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This article
presents a The Use of Acceptable Daily Exposures
convincing
justification (ADEs) for Managing the Risk of Cross
for the use of
Acceptable Contamination in Pharmaceutical
Daily Exposures
(ADEs) to
scientifically
Manufacturing
manage the
risk of cross by Stephanie Wilkins and Julian Wilkins
contamination in
all types of bio/
pharmaceutical
facilities.
Introduction
I
of quality risk management as stated in ICH
SPEs Risk-MaPP Baseline Guide has Q94is that the evaluation of the risk to quality
brought the term ADE to the forefront for should be based on scientific knowledge and
the management of cross contamination in ultimately link to the protection of the patient.
pharmaceutical manufacturing facilities. Companies are realizing this principle by in-
ADE refers to an acceptable daily exposure corporating the ADE into the companys risk
which is defined as a daily dose of a substance management program.
below which no adverse effects are expected by
any route, even if exposure occurs for a lifetime.1 Cleaning and Cleaning Validation
By this definition, the ADE is a conservative Retention is where product residue is left behind
value and is protective of all populations (in- on product contact parts of equipment. The
cluding infants, elderly, ill, etc.) by any route potential carry-over of the retained residue to
of administration. the next product can be a major source of cross
Once an ADE has been established for a contamination. The purpose of cleaning and
compound, this value can be used to set lim- cleaning validation is to minimize this source
its for cleaning validation (rinse and swab) of potential cross contamination so that there
limits and cross contamination limits. ADEs will be no adverse effects to the patient.
are established by qualified toxicologists who Traditionally, cleaning validation limits have
reference all safety data for the compound in been based on either not more than 1/1000th
question to set the various factors needed in of a therapeutic dose or 10 ppm of the previ-
the calculation of the ADE. The safety data can ous product in the maximum daily dose of the
include data generated from clinical trials used subsequent product and typically firms will
to support drug applications, package inserts use the lower of the two values. While these
for commercial products, and various resources methods were the best information at the time
that provide information on drug safety such of their inception (early 90s), they do not take
as PubMed.2 For a more detailed understand- into account the potential harm to the patient.5
ing of how ADEs are established, refer to the The therapeutic dose by definition is an amount
Risk Identification section of the Risk-MaPP that provides an effect to the patient, not a safe
Baseline Guide. level for anyone. Using a safety factor of 1000
Although the term ADE3 is fairly new, sev- has not been scientifically proven to equate to
eral companies have been using health-based a no adverse effect level for all compounds. The
limits for a while and many companies are now 10 ppm limit is not correlated to the safety of
getting ADEs developed so that their cross con- the product at all. The 1/1000th of therapeutic
tamination risk management program is based dose or 10 ppm methods are not linked to
on scientific data linked to the protection of the patient safety and therefore are not scientific
patient. Note that one of the primary principles based methods for setting the cleaning limits.