Risk Assessment
Reduced-Method Robustness
Testing of Analytical Methods
Driven by a Risk-Based Approach
Phil Borman, Marion Chatfield, Patrick Jackson, Alice Laures, and George Okafo
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AUTHORS
Factors: A1 , A2 … An
This paper describes a novel approach for
assessing method robustness that uses risk-based
assessment tools to identify, score, prioritize,
and group method parameters. The authors
evaluated these parameters using reduced
fractional factorial designs (i.e., reduced-method
robustness) to evaluate the suitability of analytical
methods before full validation. The authors’
approach helped to identify high-risk method
parameters earlier in the development process,
thereby offering potential resource savings.
Phil Borman* is a manager in analytical sciences/
chemical development, Marion Chatfield is a
manager in statistical sciences, Patrick Jackson is
an analytical chemist in analytical sciences/chemical
development, Alice Laures is an analytical chemist
in analytical sciences/chemical development, and
George Okafo is a manager in scinovo/preclinical
develoment, all at GlaxoSmithKline in the United
Kingdom, tel. +44 1438 763713, phil.j.borman@gsk.com.
*To whom all correspondence should be addressed.
Submitted: Apr 15, 2009. Accepted: May 29, 2009.
Editor’s Note: This article is being simultaneously published
in Pharmaceutical Technology Europe, with an expanded
version available at PharmTech.com/RMR.
72 Pharmaceutical Technology APRIL 2010
he development of robust and rugged analytical meth-
ods is a vital part of the drug-development process (1,
2). It is essential to ensure that levels of critical quality
attributes (CQAs) present in batches of drug substance
or drug product are accurately and precisely quantified, thus
assuring patient safety. This paper, in particular, focuses on
low-level impurities in a starting material used in the manu-
facture of an active pharmaceutical ingredient (API).
The benefits of using reliable methods in a manufactur-
ing environment can be measured in terms of reduced pro-
cess downtime and reduced overall costs (3). In most cases,
the number of atypical results and method incidents will be
minimized. Furthermore, robust analytical methods form a
key part of the control strategy in quality-by-design (QbD)
manufacturing (4, 5).
The goal of robustness testing is to evaluate the effect of
small deliberate changes in method parameters (e.g., tem-
perature, or percentage of organic modifier and pH of the
mobile phase, which are internal to the written method) on
the qualitative and quantitative abilities of the method. Rug-
gedness testing, however, evaluates whether noise factors (e.g.,
different analysts, instruments, or lots of reagents, which are
external to the written method) have an effect on the meth-
od’s reproducibility (4, 6).
A design-of-experiment (DoE) approach has been used for
analytical work—in particular, for determining robustness
of analytical methods—for more than three decades. Tradi-
tionally, the validation of analytical methods in late-phase
development has called for robustness testing to be one of
the last performed activities, after evaluating characteristics
such as specificity, linearity, range, accuracy, precision, and
sensitivity. Although this is the standard approach accord-
ing to the literature and to the International Conference on
Harmonization’s Q2 Validation of Analytical Procedures: Text
and Methodology guideline, there are some associated risks (7,
8). For instance, the identification of method parameters can
give rise to nonrobust behavior, thus leading to poor method
performance that may not be discovered until the end of the
validation study. Moreover, if there is a need to redevelop
any part of the method, it is likely that the entire validation
Pp h a r mTe
mtech.com
Risk Assessment
exercise would need to be repeated. In the time-constrained
environment of drug development where speed to market is
an important criterion of success, delays of this type could
be costly (9).
A DoE approach is not always used in the development of
analytical methods (10). Systematic approaches using high-
performance liquid chromatogrpahy (HPLC), which involve
the scouting of key components of a HPLC method (e.g., col-
umn, pH, and organic modifiers), are often used (11). A DoE
approach can be used to further optimize method conditions
resulting from such scouting work, but this approach may not
always be required. Until robustness testing is performed, the
effects of method parameters that have not been studied as
part of method development will remain unknown. There-
fore, it is desirable to check robustness for such methods in
advance of final method validation.
QbD involves identifying the riskiest parameters that can
affect method performance (4). Risk-assessment tools such
as fishbone diagrams, failure mode and effects analysis, and
prioritization matrices can help identify these parameters
(12, 13). Scientific knowledge, past experience, and judge-
ment must also be applied to identify, score, and prioritize a
method’s risk parameters.
The use of a risk-based approach to decide which param-
eters should be studied in a robustness exercise has been well
documented (4). The authors used a variant of the prioritiza-
tion matrix to rank method parameters in order of their likely
impact on key method responses (e.g., resolution of a critical
peak pair and sensitivity to detect a key impurity). The risk-
assessment data was used to construct a reduced form of a
fractional factorial design, or a reduced-method robustness
(RMR) design.
The RMR approach
Robustness studies typically use fractional factorial designs,
or in some cases, Placket Burman designs, to meet validation
requirements (14). These designs help to estimate the effects of
individual method parameters and all their interactions with
each other (15, 16). Each parameter is varied over two levels: high
(Level + 1) and low (Level — 1). The two levels of each param-
eter are then systematically combined to create the set of ex-
periments. Full two-level factorial designs permit estimation
of the effect of individual parameters and their interactions.
Although the maximum amount of information is obtained,
full factorial designs are not practical because of the elevated
number of experiments required. In fractional factorial de-
signs, only a portion of the full design is studied, thus decreas-
ing the overall number of experiments required as well as
the statistical resolution because not all the single parameter
effects or interactions are estimated independently.
It is desirable to further reduce the number of experiments
used for two reasons:
• To enable the use of such studies to provide an early indi-
cation of robustness and a direction for further method
improvement (if required)
74 Pharmaceutical Technology APRIL 2010
• To most effectively use resources for the demonstration
of robustness.
The number of experiments in fractional factorial designs
can be reduced in two ways, which can be combined:
• Reduce the number of factors
• Reduce the statistical resolution of the design.
A demonstration of how many experiments are required for
various factors and for different statistical resolutions is avail-
able in the expanded, online version of this article (Pharm-
Tech.com/RMR).
Reducing the number of factors
Before building the statistical design, a risk assessment is
performed to help determine whether the number of factors
and the resolution of the design can be reduced. A prioritiza-
tion matrix tabulates method parameters and method-per-
formance characteristics and assesses and scores the effect
of each parameter on these characteristics. Different scoring
scales can be used. For the purposes of this article, the authors
used the following scale: 1=very low impact, 3=slight impact,
5=possible impact, 7=likely impact, and 9=strong impact.
The scores for each method parameter are added together
to provide an importance score, which is used to rank each
parameter with respect to risk.
The outcome of this prioritization exercise determines
whether any method parameters can be removed from the
design, combined with other parameters, or should be in-
cluded as a single factor. It also helps identify appropriate
design resolution. The following case study offers an example
of a prioritization matrix.
The acceptability of removing a parameter partly depends
on whether it is an early or final robustness assessment. If
doubts remain as to whether or not a parameter should be
removed, the parameter can be combined with other low-risk
parameters in order to determine whether these parameters
studied together produce an effect (e.g., instrument-related
parameters with narrow ranges).
Combining parameters is a very efficient way of reduc-
ing the number of experiments to be performed, but cau-
tion is required. When two or more parameters are com-
bined, they will be studied at the same level in the design.
For example, whenever parameter A is set to Level + 1, pa-
rameter B will also be set to Level + 1. And whenever pa-
rameter A is set to Level — 1, parameter B will also be set
to Level — 1. Scientific judgement, therefore, must be used
when allocating combinations to ensure that the effects of
the parameters do not cancel each other out. If, for instance,
increasing the pH increases the resolution and the effect of
the percent organic on the resolution is unknown, it is un-
wise to group pH with percent organic in case increasing the
percent organic decreases the resolution. As a general rule,
parameters can be combined if they have the same type of
effect (e.g., if increasing the pH and the percent organic will
increase the resolution) or if they affect different method-
performance characteristics. Categorical parameters (e.g., col-
P h a r mTe c h . c o m
Risk Assessment

Least resource intensive, lowest resolution

Scoping. *This corresponds to the most limited form of RMR. Typically, four experiments make up
4 Scoping
a scoping study, two center points and two extreme sets of conditions.

8 2 lll7-4 Resolution III. Indicates that main effects may be aliased with two factor interactions. (1+2=3)
Might require further experimentation.

16 2 lV7-3 A resolution-IV design indicates that main effects may be aliased with three factor interactions.
Runs

And two-factor interactions may be aliased with other two-factor interactions. (2+2=4)

32 2 lV7-2 All the main effects will be clear of two-factor interactions.

64 2 Vll7-1 Resolution V or higher (7 in this case) designs. Assuming that no three-factor (and higher)
interactions occur; all the main effects and two-factor interactions can be estimated. (2+3=5)

128 2
7 Full design. All the main effects and interactions can be estimated.
Not really practical for analytical methods due to the number of experiments to be performed.

Most resource intensive, highest resolution

Figure 1: Statistical resolutions available for a 7-factor design and scoping experiment. RMR is reduced-method robustness.

umn batch and column age) can also be combined. Although,
the effect of these parameters is often the hardest to predict.
Studies using these concepts have been termed RMR because
they do not investigate all method parameters separately. The
parameters with the highest risk are included as single factors
in the design.
Reducing the statistical resolution of the design
Reducing the statistical resolution of the design is another way
to decrease the number of experiments required. Reducing
the resolution means that not all of the terms (single param-
eters or interactions) are estimated independently. As a result,
some terms are aliased (statistically combined), wherein the
estimated effect is the combination of the true effect of each
of the aliased terms. Depending on the number of factors
included, several resolutions may be available (see Figure 1).
In Design Expert (R) 7.1 software, or DX7 (Stat-Ease, Min-
nesota), statistical resolution is indicated by colors and no-
tation. In the notation 2k-p, 2 indicates that the design is a
2-level fractional factorial design; k represents the number
The most limited form of RMR is a scoping study (17, 18).
Typically, four experiments make up a scoping study: two
center points and two extreme sets of conditions. At one ex-
treme, the parameters are set to their chosen levels (Level + 1
or — 1) which, for all parameters together, form the condition
most likely to produce that extreme response. At the other
extreme, the parameters are set to their alternative level. The
extremes depend on prior knowledge of the parameters and
are not necessarily set at all the low and high settings—similar
to that described earlier with respect to the effect of pH and
percent organic on the resolution. The center points repre-
sent the nominal method conditions and give an indication
of repeatability; the extremes are thought to lead to the lowest
and highest expected results. Scoping experiments are often
used to check the repeatability and experimental design space
(i.e., assessment of whether the factor range settings are ap-
propriate) before committing resources to a more detailed
study. A scoping study is extremely unlikely to be suitable for
determining robustness of most analytical methods.
For RMR, a resolution-III design is most often used. Al-
ALL FIGURES ARE COURTESY OF THE AUTHORS

of factors, and p is the fraction exponent. Suppose there are
seven factors (k=7):
• When p=0, 2k is a full design and corresponds to 27, which
equals 128 experiments (runs)
• When p=1, the notation corresponds to a fractional de-
sign of 2-1, which equals 0.5. The design is cut in half,
which equates to 27-1 to 64 experiments (runs)
• When p=2, the notation also corresponds to a fractional
design of 2-2 , which equals 0.25 or a quarter of the full
design. This equates to 27-2 or 32 experiments (runs). And
so on.
76 Pharmaceutical Technology APRIL 2010
though this design does not allow direct estimation of in-
teractions, it tests the entire design space. In addition, if an
important interaction exists, it will generally be identified
even though more experiments (e.g., by “folding over” the
design) may be required to clarify whether it is the interaction
or an aliased main effect. As robustness is tested, few, if any,
significant effects are expected, which reduces the likelihood
of needing to clarify aliases. Scientific judgement can be used
to assign the likely main effect or interaction. In addition, if
an interaction exists, usually one, if not both, of the main ef-
fects will also be demonstrated (i.e., there will be hierarchical
P h a r mTe c h . c o m
Risk Assessment
evidence). Within each category
Table I: Example of resolution and aliasing considerations.
of resolution, the extent of the
aliasing increases as the number Effect Design A*: 7 factors, 16 Design B*: 7 factors, 8 runs, Design C*: 6 factors, 8 runs,
runs, res IV res III res III
of experiments is reduced. In
addition to accepting a higher Aliases** Aliases** Aliases**
degree of aliasing, careful alloca- A BD,CE,FG BD, CE
tion of parameters, or groups of B AD,CF,EG AD, CF
parameters, to each main factor C AE,BF,DG AE, BF
(denoted by a letter in DX7) can D AB,CG,EF AB, EF
assist with retaining separation of
E AC,BG,DF AC, DF
important effects.
F AG,BC,DE BC, DE
Consider a specific example in
which there are seven parameters Not used
(parameter
to evaluate and there is some risk G AF,BE,CD
grouped with
of an interaction between two pa- Allocate G
one above)
to lowest-
rameters here allocated to Factors
Allocate risk
A and F. Ideally, the design would B,D,E,G to parameter
estimate AF separately from the AF BG, DE lower-risk G,BE,CD BE, CD
main effects. Table I illustrates parameters
some considerations and choices than C
to be made for a specific example * Ignoring center points; res is resolution.
** Main effects or 2-factor interactions.
as follows:
• Design A is a resolution-IV
design that separates all main effects from two fac- lating to cause of effects and any additional experimenta-
tor interactions, but requires 16 runs (ignoring center tion (e.g., folding over the original design) required to de-
points). alias effects or separate effects of grouped parameters.
• Design B is a resolution-III design, meaning AF will be
aliased with a main effect, but only requires eight runs. If Case study: The application of RMR to a gas
this design is used, AF should be aliased with the lowest chromatographic–flame ionization detection analysis
risk parameter (letter G in this case). A gas chromatographic (GC) method with flame ioniza-
• If it is appropriate to group two parameters, this leads to tion detection (FID) for the analysis of a starting material
six factors and design C which, despite being resolution (N-acetyl piperazine, NAP) had been observed in the past to
III, does separate out AF from main effects. produce variable results; the cause for this variation, however,
If no two parameter interactions are of particular risk, then was unknown. Therefore, it was deemed necessary to conduct
design B rather than design C should be used because there robustness testing to identify and control any parameters that
would only be disadvantages from grouping parameters. might responsible for the variation. Robustness testing was
The literature suggests the use of supersaturated designs, planned and conducted using the RMR principals outlined
that is, designs where the number of main effects exceeds the above. Details of the chromatographic conditions and a typi-
number of runs, in process development (19). This approach cal sample chromatogram are shown in the expanded, online
is a group-factor screening-type design. Risk assessment version of this article.
combined with scientific understanding is used to provide Parameter risk assessment and prioritization. Parameters for the
the grouping scheme, an aspect that Lin suggests is seldom method were brainstormed and categorized on a fishbone
discussed, but crucial (20). Although supersaturated designs using mind-mapping software (see the expanded online ver-
have been suggested for analytical methods,these focus on sion of this article for a demonstration). The fishbone catego-
designs, which have factors partially correlated in the design ries were as follows: equipment, environment, measurement,
rather than using grouping (21, 22). Consequently, the sta- method, materials, and people. The parameters were given a
tistical analysis is not straightforward and Dejaegher and variable classification of C, N, or X as described by Borman
Heyden even suggest it should not be used for estimating et al (4). The X (experimental) parameters are the parameters
effects in analytical method robustness testing (22). Although that will be considered for inclusion in the robustness study.
there may be situations where those designs are useful, the These include instrumental parameters such as flow rate and
approach of grouping factors used in this paper has the fol- temperature, which are given a set point in the method, but
lowing advantages: will vary in line with the precision of the instrument. These
• Easy for analysts to use existing knowledge of fractional parameters could also be related to the sample preparation
factorial design and software (e.g., heating of NAP or sonication time) where variability
• Careful grouping of parameters reduces ambiguities re- is derived from how the operator follows the method proce-
78 Pharmaceutical Technology APRIL 2010 P h a r mTe c h . c o m
Risk Assessment
Table II: Risk-scoring of X parameters and RMR decision based on risk-scoring for GC–FID method parameters.
Method Resolution % area % area % Area LOQ RT imp C RT NAP Importance RMR Range in RMR
characteristic imp A to imp A imp B imp C score strategy study
in columns/ imp B
Parameters in rows
Type of liner 5 9 9 9 5 1 1 39 Single A or B
Initial oven temperature 9 5 5 5 3 5 5 37 Group 1 137–143 °C
Temperature program 9 3 3 3 5 5 5 33 Single 28–32 °C/min
(gradient)
Injection 1 7 7 7 5 1 1 29 Group 4 240–260 °C
temperature
Final oven temperature 1 1 1 1 5 9 9 27 Group 2 235–245 °C
Split ratio 3 5 5 5 5 1 1 25 Group 2 1:13–1:17
Split time 3 5 5 5 5 1 1 25 Excluded n/a
Column flow 3 5 5 5 5 1 1 25 Group 3 1.0–1.4 mL/min
Age 7 3 3 3 5 1 1 23 Group 5 Used or new
(analytical column)
Column loading 3 3 3 3 9 1 1 23 Group 3 0.2–2 uL
Heating time 1 5 5 5 5 1 1 23 Separate n/a
(no sonication) study
Heat and 1 5 5 5 5 1 1 23 Separate n/a
sonication time study
Reheating sample 1 5 5 5 5 1 1 23 Separate n/a
study
Sample size for 1 5 5 5 1 1 1 19 Separate n/a
melting in sonic bath study
Batch 3 1 1 1 3 1 1 11 Group 5 X or Y
(analytical column)
Final oven hold time 1 1 1 1 1 5 1 11 Group 3 3–5 min
Injection speed 1 1 1 1 1 1 1 7 Excluded n/a
Temperature (detector) 1 1 1 1 1 1 1 7 Group 1 270–290 °C
Initial oven hold 1 1 1 1 1 1 1 7 Group 4 3–5 min
RMR is reduced-method robustness; GC is gas chromatographic; FID is flame-ionization detection; imp is impurity; LOQ is limit of quantitation; RT is retention time; NAP is N=acetyl
piperazine.

dure. To establish which parameters were most important to

the method, GC experts scored and prioritized the X param-
eters using a prioritization matrix. The method characteris- [A] = A + BD + CE + FG + BCG + BEF + CDF + DEG
tics were: resolution of impurity A and impurity B, % area [B] = B + AD + CF + EG + ACG + AEF + CDE + DFG
impurity A, % area impurity B, % area impurity C, limit of [C] = C + AE + BF + DG + ABG + ADF + BDE + EFG
quantitation (LOQ), retention time (RT) for impurity C, and
[D] = D + AB + CG + EF + ACF + AEG + BCE + BFG
RT for NAP. Each parameter was assigned a score between
1 and 9 for each method characteristic, as described in the [E] = E + AC + BG + DF + ABF + ADG + BCD + CFG
RMR section above, and the overall importance score was [F] = F + AG + BC + DE + ABE + ACD + BDG + CEG
calculated (see Table II) [G] = G + AF + BE + CD + ABC + ADE + BDF + CEF
Parameters were grouped primarily based on their level
of risk or ability to affect different responses. This approach
Figure 2: Alias list for seven factors in a resolution-III design.
provides for a simpler data analysis because there is less am-
biguity around assigning significant factors. possible to determine which of the two parameters is respon-
Parameters such as column flow and column loading af- sible for any effect observed (only the total effect, and whether
fect signal-to-noise ratio and are in the same group. Because it is large enough to cause concern, can be assessed).
the direction of their effects was thought to be the same, this The single factors are high-risk factors that cannot be easily
combination was deemed acceptable. It will, however, be im- combined with other factors. The excluded factors are those
80 Pharmaceutical Technology APRIL 2010 P h a r mTe c h . c o m
Risk Assessment
Table III: Allocation of factors. ration factors study, compared with 32: 19 parameter resolu-
tion III design, or 40, in which sample preparation is usually
Parameters Risk Allocated factors
evaluated separately, ignoring center points. The expanded
Type of liner High C online version of this article demonstrates this point.
Temperature gradient High F In a resolution-III study, the two-factor interactions are
Group 1 High G aliased with single factors. Therefore, it is important to al-
Group 4 Medium E locate the factors carefully to minimize the confusion this
Group 3 Low A can cause during the analysis of the study if the factor is seen
to have an effect. It is advisable to review the alias list before
Group 2 Low B
finalizing the design and to assess whether the two-factor
Group 5 Low D
interactions aliased with each single factor could have the
same effect on any of the responses assessed in the study. If
with low risk, or, in the case of split time, their effect will be the same effect is likely, then factors should be reallocated,
accounted by another factor (split ratio). The 19 parameters which will make the analysis of the study easier and lower
detailed in Table II were risk-assessed and a study contain- the likelihood of having to perform further experimentation
ing seven instrumental factors was created by eliminating to de-alias factors (see Figure 2).
some parameters, combining other low-risk parameters, and Given the symmetry of the aliasing pattern, there is little
combining parameters that were thought to have similar ef- opportunity for smart allocation of factors. However, from
fects. The combination of parameters was quite aggressive the risk assessment, it is known that some parameters have a
to obtain a 7-factor study where the number of experiments higher risk than others; also, as a rule, three-factor interac-
required was reduced. The resolution of the design was kept to tions are less likely than two-factor interactions (which are
a minimum (III) to reduce the resources required to run the less likely than single factors). The factors were allocated to
experiment. These steps cut the total number of experiments reduce the complexity of the analysis (see Table III).
required by at least 50% (i.e., 16 experiments: eight for the A, B, and D are low-risk groups, making it easy to discard
instrument factors study and eight for a further sample prepa- any two-factor interaction containing any of these factors. C,

Interaction
Design-Expert Software D: Group 5 (column)
0.2
% area Impurity B 4

D1 D1
D2 D2
% area Impurity B

0.2
X1 = Group 4 2
X2 = Group 5 (column)

Actual 0.2
A: Group 3 = 0
0
B: Group 2 = 0
C: Type of liner = C1
F: Temp gradient = 30
G: Group 1 = 0 0.1
8

0.1
6

- - 0.0 0.5 1.0

1.00 0.50 0 0 0

E: Group 4

Figure 3: Predicted effect of Group factors 4 and 5.

82 Pharmaceutical Technology APRIL 2010 P h a r mTe c h . c o m

Risk Assessment
F, and G are high-risk groups and all the two-factor interac-
tions they are aliased with contain either A, B, or D. There
should not be any ambiguity, therefore, in determining the
cause of an effect. Had A, B and C been allocated to the low-
risk parameters, on the other hand, then D, E, and F would
have been aliased with one two-factor interaction that did
not contain any of these low-risk parameters, and is therefore
more likely (see Figure 2). In this later example, the complex-
ity of the analysis would not have been reduced.
Results
The statistical design described herein had additional com-
plications because of the need to block runs (i.e., to reduce
the number of column and liner changes) and some missing
results in the data. For these reasons, modeling of the data was
complicated and has not been included in this article. How-
ever, a brief summary of the conclusions is provided below.
The study showed the method was robust for the responses
collected (see Table III). There was one control identified fol-
lowing the RMR study that was required to minimize vari-
ability in the level observed for one of the impurities (B). One
of the factors that was most responsible for this variation was
the combined injection temperature/initial oven-hold time
group factor (Group 4). The most likely cause of this variation
is the temperature of the injector (240–260 °C) rather than the
length of time the oven is kept at the minimum temperature
84 Pharmaceutical Technology APRIL 2010
of the gradient (140 °C) because the impurity is known to be
thermally labile. The plot in Figure 3 displays the predicted
effect of increasing the temperature of the injector (Group
4) combined with the effect of the other most significant
factor (the column—Group 5). Therefore, a tighter control
was placed around the injector temperature to minimize the
variability seen for this impurity before proceeding to full
method validation. Without the careful combination of fac-
tors that preceded this study, it could have been harder to
deduce which parameter was the cause of the variability.
Despite being considered lower risk, a difference was also
noticed between the two columns tested (see Figure 3) with
some of the impurities being observed at slightly different
levels on the two columns. This difference illustrates the im-
portance of including parameters in robustness assessment—
even if assessed as lower risk. As the age of the column and
the column batch were grouped, it was impossible to identify
whether the observed difference was derived from column
batch-to-batch variability or from the performance of a col-
umn varying with time. It was recommended that this issue
be further assessed as part of a method ruggedness study.
Conclusions
The use of risk-based assessment tools to identify, score, and pri-
oritize method parameters coupled with RMR is a novel adapta-
tion of already established techniques. RMR provides an effective
P h a r mTe c h . c o m
Risk Assessment
means of reducing the number of experiments required to assess
method suitability and performance. This approach has been
successfully applied to assess robustness of a GC–FID method
used for the analysis of a key pharmaceutical starting material.
The results from this study allowed the analyst to identify key
method parameters by performing 16 experiments instead of the
usual 32 or 40. This simple approach can easily be applied to any
analytical method and provides an analyst with a checkpoint for
progression of analytical methods in drug development. If all of
the important parameters are accommodated and testing shows
the method is robust, then a further robustness study may not
be needed when proceeding to full validation.
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Acknowledgments
The authors wish to thank Luca Martini, Anna Nicoletti, and
Jill Trewartha who were involved in the GC–FID RMR study
mentioned in this article.
For an expanded version of this article, including additional tables and figures, log
onto PharmTech.com/RMR.
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