associated with
cleaning shared equipment, it is strongly recommended that the
actual Maximum Allowable Carry Over (MACO) calculations be

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 In this event, adding additional cleaning/rinse cycles, modifying
the solvent system utilized, heating the cleaning streams to
increase product solubility, implementing manual scrubbing,
increasing the quantities of solvent utilized, and re-considering
dedication of equipment components to the process may be
necessary.
The cleaning acceptance criterion for visual inspection is
straightforward but the assessment must be strengthened with
adequate lighting and trained operators. The acceptable
residue swab and rinse levels for each piece of equipment are
predetermined via Maximum Allowable Carry Over (MACO)
calculations. The details of these calculations are beyond the
scope of this article. There are three most common types of
MACO calculations, each tailored for specific rational and
information available. The three MACO calculation types are:
1. Dosage MACO - based on a normal therapeutic dose of
Product A (previous), the maximum daily dose of Product B
(next) and the minimum batch size of Product B (next).
2. Toxicology MACO - based on toxicological information (LD50
or OEL) of product A (previous), normal daily dose of Product
B (next), safety factors based on if Product B is administered
topically, orally or parenterally, and minimum batch size of
Product B (next).
3. General Limit MACO typically based on an assumed 10
ppm limit. Use of the general limit MACO should only be used
when no data yet exists and such use should be justified or
explained.
The MACO limits established above are used to calculate
Acceptable Swab Residue and Acceptable Rinse Residue
limits.
PREVENTING CROSS CONTAMINATION FROM
SHARED FACILITIES
24
In addition to preventing cross contamination from shared
equipment, it is imperative that cross contamination from the
processing environment be prevented. For the most part, the
measures employed to protect employees from exposure to
potent compounds also function to prevent cross contamination
of potent compounds into other products.
Monographic supplement series: CROs/CMOs - chimica oggi/Chemistry Today - vol. 30 n. 4 Jul/Aug 2012
For example, the use of gowning / degowning rooms and the
use of air balancing to contain potent compounds in a specific
area simultaneously protects personnel in other areas from
exposure and prevents contamination of products in other areas.
Equipment designs, engineering controls and administrative
controls designed to contain potent compounds for personnel
safety also prevent cross contamination. Containment of the
potent compound is key.
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 potency category. For example, a policy of no open
handling of dry powders with a potency of category three or
higher determines the choice of product isolation equipment
in favour of a contained pressure filter dryer with a continuous
liner for product discharge as opposed to a centrifuge which
discharges wet cake into an open container. Another common
example is that a standard lab hood is suitable for a category
one compound but a lab hood specially designed for potent
compounds is required for a category three compound. The
lab hood designed for handling potent samples will have design
measures such as a lower face velocity of 60-80 feet per minute
with air introduced in a non-turbulent fashion, as well as other
measures, to better ensure containment of the compound.
With a wide variety of equipment available depending on the
intended use and the manufacturer, the majority of potent
compound handling equipment has an advertised containment
level down to 1 g/m3. Specialized items designed to handle
much more potent compounds, such as isolators, will have
advertised containment levels which are lower than 1 g/m3. The
advertised containment levels from manufacturers are typically
conservative, in our experience, but can be used as guides for
effective containment in the preliminary stages of process review.
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 does lactose
because naproxen sodium tends to be dustier and has more
challenging electrostatic properties. When feasible, monitoring
containment with the potent compound itself is preferred. This
option is not always available because a compound is new
and analytical methods suitable for industrial hygiene samples
have not yet been developed. Demonstration of a statistically
significant containment level requires at least six sampling events.
In practice, it is not always possible to accomplish six sampling
events in one session and these measurements may need to be
spread out over a number of opportunities. 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 be more impactful
than the choice of equipment. For example, it is not uncommon
for a containment booth to demonstrate extremely low exposures
during an operation inside the booth but have exposures
increase depending upon how an operator removes their gloves
from the booth or how degowning is accomplished. The point
the established equipment manufacturers have done a fine job
in designing the equipment to contain potent compounds and
the operational details will likely 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 compound in that same
piece of equipment unless the operational practices and the
characteristics of the second potent compound are essentially
identical. Testing of containment levels with the new potent
compound is strongly recommended.
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
potency 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 between 50 to 100 g/m3 and directionalized
laminar flow booths may be effective to 50 g/m3. Closed in-
line sampling systems, continuous bag systems, isolator/glove
box technology, split butterfly valves, and rapid transfer ports all
perform the duty of ensuring 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 should be dictated by a site policy or
procedure that establishes the containment strategy associated
with each potency category. Administrative controls would
identify items such as required personal protective equipment,
gowning and degowning requirements, cleaning requirements
and procedures, and so on. The point of this practice 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 percent solution of a compound is
dictated by the potency category of the compound, with a
category two compound being treated with fewer precautions
than a category four compound.
Monographic supplement series: CROs/CMOs - chimica oggi/Chemistry Today - vol. 30 n. 4 Jul/Aug 2012
A potent compound manufacturer ought to have an Industrial
Hygiene (IH) program that includes monitoring to ensure that the
containment measures put in place are adequate for protecting
personnel. IH monitoring tests whether the containment
measures are adequate or not and benefits both employee
health concerns and prevention of cross contamination. A
proper IH monitoring program verifies that the expected level of
containment is being achieved.
SUMMARY
In summary, potent API manufacturing is frequently conducted
in facilities that produce multiple products. The key to preventing
cross contamination of potent compounds into other products
is to establish a site policy and system that establishes the
administrative and engineering standards, controls and
practices for containment of potent compounds. It is important
to focus on the entire facility and not just on the production area
when preventing cross contamination. An OEL determination
or assessment is the foundation of a sound program in order
to effectively and efficiently determine the proper engineering
controls, administrative controls, policies and procedures
and cleaning verifications. Verifying the effectiveness of the
containment control strategy by an Industrial Hygiene 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 and for verifying that containment
measures are adequate for preventing cross contamination.
REFERENCES AND NOTES
1. R.H. Ku, Chemical Health & Safety, January/February (2000).
2. A.W. Adder, R.G. Busman et al., Procedures for determining an
Acceptable Daily Exposure (ADE) under Risk-MaPP., Safe Bridge
25
Consultants, Inc., October (2010).