Analytical Method Comparability in

Registration and Post-Approval Stages: A

Risk-Based Approach
A risk-based approach is recommended for analytical method
comparability for HPLC assay and impurities methods.
Oct 2, 2014
By: Hafez Abdel-Kader, Mark Argentine, Jeff Hofer, Nancy Benz, Rick Burdick, Marion Chatfield, Frank
Diana, Hui Fang, Yuan Huang, Shreekant Karmarkar, Lakshmy M. Nair, Theresa Natishan, Andrea M.
Pless, Qinggang Wang, Zeena Williams
PHARMACEUTICAL TECHNOLOGY
Volume 37, Issue 10, pp. 60-70
To ensure the quality of drug products and patient safety, pharmaceutical companies need to manage
and justify changes in chemistry, manufacturing, and controls (CMC). Analytical methods are integral
parts of CMC, and some common reasons to change analytical methods used in regulated environments
include applying new analytical technologies and accommodating changes in chemical or formulation
processes. When changes are made to analytical methods, pharmaceutical companies need to compare
the new method and the existing method, and to demonstrate that the new method will provide equivalent
or better performance to that of the existing method.
There are two concepts related to comparing two analytical methods for the same test: analytical method
comparability and analytical method equivalency. Chambers et al. considered that analytical method
comparability refers to studies to evaluate similarities and differences in method performance
characteristics between two analytical methods (i.e., accuracy, precision, specificity, detection limit, and
quantitation limit), while analytical method equivalency is a subset of analytical method comparability and
refers to studies to evaluate similarities between two analytical methods in regard to generating results
for the same sample (1). In other words, analytical method equivalency evaluates whether the new
method can generate equivalent results to those from the existing method. In a recent publication,
Chatfield et al. suggested another way to differentiate these two concepts, where analytical method
equivalency is restricted to a formal statistical study to evaluate similarities in method performance
characteristics (2). In a United States Pharmacopeia (USP) stimuli paper, Hauck et al. also discussed
other approaches to assessing equivalence such as result equivalence (3).
Unlike analytical method validation, where clear regulatory guidelines such as International Conference
on Harmonisation (ICH) Q2, are available, there is little regulatory guidance on how or when to perform
analytical method comparability or equivalency. In a draft guidance published by FDA in
2003, Comparability Protocols-Chemistry, Manufacturing, and Controls Information, the agency stated
that proper validation is required to demonstrate that the new analytical method will provide similar or
better performance compared with the existing method. On the other hand, the agency also stated that
whether an analytical method equivalency study is needed and how to perform it will depend on the
extent of the proposed change, type of product, and type of test (e.g., chemical, biological) (4). Another
relevant document on analytical method comparability is USP General Chapter <1010> Analytical
Data-Interpretation and Treatment, which was first published in USP 28 in 2005 (5).
In this General Chapter under the section of Comparison of Analytical Methods, statistical-based
approaches to compare method precision and accuracy are discussed with some examples. Most
recently, an FDA draft guidance on analytical method validation was issued in 2014 (6), and the concept
of analytical method comparability is discussed. However, in this draft guidance, the use of formal
statistical studies is recommended whenever a change is made to an analytical method that has stability
indicating properties. While this approach is valid and rigorous, the draft guidance does not consider less
formal but suitable alternatives for method comparison assessments by leveraging a quality- and
risk-based assessment strategy.
Based on a 2003 Pharmaceutical Research and Manufacturers of America (PhRMA) workshop,
Chambers et al. published a position paper on analytical method equivalency (1). The authors
summarized industry practice at the time and provided perspectives on when and how analytical method
equivalency should be performed. The authors noticed that a wide range of different practices were used
by pharmaceutical companies for analytical method equivalency, including only validation of the new
method, side-by-side result comparison against pre-defined acceptance criteria, as well as formal
statistical demonstration. Such wide variations are clearly not preferred by either regulatory agencies or
the industry and may lead to delay in regulatory review.
The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) is a
pharmaceutical industry association formed in 2010 with the mission of advancing science-based and
scientifically driven standards and regulations for pharmaceutical and biotechnology products worldwide.
In 2011, an IQ working group, Analytical Method Comparability, was formed to assess current practices
by IQ member companies and to recommend best practices on analytical method comparability for
analytical methods used in regulatory environments. Harmonized approaches on analytical method
comparability, if in existence, will not only improve industry compliance to ensure product quality and
patient safety, but also align with quality-by-design (QbD) principles and may also reduce the regulatory
filing burden on method change control, which in turn may encourage innovation in pharmaceutical
analyses.
As a starting point, the working group purposely limited its initial scope to changes in high-performance
liquid chromatography (HPLC) assay and impurities methods in registration and post-approval stages.
The rationale for this decision is that new developments in instrumentation and column technologies led
to the birth of ultra-high pressure liquid chromatography (UHPLC) (7). An HPLC impurities analysis that
used to routinely take 30 min or more to perform by conventional HPLC can now be achieved within a
few minutes by UHPLC with better sensitivity and less solvent consumption. Though UHPLC has
witnessed increasing popularity by pharmaceutical companies for new products, implementation of
UHPLC in legacy products has been slow, partially due to the heavy regulatory filing burden upon
method change control. CMC related changes, including changes in analytical methods, are regulated
most stringently in registration and post-approval stages. While HPLC assay and impurities methods
were the starting point, it is reasonable to anticipate that the general concepts developed in this position
paper can be applied to other analytical methods.
The working group conducted a survey on analytical method comparability among IQ member
companies, and the results are summarized in the next section. Based on the survey results and
discussions among working group participants, the working group recommends a risk-based approach
for analytical method comparability of HPLC assay and impurities methods in registration and
post-approval stages. The views in this article are those of the authors and do not reflect the official
policies of their respective companies.
Survey summary
A survey of industry practice on analytical method comparability for HPLC assay and impurities methods
in registration and post-approval stages was carried out among IQ member companies. The survey
contained 17 questions covering the following aspects with regard to industry practice on analytical
method comparability: background and internal governing documents, regulatory interactions, general
practice, quality assurance (QA) and statistician involvement, and detailed procedures. Nine questions
were required to be answered as a Yes or No response, with the option to provide additional written
details; written responses were required for the remaining eight questions. A total of 19 responses were
received from 15 IQ member companies. Three companies provided multiple responses from different
divisions within the same company. The survey results were discussed during subsequent working group
meetings. Though this is a relatively small survey and the percentage numbers undoubtedly have a large
margin of error, the authors believe that the results, described in the following section, provide a
meaningful picture of current industry practice on analytical method comparability for HPLC assay and
impurities methods.
Background and internal governing documents
With regard to the definitions of analytical method comparability and analytical method equivalency, 68%
of participants thought that these terms represented two different concepts. From subsequent working
group discussions, it was clear that most participants agreed with Chambers et al. that analytical method
equivalency is the evaluation of whether equivalent results can be generated by two different analytical
methods; analytical method comparability is a broader and less defined term (1). Meanwhile, some
participants also indicated that analytical method equivalency should be restricted to a statistical
demonstration of equivalence, as described by Chatfield et al. (2).
With regard to internal governing documents, 79% of participants indicated that there are no specific
standard operating procedures (SOPs) or guidelines on analytical method comparability within their
company. On the other hand, 53% of participants mentioned that there are some general discussions on
analytical method comparability within their companys change control policies or SOPs. Some
participants, for example, indicated that it is part of their risk assessment workflow to evaluate if an
analytical method equivalency study should be performed when a change is made to an analytical
method.
Regulatory interactions
With regard to regulatory interactions, 68% of participants indicated that they have had successful
regulatory reviews of analytical method comparability packages for a registration filing or post-approval
change. Additional written comments showed that a complete analytical method comparability package
typically includes method information, method validation, equivalency data, and the reason for the
change. Meanwhile, 47% of participants indicated that they have received questions on analytical
method comparability from health authorities. Additional written comments suggested that regulatory
authorities have expectations that analytical method equivalency needs to be demonstrated when
changes are made to an analytical method; however, the feedback also indicated that there were no
consistent requirements on what kind of data package should be provided. In general, more data are
required when the method change is more significant.
In one example, when an HPLC assay method was replaced with an UHPLC assay method, method
equivalency was demonstrated using a side-by-side comparison of both methods for three lots of
material; this approach was accepted by FDA. In this example, the change was considered minor as the
separation mechanism (i.e., reversed-phase HPLC) was not changed. In another example, however,
when a normal-phase HPLC assay and impurities method was replaced by a reversed-phase HPLC
method during registration stability testing, several questions were received from FDA requesting
detailed explanations due to the significant difference in methodology, which impacted the impurity profile
and the specifications. The agency requested detection limits and quantitation limits of all impurities by
both methods and full disclosure of the impurity profiles by both methods on all lots tested. To help justify
the change, the company also provided overlapping stability data for 3-6 stability time points to
demonstrate that the reversed phase HPLC method provided better characterization of the drug product.
General practices
With regard to general practices, all participants stated that in addition to validation, they would also
evaluate whether an analytical method comparability or equivalency study is needed when a change is
made to an analytical method, while 63% of participants specified that not all method changes will need a
comparability or equivalency study. From additional written comments, it was clear that risk-based
approaches are adopted by most companies when evaluating whether an analytical method
comparability or equivalency study is needed for method changes. The risks are typically evaluated
based on the types of the changes, and in general, the more significant the change, the more likely a
comparability or equivalency study will be needed.
For example, as indicated by some participants, neither validation nor equivalency will be necessary for
compendial HPLC method changes if the changes are within the ranges allowed in the USP General
Chapter <621> Chromatography. For non-compendial HPLC methods, such as those included in a new
drug application (NDA) filing, no equivalency study will be needed if the change is within the established
method robustness ranges. On the other hand, a comparability or equivalency study is typically required
if the changes are outside of these ranges, such as a change in liquid chromatography (LC) stationary
phase chemistry or a change in detection technique (e.g., from ultraviolet to mass spectrometry). Some
companies also evaluated the risks based on the stage of the development. One participant mentioned
that equivalency studies are performed for any changes to an HPLC method in post-approval stages.
If an analytical method comparability or equivalency study is deemed necessary, different practices still
exist amongst the participants. A majority of participants (74%) agreed that, in addition to validation of the
new method per ICH guidelines, a simple side-by-side comparison of representative batch results
generated by both methods against pre-defined acceptance criteria (some companies referred this
practice as cross-validation or as a bridging study) is usually sufficient. A more conservative practice
(16%) is a demonstration of method equivalency through formal statistical analysis. One participant
indicated that whether such a formal statistical analysis is necessary will also be evaluated based on the
types of the changes as part of the risk assessment workflow. Another less common practice (5%) is to
conduct a full validation of the new method; the two methods are considered equivalent if they are both
validated.
QA and statistician involvements
With regard to quality assurance (QA) and statistician involvement, 68% of participants indicated that QA
is involved in analytical method comparability or equivalency studies, such as approval of study protocols,
while only 26% indicated that statisticians might be involved. One participant indicated that statisticians
are involved in the design of the equivalency study, setting acceptance criteria, data evaluation, and
report writing; while other participants stated that statistician assistance is only required when it is
deemed necessary by analytical scientists.
Detailed procedures
With regard to detailed procedures, though the survey was on analytical method comparability for HPLC
methods, responses from almost all participants were only focused on analytical method equivalency.
This suggested that analytical method equivalency (i.e., demonstration of no practically significant bias in
mean results) is the primary goal when a change is made to an HPLC method. Most participants did not
use formal statistical approaches, but for those who did, statistical approaches are used throughout the
study to ensure a statistically meaningful outcome.
An analytical method equivalency study typically consisted of acceptance criteria, study design (sample
selection, sample size, and test plan), data evaluation, and documentation. With regard to acceptance
criteria, most participants started with generic acceptance criteria derived from internal SOPs on
analytical method validation or method transfer, such as 1.5-3.0% for assay, and 10-30% relative for
impurities (or an absolute difference, such as 0.03%, for levels close to quantitation limits). Such
acceptance criteria could be loosened or tightened based on the specific method and product involved
(e.g., product types).
On the other hand, some participants indicated that a method specific criterion will be set based on the
statistical evaluation of the precision of the method and the acceptance criteria of the relevant product
specifications. With regard to study design, representative batches are typically used, with spiking of
impurities if necessary. Some participants also suggested that stability samples over a few time points
could be used (cross-over testing), though this practice was discouraged by Chambers et al. to avoid
generating concerns of regulatory compliance.
A wide range of different practices exist among participants in terms of sample size (number of batches)
and test plans. Some examples include using six replicate preparations of one or two batches, three
replicate preparations of three batches in three runs (fresh reference standard preparations for each run),
and one preparation for each of 20-30 batches, etc. Some participants indicated that statistical
approaches are used to determine sample size (statistical power calculation based on acceptance
criterion and method precision) and test plan (evaluation and control of other factors not related to the
change). Some of these statistical approaches were discussed by Borman et al. (8).
With regard to data evaluation, most participants simply compared difference in mean results against
pre-defined acceptance criteria, while some participants indicated that a statistical test will be used.
Concerning the specific statistical tests, the two one-sided t-test (TOST) is most often used (9), while the
two-sample t-test is also used by some participants. With regard to documentation, most participants use
a pre-approved study protocol and provide a study report once the study is completed.
In summary, it is fair to say that compared to analytical method validation, analytical method
comparability or equivalency is a more science-driven and less regulated field. The survey results show
that risk assessments are commonly performed by pharmaceutical companies to evaluate the impact of
the changes, including whether an analytical method comparability study is necessary. If analytical
method comparability is deemed necessary, different practices exist among pharmaceutical companies
on how to perform the study.Though formal statistical approaches are used by some companies to
provide a statistical meaningful declaration on whether the two methods were equivalent, a simple
side-by-side comparison against pre-defined acceptance criteria remains the most popular approach for
changes made to HPLC methods. On the other hand, the survey results also show that though regulatory
authorities have expectations that analytical method equivalency needs to be demonstrated when
changes are made to an analytical method, there seems to be no consistent requirements on what kind
of data package should be provided. In general, more data are required when the extent of the change is
more significant.
Overall, the survey results suggest that risk-based approaches should be adopted for analytical method
comparability. In other words, whether an analytical method comparability or equivalency study is
needed and how it is performed should be decided based on the risks associated with the changes. In
the FDA draft guidance on comparability protocols, the agency states that The need and plan for
providing product testing to compare the two (analytical) procedures could vary depending on the extent
of the proposed change, type of product, and type of test (e.g., chemical, biological) (4). This statement
suggests that risk-based approaches are expected by FDA as well. In the next section, a risk-based
approach for analytical method comparability for HPLC assay and impurities methods in registration and
post-approval stages is proposed based on the survey results and the subsequent working group
discussions.
A risk-based approach for analytical method comparability
When a change is made to an analytical method, a risk assessment should be performed to evaluate the
potential impact. Though analytical method equivalency (i.e., no practically significant bias in mean
results) is an important factor, other method performance characteristics, such as precision, should be
evaluated as well. Impact on method performance depends upon the nature of the method as well as the
type and the extent of the change. With regard to HPLC, the mechanistic understandings of both
thermodynamic and kinetic aspects of HPLC separation processes have been well developed in the past
few decades. In the same time period, improvements to LC instrumentation and column technologies
have made HPLC one of the most reliable techniques in analytical laboratories around the world. The
knowledge of HPLC separation and the reliability of modern HPLC instruments have enabled analytical
scientists to better understand the potential impact on method performance from certain types of
changes to HPLC methods. Therefore, changes to HPLC methods could be categorized based on the
risks associated with the changes (e.g., low risk, medium risk, or high risk). These changes would be
accompanied by a commensurate amount of work to assess comparability, as depicted in Table I.


Table I: A risk-based assessment of analytical method changes and the corresponding
minimum analytical comparability activities associated with the change.
Change
categorization
Examples Validation Comparability
Low risk Small changes to the high
performance liquid
chromatrography (HPLC)
operating parameters within
accepted ranges
(e.g. USP<621> or within
established method robustness
ranges).
No No ----
Medium risk Changes to the HPLC operating
parameters outside of low risk
ranges, but not involving any
change to the underlying
principles of the existing
analytical method (e.g. column
chemistry).
Yes Yes Side-by-side
comparisons
High risk Changes to the underlying
principles of the existing
analytical method (e.g. liquid
chromatrography-ultraviolet
(LC-UV) to liquid
chromatography-mass
spectrometry (LC-MS)).
Yes Yes Formal
statistical
studies
Low-risk changes are small changes to the HPLC operating parameters, such as changes allowed by
USP General Chapter <621> Chromatography for a compendial HPLC method or changes within the
established robustness ranges in analytical method validation (10-11). Two examples of low-risk
changes are the column temperature within 10C or the flow rate within 50% from the target values of a
compendial isocratic HPLC method. In low-risk situations, additional method validation and comparability
studies should not be required, as the changes have already been assessed within the initial validation
experiments and any impact is generally understood and predicted based upon mechanistic models.
Medium-risk changes are changes to the HPLC operating parameters outside the established robustness
ranges evaluated during the method validation, but do not involve any change to the underlying principles
of the existing analytical method. An example of a medium-risk change includes an HPLC column
change to a smaller particle size and/or shorter column length or diameter with appropriate scaling
considerations to speed up a gradient HPLC method (i.e., conversion from HPLC to UHPLC
methodology without appreciable change in separation mechanism). Other medium-risk changes might
include changes in column stationary phase from C18 to C8 or a change in organic solvent in mobile
phases from acetonitrile to methanol as long as the characteristics of method performance (e.g.,
specificity, accuracy, precision) remains practically unaffected, which can be confirmed through
successful completion of associated method validation activities prior to implementation of any
comparability studies.
Finally, high-risk changes are those changes that either involve a change to the underlying principles of
the existing analytical method or a change in a critical method parameter that has high impact to method
performance. Some examples of high risk underlying analytical principle changes include conversion of
a microbiological potency method to a reversed-phase HPLC potency method, a normal-phase HPLC
method to a reversed-phase HPLC method, a UV detection to a mass spectrometry detection, or an
assay method by HPLC to a near-infrared (NIR) real time release method.
The HPLC risk categorization examples discussed previously should serve as a general guideline for risk
assessment, and it is recommended that each HPLC method change should be evaluated and
categorized on a case-by-case basis. Application of QbD principles to analytical methods has been
discussed recently (12-16) and can assist method change assessments. Identifying critical method
parameters through a comprehensive risk assessment is an integral step in an analytical QbD workflow.
The knowledge gained through analytical QbD should also be applied in risk assessment and
categorization when a change is made to an existing HPLC method. For example, a change in detection
wavelength for an HPLC impurities method may be an example of a medium-risk change or a high-risk
change. If all impurities are quantified by calibration with external standards of each impurity, the change
should be of medium risk; however, quantification of impurities based upon response-corrected areas
could potentially represent a high-risk change if relative response factors are assumed to be 1.0, a
common industry practice for impurities with calculated response factors between 0.8-1.2 (11). In such a
situation, a change in detection wavelength could lead to an appreciable bias in impurity results.
For changes in the low-risk category, potential impact on method performance is usually low. The risks
will be further guarded by system suitability evaluation, such as the resolution between critical pairs,
performed in each HPLC run; therefore, low-risk changes can take place without additional studies.
Neither additional validation nor analytical method comparability studies are necessary. This approach
agrees with the requirements from USP and ICH.
For any changes beyond low risk, justification and validation of affected method parameters are generally
required. Additionally, both health authorities and pharmaceutical companies expect that analytical
method comparability or equivalency studies should be performed. A question of interest is whether a
formal statistical demonstration of analytical method equivalency is always necessary. Chambers et al.
discussed the differences between validation and equivalency, and emphasized that validation alone
cannot guarantee equivalence because validation experiments are not designed to detect small bias
between mean results (1). This statement is fair, but it should be emphasized that the risk of
non-equivalency decreases as successful validations of both methods have been completed.
For medium-risk changes, where underlying principles remain the same for both methods (e.g.,
reversed-phase HPLC methods with UV detection), the risk of having a practically significant difference in
mean results is rather low when both HPLC methods are successfully validated in the same manner with
the same pre-defined criteria. For example, a co-elution of two impurities would potentially fail
equivalency, and would fail validation on method specificity as well. In addition, validation studies also
confirm improvement or similarities of other method performance characteristics, such as precision.
Therefore, the authors recommend that a side-by-side comparison against pre-defined acceptance
criteria should be sufficient for medium-risk changes. Though not a formal statistical approach, the
side-by-side comparison study should be designed carefully. Acceptance criteria could be based on
internal SOPs on analytical method validation or method transfer. Generic limits of 1.0-2.0 % for drug
substance assay, 2.0-3.0 % for drug product assay, and 10-30% relative for impurities can be considered
as a starting point. Such acceptance criteria can be loosened or tightened based on the specific method
involved. Representative batches, preferably covering a wide range of results, should be chosen for the
study. Spiking impurities should be considered, if no suitable batches can be identified containing the
impurities at appropriate levels (e.g., the specification limit). QA should be consulted if active GMP
samples, such as GMP release and registration stability study samples are considered to be used for
comparison. Material limitation is usually not a concern at registration and post-approval stages, and
typically three batches or more should be used for the study. Factors affecting intermediate precision
and/or reproducibility, such as analyst, instrument, and environment, should be included in the study if
possible. For example, a common test plan is triplicate preparations of three batches in three runs, with
each run using fresh standard preparations, and altering factors of analyst, instrument, and/or
environment as well.
Because high-risk changes usually involve a change to the underlying principles between the existing
and the new methods, the risk of being non-equivalent is high, even with successful validations of both
methods. In some cases, the validation plan and acceptance criteria between the two methods have to
be modified to accommodate the changes to the underlying principles. For example, the specificity
evaluation for a NIR assay method will be different (test procedure and acceptance criterion) from that for
an HPLC assay method. Therefore, the authors recommend that statistical principles should be followed
throughout the study and a formal statistical assessment of the data should be applied for high-risk
changes to ensure a statistically meaningful outcome. This includes selection of the acceptance criterion,
design of the test plan, data validity evaluation (e.g., outlier testing), and an equivalency test (e.g., TOST).
Note the two-sample t-test should not be used as an equivalence test (or as acceptance criteria for a
side-by-side comparison) as it is designed to detect a difference of means, not to establish whether the
means are equivalent based on a measure of practical importance (1, 9). Besides method equivalency,
other method performance characteristics, such as precision, should also be evaluated (though note that
a large difference in precision is likely to cause the TOST to fail (9). In other words, an analytical method
comparability study should be performed for high-risk changes. Detailed procedures for statistically
guided analytical method comparability and equivalency studies can be found in the USP General
Chapter <1010> and some external scientific publications as well (2, 5, 8, 9, 17). Due to the involvement
of advanced statistics, statistician assistance should be sought. The proposed analytical comparability
activities for a specific HPLC risk categorization does not preclude a more stringent assessment being
applied (e.g., if the analytical method is to be applied in a situation where even a very small difference in
means could be problematic).
Conclusion
Analytical method comparability or equivalency remains as a more science-driven and a less regulated
field, and different practices currently still exist among pharmaceutical companies. Harmonized practices
will not only improve industry compliance to ensure product quality and patient safety, but also reduce the
regulatory filing burden on method change control, which in turn will prompt innovation in pharmaceutical
analysis. In this position paper, the IQ working group on analytical method comparability recommends a
risk-based approach for analytical method comparability for HPLC assay and impurities methods in
registration and post-approval stages. It is the working groups hope that this paper can help to stimulate
further discussions among the industry and health authorities to define acceptable industry practices for
assessing analytical method comparability or equivalency in general.
Authors note
This position paper was prepared with the support of the International Consortium for Innovation and
Quality in Pharmaceutical Development (IQ). IQ is a pharmaceutical industry association formed in 2010
with the mission of advancing science-based and scientifically driven standards and regulations for
pharmaceutical and biotechnology products worldwide. Visit www.iqconsortium.org for more information.
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About the authors
Hafez Abdel-Kader is a director at Sanofi; Mark Argentine is a senior research advisor, and Jeff Hofer is a
research advisor, both at Eli Lilly; Nancy Benz is a director at AbbVie; Rick Burdick is a quality
engineering director at Amgen; Marion Chatfield is a manager statistician at GlaxoSmithKline; Frank
Diana is a vice-president at Endo Pharmaceuticals; Hui Fang and Yuan Huang are both senior scientists
at Eisai; Shreekant Karmarkar and Lakshmy M. Nair are both senior research scientists at Baxter;
Theresa Natishan is a director at Merck; Andrea M. Pless is an associate director at Teva; Qinggang
Wang* is a principal scientist at Bristol-Myers Squibb, qinggang.wang@bms.com; and Zeena Williams is
a senior associate director at Boehringer Ingelheim. * To whom all correspondence should be addressed.