Organic Process Research & Development 2010, 14, 943–945
Letters to the Editor
A Tool for the Semiquantitative Assessment of Potentially
Genotoxic Impurity (PGI) Carryover into API Using
Physicochemical Parameters and Process Conditions
Table 1. Physicochemical parameters and associated
standard purge factors
physicochemical
parameters
purge factors
reactivity
highly reactive ) 100
Introduction
moderately reactive ) 10
low reactivity/unreactive ) 1
freely soluble ) 10
The threat posed by genotoxic impurities (GIs) in drug
substances generally arises from the use of electrophilic agents
(alkylating agents) within the synthesis. Such reagents are used
in the buildup of the molecular structure through carbon-carbon
and carbon-nitrogen bond formation, and their use is essentially
ubiquitous, given the current methodology available to the
synthetic chemist. This suggests that any synthetic drug therefore
possesses a latent GI-related risk. Yet this is a very simplistic
assessment that fails to take into account the inherently reactive
nature of the agent of concern and its likely fate in the
manufacturing process downstream of its point of introduction.
It is a paradox that the very reactivity that renders the agent a
concern from a safety perspective is the same property that will
generally ensure its effective removal in the downstream
process.
solubilitya
volatility
moderately soluble ) 3
sparingly soluble ) 1
boiling point >20 °C below that of the
reaction/process solvent ) 10
boiling point (10 °C that of the
reaction/process solvent ) 3
boiling point >20 °C above that of the
reaction/process solvent ) 1
ionisation potential of GI significantly
different to that of the desired
productb
ionisability
physical processes - chromatography - GI elutes prior to
chromatography
desired product ) 100
chromatography - GI elutes after
desired product ) 10
others, evaluated on an individual basis
Since the advent of the EMEA Guideline (EMEA/CHMP/
QWP/251344/2006) covering the control of GIs, regulatory
authorities have demanded proof that any GI is controlled in
line with limits expressed in the guideline and its Q&A
supplement (EMEA/CHMP/SWP/431994/2007 Revision 2).
Such proof has generally taken the form of extensive analytical
data; chemical-based arguments alone have often proved to be
unacceptable despite, in many cases, the compelling nature of
the assessment concerned. A significant amount of effort has
therefore been expended in many cases ‘to prove a negative’.
The challenge is therefore to develop an approach that allows
the likelihood of potential carryover of a GI to be assessed
before exhaustive analytical testing is performed. Pierson et al1
sought to examine this on the basis of the number of
manufacturing stages away from the final product the agent is
introduced. Such an approach, although useful, is empirical and
may only partially eliminate regulatory concerns. AstraZeneca
presents a tool developed to bring a degree of quantitation into
the PGI fate assessment. This is based on the principle of
assessing key physicochemical properties of the agent of
concern, relating them to the downstream processing conditions
through the application of a standard system of scoring them
to establish a ‘purge factor’. This has been applied to a number
of processes for which data was already available, and has
exceeded our expectations in its robustness to date; a case study
example is included below.
a This relates to solubility within the context of a recrystallisation process
whereby the impurity in question, if highly soluble, will remain within mother
liquors and hence be purged from the desired product. b This relates to a deliberate
attempt to partition the desired product/GI between an aqueous and organic layer,
typically achieved through the manipulation of pH to change the ionised/unionized
state of one of the components.
the solubility term relates to the solubility of the GI in question
in the solvent system used during the isolation (crystallisation)
of the desired product. For each of these terms a score is
assigned on the basis of the physicochemical properties of the
GI relative to the process conditions. These are then simply
multiplied together to determine a ‘purge factor’ for each stage
of the process. The overall purge factor is a multiple of the
factors for individual stages. The values assigned are illustrated
in Table 1.
Case Study
To illustrate the effectiveness of such an approach a case
study is provided. This illustrates both the outcome of the
predictive purge factor and the real measured values. The
synthetic scheme for the process concerned is presented in
Figure 1. The PGIs concerned are the AZD9056 aldehyde,
AZD9056 chloride, and isopropyl chloride.
Theoretical Purge Factors
For each of the three identified potentially genotoxic impuri-
ties (PGIs) a theoretical purge factor was calculated. Details of
the factors and their derivation are described in Table 2.
Methodology
The following key factors were defined in order to assess
the potential carry-over of a GI: reactivity, solubility, volatility,
ionisability, and any additional physical process designed to
eliminate impurities such as chromatography. For clarification,
Measured Purge Factors
For each of the three impurities experimental purge factors
were determined; these are recorded in Table 2.
In the case of AZD9056 aldehyde, this was achieved through
tracking the residual level at successive stages. A comparison
(1) Pierson; et al. Org. Process Res. DeV. 2009, 13 (2), 285–291.
10.1021/op100071n 2010 American Chemical Society
Published on Web 03/24/2010
Vol. 14, No. 4, 2010 / Organic Process Research & Development
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Teasdale, Andrew
