20/12/2017 The Application of Quality by Design to Analytical Methods

Home > The Application of Quality by Design to Analytical Methods

The Application of Quality by Design to Analytical

Methods
To monitor and control processes or products, analytical methodology must be fit for
purpose. An approach to apply quality by design principles to the design and
evaluation of analytical methods has therefore been developed to meet these needs.

This article features a downloadable template on which to conduct a failure mode

effect analysis (FMEA).
Oct 02, 2007
By Pharmaceutical Technology Editors
Pharmaceutical Technology
Volume 31, Issue 10

During the past few years, regulatory agencies have placed an increased emphasis on
pharmaceutical process understanding. The US Food and Drug Administration's
Pharmaceutical CGMPs for the 21st Century—A Risk Based Approach [1] describes
how combining a focus on process understanding with a structured risk-assessment
process can help develop control strategies that enhance process robustness (1).
Similar concepts are also discussed in ICH Q8 Pharmaceutical Development [2] and
International Conference on Harmonisation (ICH) Q9 Quality Risk Management [3] (2,
3). Collectively, these principles are described as "quality by design" (QbD). As defined
by Janet Woodcock in 2004, "QbD means that product and process performance
characteristics are scientifically designed to meet specific objectives, not merely
empirically derived from performance of test batches." This article describes how the
principles of QbD being developed for manufacturing processes can equally well be
applied to ensure that analytical tests methods and process analytical technology
(PAT) are robust, as defined by ICH Q2(R1), and rugged, as defined by the United
States Pharmacopeia (USP) (4, 5).

Terminology
Analytical method robustness testing typically involves evaluating the influence of
small changes in the operating conditions. Ruggedness testing identifies the degree of
reproducibility of test results obtained by the analysis of the same sample under
various normal test conditions such as different laboratories, analysts, and
instruments. The term robustness has been used differently when describing chemical
processes and includes factors deemed as robustness parameters and ruggedness
factors in the analytical world. Processes, for example, have been defined as robust if
they have the ability to tolerate the expected variability of raw materials, operating
conditions, process equipment, environmental conditions, and human factors (6).

The examples in this article are based on chromatographic and PAT methods to
support new-product development. Nonetheless, the concepts can be applied to any
method type and can be used to improve the reliability of established methods. As the
principles described in this article bring fundamental method understanding, the
adoption of this approach will reduce manufacturing resources involved with
investigating out-of-specification results as well as increase the confidence in analysis
testing cycle times. They also lay the foundations for less regulatory oversight of
method changes, which should facilitate innovation and continuous improvement.

Processes must meet current good manufacturing practices to ensure drug products
meet safety and efficacy requirements (7). Traditionally, this requirement has been met
by performing process validation studies on three batches. It has been recognized that
this approach is unlikely to fully represent routine manufacture and unlikely to cover all
potential sources of variability (e.g., raw materials, operators, shifts, reactor vessels).
Moheb Nasr, director of the Office of New Drug Quality Assessment at FDA [4], has

http://www.pharmtech.com/print/225359?page=full 1/7
20/12/2017 The Application of Quality by Design to Analytical Methods
identified this issue as a challenge to the regulatory process and has stated that there
is currently a "focus on process validation and not process understanding" (8).

In a similar way, the traditional approach to analytical method validation described in

ICH Q2(R1) and analytical method transfer represents a one-off evaluation of the
method and does not provide a high level of assurance of method reliability. The
limited understanding of a method obtained through these traditional approaches has
often led to it passing the technology transfer exercise (by chance) from development
into use in commercial manufacturing facilities. In reality a significant method variable
had not been fully explored, thereby leading to method failure some months post-
transfer. Even when transfers have failed (the more desirable scenario if the method is
poor, enabling issues to be identified), significant resources are often required to
attempt to remedy the causes of the transfer failure, usually at a time when there is
considerable pressure to support the introduction and launch of a new product. Both of
these scenarios are undesirable and would be recognized in many pharmaceutical
analysis laboratories as significant issues.

Current approaches to analytical technology transfer—in which, for example, three

batches have been analyzed each in duplicate at the transferring and receiving sites—
represent a one-off exercise aimed at proving that a receiving laboratory can operate
the analytical method (9–12). These approaches really only confirm that the analyst,
equipment, and other components involved in the exercise can operate the method at
the time of the transfer exercise. The desired state is proving that the method will be
reliable (robust and rugged) throughout the life cycle of its use. Instead of the generic
technology-transfer exercise, it is more appropriate that a risk assessment be
performed to identify potential variables and that this should dictate which robustness
and ruggedness experiments are performed. The latter can be tested as part of a
measurement systems analysis study in which the most likely sources of variability are
identified and studied. All the knowledge (not just the technology) should then be
transferred; any future changes to the method or the environment in which it is
operated should be risk assessed; and, if appropriate, equivalency should be
demonstrated as part of an overriding change-control procedure.

The current reality is that the pharmaceutical industry has 6-sigma products on the
market but only 2.5 sigma processes (13). The capability of many analytical methods
and controls used to monitor these processes is nearly as poor. Nevalainen et al., for
example, have estimated analytical performance at the 3.85-sigma level (14). To move
pharmaceutical processes and analytical methodology toward much improved sigma
capability, an objective, cross-functional, data-driven assessment of all the steps within
a process or method must be performed.

A framework for applying QbD to analytical methods

1: The high-level components of how quality by design can be applied to processes and
cal methods.
Figure 1 illustrates the high-level components of how QbD can be applied equally to
processes and analytical methods. It displays how QbD for analytical methods is
driven by the overall process-control strategy.

Method performance requirements (design intent). Fundamental to any method

development is being clear about the design intent of the method (i.e., the criteria that
must be met). Method-performance criteria and method-operational intent are two
important aspects of this design intent.

Method-performance criteria. These criteria are driven by an understanding of the

process monitoring and control requirements; that is, the process critical quality
attributes (CQAs) and specification limits. CQAs are identified, through a thorough
understanding of those characteristics of a drug substance or a drug product that may
need to be controlled to ensure the safety or efficacy of a product. For methods
measuring these CQAs, criteria, such as the following, would need to be met:

Precision—the need for method variability to be a small proportion of the

specification
Selectivity—being clear on which impurities actually need to be monitored at
each step in a process and ensuring adequate discrimination between them
Sensitivity—ensuring the method is sufficiently sensitive relative to the
specification limit.

PAT methods often meet the criteria above in a different way from traditional end-point
testing methods such as high-performance liquid chromatography (HPLC). Selectivity,
for example, may be achieved through a multivariate model as opposed to resolution
between adjacent peaks in an HPLC method. For these methods, precision could be
demonstrated by checking the prediction validity of the model.

Method operational intent. These criteria address the aspects of the method that are
required to facilitate ease of use in routine operation (e.g., analysis time, acceptable
solvents , available equipment). Opportunities for the implementation of improved or
new technology also may be identified. These criteria can be generated by performing
an analysis of the voice of the customer (VoC) (i.e., the aspects of a method that are
considered important for the quality control laboratories within manufacturing where
the commercial methods will be operated).

Method development (design selection). Fundamental to design selection is the

method-development phase. To develop a QbD method, the method performance

http://www.pharmtech.com/print/225359?page=full 2/7
20/12/2017 The Application of Quality by Design to Analytical Methods
criteria must be understood as well as the desired operational intent that the eventual
end user would wish to see in the method. To deliver the latter, methods must take into
account the VoC.

The method development process should use an agreed standardized approach

between development and manufacturing. For example, within GSK there is a
companywide strategy for chromatographic methods that is based on the best
scientific knowledge and expertise that is aimed at minimizing unnecessary and
detrimental diversity. The design of the method is a key decision. Issues that may
easily be solved by appropriate selection at this point are likely to be more difficult to
fix later, if trying to optimize a poor method not suited to meet its method-performance
criteria. Consideration also must be given to whether on-line methods can be used in
place of traditional lab-based methods. This assessment takes place once the CQAs
for the process have been identified.

Through a thorough understanding of the design intent, methods for commercial

operation would be designed only for those specific impurities relevant to the
commercial product. Historically, the methods transferred into quality control
laboratories have often taken into account potential impurities detected in earlier
routes of synthesis, which cannot be formed from the commercial route or monitor
theoretical degradation products that, in practice, are not formed during routine
stability studies. Significant opportunities exist to identify what is truly critical to control
and reduce method complexity once sufficient process understanding is obtained.

Risk assessment and analytical design-space definition (control definition). It is

imperative to reach a high degree of confidence that the analytical method will meet all
method performance criteria under all conditions of use as it progresses through the
lifecycle. This confidence level can be achieved by using a rigorous approach for
identifying all the potential method factors that may need to be controlled to ensure
method performance and through the use of risk assessment tools and prioritized
experimentation that eliminate areas of risk.

To maximize the benefits of performing a risk assessment, the analysts who have
developed the method should work as a team with the analysts who will be using the
method in manufacturing. To fully understand the method, a walk-through is
recommended that involves all the analysts observing one analyst using the method
from start to finish in the manufacturing environment. Each of the steps within the
method can then be mapped out separately (e.g., sample preparation, dissolution,
extraction, chromatographic separation, data analysis).

Figure 2: Fishbone diagram created for an HPLC assay and impurities method.

A cause-and-effect diagram, also known as a fishbone or Ishikawa diagram, can then

be used after the walk through to facilitate brainstorming of all the potential factors that
may influence the method performance criteria (15). Mind-mapping software can be
valuable in this exercise because it facilitates the collection of all the detailed factors
that represent potential variables in the method. Figure 2 shows an example of part of
a fishbone performed on a tablet HPLC assay–impurities method. Under each
subheading, there are further factors (not shown in Figure 2). For example, for HPLC,
subfactors include the pump, dwell volume, autosampler, and detector. With
information obtained from operating the method and the walk-through, analysts are
encouraged to draw upon their past experience of the operation of similar methods on
various products to ensure that previous lesssons learned are incorporated into the
risk assessment. Establishing a corporate knowledge repository for important factors
for each technique can facilitate this learning process.

http://www.pharmtech.com/print/225359?page=full 3/7
20/12/2017 The Application of Quality by Design to Analytical Methods

ng.

Risk assessment tools such as a priority matrix and failure mode effect analysis
(FMEA) (16–18) can be used to identify where variability in a factor or failure of part of
the system might represent a risk to the method's ability to deliver the design intent.
Before any experimentation is performed, the method must be improved where
possible by using the output from the FMEA. As many high-risk factors as possible are
controlled or fixed to eliminate the potential sources of variability. Table I shows an
example of part of an FMEA for a PAT near infrared (NIR) method used for drying
monitoring. An additional column entitled "Action" is not shown in Table I. This column
is used to lower or mitigate the risk identified for the failure modes that have been
identified.

Click here to download a template on which to conduct a failure mode effect analysis
(FMEA). [5]

A tool known as CNX can help classify all the factors in the fishbone diagram. The
team decides which factors should be controlled (C), which are potential noise factors
(N), and which should be experimented on (X) to determine acceptable ranges. The
factors have been categorized using CNX in Figure 2.

Robustness studies are performed for the highest risk parameters for which
acceptable ranges will need to be identified (X-type factors). Design of experiments
(DOE) is used to assess the multidimensional combination and interaction effects of
these factors. For the highest risk noise (N-type factors), a ruggedness study is
performed using a measurement systems analysis (MSA) design. This study aims to
challenge the method, giving as much opportunity as possible for any problems to
surface.

http://www.pharmtech.com/print/225359?page=full 4/7
20/12/2017 The Application of Quality by Design to Analytical Methods

Figure 3: Flow chart overview of a risk assessment process.

Once the method has been evaluated by DOE and MSA and improved as necessary,
the FMEA can be used once again to assess the risk attached to operating the method
and establish the proven acceptable ranges for the method factors. The output of the
statistical studies is documented as the analytical method design space. Figure 3
provides an overview of the whole risk-assessment process.

Analytical method control strategy (control verification). Using the appropriate

risk-assessment tools, the critical factors and their acceptable ranges (from the risk
assessment or experimental work) are explicitly defined in the method. Throughout a
method's life cycle, which often stretches over many years, it is inevitable that there
will be changes in the method environment that can affect its operation. Changes and
improvements to a method should be made with reference to the method knowledge
repository, which contains all the information from design space definition activities.
This repository should contain the risk-assessment information and results from
method ruggedness and robustness studies.

Any proposed changes that take the method outside its proven design space are risk
assessed. For high-risk changes, an evaluation or equivalence exercise should be
performed to ensure method performance criteria are still met. Method-specific
lesssons learned are used to update the method knowledge repository. Technique
lesssons learned are used to enhance the risk-assessment process for future
methods.

Opportunities of and barriers against a QbD approach to analytical methods

There are several opportunities of this QbD approach to analytical methods, including:

Methods will be more robust and rugged, resulting in fewer resources spent
investigating out-of-specification results and greater confidence in analysis
testing cycle times
Resources currently invested in performing traditional technology transfer and
method validation activities will be redirected to ensuring methods are truly
robust and rugged
The introduction of new analytical methods—from research and development
to quality control laboratories—using a QbD approach will lead to a higher
transfer success rate than with traditional technology-transfer approaches
A specified process will help the systematic and successful implementation of
the QbD methodology and fosters a team approach
A true continuous learning process is established through the use of a central
corporate knowledge repository that can be applied across all methods
By registering only a commitment to ensure method changes meet the
registered method performance criteria, flexibility to continuously improve
methods can be achieved.

The QbD approach to analytical methods also faces several barriers, including the
following:

Current expectations of analytical technology transfer and method validation

must change because current validation guidance does not lead to methods
that can always be reliably operated
Acceptance must be gained for registration of the method performance criteria
rather than the method conditions
External guidance must be developed in this area; ICH guideline Q2(R1)
requires revision (or removal) and Center for Drug Evaluation and Research
guidance must be created for analytical methods
A common language for some of the new terms is required, including analytical
method design space, analytical method control strategy, and method
performance criteria
Analysts must learn new tools and skills
A consistent worldwide approach is required for this initiative to be effective.

Conclusion

http://www.pharmtech.com/print/225359?page=full 5/7
20/12/2017 The Application of Quality by Design to Analytical Methods
The goal of a well-characterized method development effort is to develop a reliable
method that can be demonstrated with a high degree of assurance to consistently
produce data meeting predefined criteria when operated within defined boundaries.
The process detailed in this article illustrates how QbD can be applied to the
development and evaluation of analytical methods.

During method development, all potential factors (the inputs) and all critical analytical
responses (the outputs) are studied to determine the relationships. Critical analytical
factors are identified in an approach that parallels what is described for process
development in ICH Q8 and Q9. The QbD process outlined in this article relies on an
active partnership of analytical scientists at both the development and operational
laboratories as methods are developed and as factors that lead to potential method
failures are identified and controlled. A corporate knowledge repository is required
throughout the process to ensure critical information is captured that can be reviewed
and added to in the future such that lesssons learned can be applied to the specific
method under consideration and also to other similar methods being applied to other
products. Such a repository (in line with concepts described in the draft ICH Q10) will
enable continuous improvement and change control of the method to take place
throughout its lifecycle.

Rather than continuing to perform analytical technology transfer exercises and ICH
validation, a QbD approach based on a risk-assessed change control procedure
should be adopted. Each time a method is changed, a risk assessment should be
performed. Where the change is identified as having a potential to take the method
outside its known design space, a method evaluation and, if appropriate, an
equivalency exercise should be performed to ensure method performance criteria are
still met. This will allow for method improvements to be made via internal change
control procedures, and even switches between different techniques (e.g., HPLC
versus NIR) may become much easier to implement.

A QbD approach for analytical methods that includes risk assessment, robustness
testing, and ruggedness testing is much more rigorous than ICH validation
requirements (Q2(R1)). It also includes an assessment of method variability compared
with the specification limits, which is one of the most important method attributes to
test when deciding whether the method is fit for its purpose. The approach described
herein suggests that ICH Q2(R1), while adding some value, must be substantially
rewritten to take account of the QbD risk-based approaches described in this article.

This new QbD process offers the opportunity for much greater regulatory flexibility in
the future. The method performance criteria could potentially be registered instead of
the method itself. The method used could be referred to as an example of how to
attain the required method performance criteria. Any changes to this method would be
covered by internal change control procedures.

Phil Borman,* is a manager in Strategic Technologies, Chemical Development, at

GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY UK, tel. 44
1438 763713, fax 44 1438 764414, phil.j.borman@gsk.com [6]
Marion Chatfield is a manager in Statistical Sciences at GlaxoSmithKline
(Hertfordshire). Phil Nethercote is a director in New Product Support, Global
Manufacturing Supply at GlaxoSmithKline (Ayrshire, UK). Duncan Thompson is a
senior process analyst in Strategic Technologies, Chemical Development at
GlaxoSmithKline (Hertfordshire). Keith Truman is vice-president of the Scientific
Information Centre of Excellence, Pharmaceutical Development, at GlaxoSmithKline
(Hertfordshire).

*To whom all correspondence should be addressed.

Submitted: June 21, 2007. Accepted: Aug. 2, 2007.

References

1. US Food and Drug Administration, Pharmaceutical CGMPs for the 21st Century—A
Risk Based Approach, 2004.

2. The International Conference on Harmonisation of Technical Requirements for

Registration of Pharmaceuticals for Human Use, Quality Guideline Q8 Pharmaceutical
Development, 2006.

3. The International Conference on Harmonisation of Technical Requirements for

Registration of Pharmaceuticals for Human Use, Quality Guideline Q9 Quality Risk
Management, 2006.

4. The International Conference on Harmonisation of Technical Requirements for

Registration of Pharmaceuticals for Human Use, Quality Guideline Q2(R1) Validation
of Analytical Procedures: Text and Methodology, 2005)

5. USP 29–NF 24 (United States Pharmacopoeial Convention, 2006), Chapter ‹1225›.

6. M. Glodek et al., "Process Robustness —A PQRI White Paper," Pharm. Eng. 26 (6),
1–11 (Nov.–Dec. 2006).

7. FDA 21 CFR Title Parts 210– 226 (2006).

8. M. Nasr, "FDA Perspective on the Implementation of Quality by Design," paper

presented at the Ninth APIC/CEFIC (Prague, Czech Republic, Oct. 2006).

9. M. Swartz and I. Krull, "Analytical Method Transfer," LC-GC 24 (11), 20–24, (2006).

10. ISPE Good Practice Guide: Technology Transfer (ISPE, Tampa, Florida, 2003).

11. S. Scypinski et al., "Analytical Method Transfer," Pharm. Technol. 26 (3), 84–88
(2002)

12. PhRMA Analytical Research and Development Workshop, Wilmington, Delaware,

Sept. 20, 2000.

13. "The Metamorphosis of Manufacturing," IBM report, Apr. 2005.

14. D. Nevalainen et al., "Evaluating Laboratory Performance on Quality Indicators

with the Six Sigma Scale," Arch. Pathol. Lab. Med. 124, 516–519 (2000).

15. K. Ishikawa, What is Total Quality Control? The Japanese Way (Prentice-Hall,
Englewood Cliffs, NJ, 1985), 63–64.

16. D. Stamatis, Failure Modes and Effects Analysis, FMEA from Theory to Execution
(ASQ Qualtiy Press, Milwaukee, WI, 2d ed., 2003).

http://www.pharmtech.com/print/225359?page=full 6/7
20/12/2017 The Application of Quality by Design to Analytical Methods
17. R. McDermott, R. Mikulak, and M. Beauregard, The Basics of FMEA (Quality
Resources, New York, 1996).

18. Dyadem Press, "Guidelines for Failure Modes and Effects Analysis (FMEA) for
Medical Devices," 2003.

© 2017 UBM. All rights reserved.

Source URL: http://www.pharmtech.com/application-quality-design-analytical-methods

Links:
[1]
http://Pharmaceutical%20CGMPs%20for%20the%2021st%20Century%E2%80%94A%20Risk%20Based%20Approach%7C~http://www.fda.gov/cder/gmp/gmp2004/GMP_finalreport2004.htm
[2] http://Pharmaceutical%20Development%7C~http://www.ich.org/cache/compo/276-254-1.html
[3] http://Quality%20Risk%20Management%7C~http://www.ich.org/cache/compo/276-254-1.html
[4] http://Office%20of%20New%20Drug%20Quality%20Assessment%20at%20FDA%7C~http://www.fda.gov/cder/ondc/default.htm
[5]
http://Click%20here%20to%20download%20a%20template%20on%20which%20to%20conduct%20a%20failure%20mode%20effect%20analysis%20(FMEA).%7C~www.pharmtech.com/pharm
Packaging-Resources/ArticleStandard/Article/detail/464686
[6] mailto:phil.j.borman@gsk.com

http://www.pharmtech.com/print/225359?page=full 7/7