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STIMULI TO THE REVISION PROCESS

Stimuli articles do not necessarily reflect the policies
of the USPC or the USP Council of Experts

Proposed New USP General Chapter: The Analytical

Procedure Lifecycle ⟨1220⟩
USP Validation and Verification Expert Panel: Gregory P Martin, MS (Chair); Kimber L
Barnett, PhD; Christopher Burgess, PhD; Paul D Curry, PhD; Joachim Ermer, PhD;
Gyongyi S Gratzl, PhD; John P Hammond; Joerg Herrmann, PhD; Elisabeth Kovacs;
David J LeBlond, PhD; Rosario LoBrutto, PhD; Anne K McCasland-Keller, PhD; Pauline L
McGregor, PhD; Phil Nethercote, PhD; Allen C Templeton, PhD; David P Thomas, PhD;
a
ML Jane Weitzel; Horacio Pappa, PhD

ABSTRACT
An analytical procedure must be demonstrated to be fit for its intended purpose. It is
useful to consider the entire lifecycle of an analytical procedure, i.e., its design and
development, qualification, and continued verification. The current concepts of
validation, verification, and transfer of procedures address portions of the lifecycle but
do not consider it holistically. The purpose of this proposed new chapter is to more
fully address the entire procedure lifecycle and define concepts that may be useful.
This approach is consistent with the concept of quality by design (QbD) as described
in International Council for Harmonisation (ICH) Q8-R2, Q9, Q10, and Q11. The
lifecycle approach can potentially be applied to all procedures, although the level of
effort should be consistent with the complexity and criticality of the procedure.

INTRODUCTION
This Stimuli article provides the framework for The Analytical Procedure Lifecycle
⟨1220⟩. This article describes the current thinking of the USP Validation and Verification
Expert Panel which advises the General Chapters—Chemical Analysis Expert Committee
with regard to future trends in analytical procedures development, qualification, and
continued monitoring. These concepts are described here for the purpose of offering an
alternative approach to the classical analytical validation and subsequent verification and
transfer, viewing these activities as a continuum and closely interrelated rather than as
discrete actions. This enhanced approach potentially offers several advantages,
including:

• Improved understanding of the procedure and control of sources of variability,

which are linked to the intended use of the procedure as described in the analytical
target profile (ATP)
• Procedures that are more robust, resulting in fewer failures during use and during
qualification in a new laboratory
• Reduction of overall resources required for a new or revised procedure. The levels
of effort, formality, and documentation should be commensurate with the level of
risk
• Identification of adverse trends, allowing proactive measures and facilitation of
continued improvements and change control through continued monitoring

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The Validation and Verification Expert Panel considers this lifecycle approach to still be
evolving, as International Council for Harmonisation (ICH) Q8, Q9, and Q10 concepts are
being adopted by the analytical community. Therefore, it is advisable to provide
guidance on how to incorporate lifecycle management strategies into analytical
procedures, which will increase flexibility in demonstrating the fitness of analytical
procedures while leaving the option open to use the classical approach described in
Transfer of Analytical Procedures ⟨1224⟩, Validation of Compendial Procedures ⟨1225⟩,
and Verification of Compendial Procedures ⟨1226⟩. In addition to offering a preview of the
proposed general chapter, the General Chapters—Chemical Analysis Expert Committee
and the Validation and Verification Expert Panel are seeking specific input from users in
the pharmaceutical industry regarding the following questions:

1. Would a general chapter on the lifecycle approach be valuable?

2. Is the information presented herein sufficient for implementation of an analytical
procedure under the quality by design (QbD) approach?
3. Would incorporation of references to statistical tools, either in this chapter or in
another chapter, be valuable?
4. Can you provide input or approaches that would improve this proposed general
chapter?

The content and scope of the proposed general chapter will be refined on the basis of
responses to this Stimuli article. Because stakeholders may have differing views, the
objective of this Stimuli article is to identify and build areas of consensus that may be
included in ⟨1220⟩.
THE LIFECYCLE APPROACH
Reportable values generated using qualified analytical procedures provide the basis for
key decisions regarding compliance of a test article with regulatory, compendial, and
manufacturing limits. These values may be applied against decision rules that provide a
prescription for the acceptance or rejection of a drug product or drug substance. This is
based on the analytical measurement, the uncertainty of the measurement, and the
acceptance criteria, taking into account the acceptable level of risk of making a wrong
decision.
Application of lifecycle management concepts to analytical procedures is based on QbD
and provides an opportunity to use the knowledge gained from the application of
scientific approaches and apply that knowledge to reportable values generated when
using the analytical procedure. The concept of QbD is understood as a systematic
approach that begins with predefined objectives and emphasizes product and process
understanding and process control, based on sound science and quality risk management
(ICH Q8). The quality risk management (QRM) for an analytical procedure is a
systematic process for the assessment, control, communication, and review of risk to the
quality of the reportable value across the analytical procedure lifecycle. It is important to
understand and control sources of variability to ensure that measurement uncertainty is
aligned with the decisions that will be made using results generated by an analytical
procedure.
Lifecycle Stages
In order to provide a holistic approach to controlling an analytical procedure throughout
its lifecycle, one can use a three-stage concept (see Figure 1) that is aligned with current
process validation terminology:

Stage 1: Procedure Design and Development

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Stage 2: Procedure Performance Qualification

Stage 3: Continued Procedure Performance Verification

Figure 1. The analytical procedure lifecycle.

Analytical Target Profile

A fundamental component of the lifecycle approach to analytical procedures is having a
predefined objective that stipulates the performance requirements for the analytical
procedure. These requirements are described in the ATP. The ATP states the required
quality of the reportable value produced by an analytical procedure in terms of the target
measurement uncertainty (TMU). ATP criteria are derived from external requirements
and not only from the performance of the analytical procedure. The acceptable level of
risk of making an incorrect decision is considered when establishing an ATP. The
reportable value may be the mean of multiple analytical results, if there is a defined
replication strategy that is documented in the procedure. TMU is the maximum
uncertainty that can be associated with a reportable result while still remaining fit for its
intended purpose. TMU is a consolidation of the uncertainty from all sources, as
illustrated in Figure 2.

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Figure 2. Consolidation of attributes contributing to TMU through accuracy (bias) and

precision.

When establishing an ATP, the following should be considered, where relevant:

• Sample to be tested
• Matrix in which the analyte will be present
• Allowable error for the measurement as assessed through accuracy (bias) and
precision, both of which make up the TMU
• Allowable risk of the criteria not being met (proportion of results that are expected
to be within the acceptance criteria)
• Assurance that the measurement uncertainty and risk criteria are met

The current ICH and USP validation guidance can be incorporated into an ATP, with
emphasis on the quality of the reportable value as shown for a drug product assay
(Example 1).
EXAMPLE 1: ATP #1
The procedure must be able to quantify [analyte] in the [description of test
article] in the presence of [x, y, z] with the following requirements for the
reportable values: Accuracy = 100% ± D% and Precision ≤ E%.
The ATP inputs for [analyte], [description of test article] and [x, y, z] (which may be
impurities or excipients) can be specified. Values for D and E should be specified. For
example, D may be expressed as a percentage of label claim and E may be expressed as
a percentage of relative standard deviation (%RSD). Alternative units are acceptable as
long as they are unambiguous.
Advantages of this approach to an ATP are:

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• The ATP is easy to understand, calculations are relatively straightforward, and data
are easy to assess for ATP conformance by non-statisticians.
• The ATP includes criteria for accuracy (bias) and precision of the reportable value
and is therefore linked to the quality of the reportable values.
• This approach encourages understanding and control of sources of variability
(defined control strategy).

Limitations of this approach include:

• Accuracy (bias) and precision are assessed separately so that the TMU of the
results is not explicitly defined.
• This approach does not quantify the risk of making a wrong decision by including
probability and confidence criteria. However, while the level of risk is not
transparent, risk can be controlled through the alignment of specifications and
accuracy (bias)/precision criteria such that reportable values that are within
specification have a low probability of being on an edge of failure with respect to
clinical relevance.

In current approaches, criteria for accuracy (bias) and precision are often established
based on generally accepted industry practices using default criteria. However, in a QbD
approach, these criteria are aligned with the specification and product and process
needs, and the criteria focus on the reportable value.
EXAMPLE 2: ATP #2
The procedure must be able to quantify [analyte] in the [description of test
article] in the presence of [x, y, z] so that the reportable values fall within a
TMU of ±C%.
The ATP inputs for [analyte], [description of test article] and [x, y, z] (which may be
impurities or excipients) can be specified.
This example contains criteria for the TMU, (±C%), which is directly linked to the
results generated by the procedure. The TMU considers the acceptable difference
between the measured reportable value and the target value and can be established
based on a fraction of the specification range.
The ATP serves as a reference point for assessing the fitness of an analytical procedure,
not only in the development phase but also during all changes within the analytical
lifecycle. Note that the ATP is not linked to a specific analytical procedure. Thus, it is
conceivable that more than one analytical procedure could meet the requirement of an
ATP, and that an alternate procedure that meets the requirement stated in the ATP
would be acceptable.
For procedures that do not already have an ATP, including existing procedures in
compendial monographs, one can be constructed. For instance, the ATP may be based
on product acceptance criteria and any existing requirements for the analytical procedure
as stated in the monograph.
In assessing new or existing procedures for their ability to meet an ATP, analysts may
use statistical methods for analyzing prospectively designed studies. In the case of
existing procedures for which significant data are available, statistical procedures for
retrospective evaluation of historical data, such as stability data, laboratory
investigations, check samples/controls, release data, and others may be used. The level
of variability present in the historical data may trigger additional studies that aim to
understand and reduce or eliminate sources of variability and also improve the data
quality by means of an optimized control strategy to meet the ATP.
STAGE 1: PROCEDURE DESIGN AND DEVELOPMENT

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Knowledge Gathering
When the need for a procedure is identified, relevant information should be gathered
prior to conducting laboratory studies. Such information may include known chemical
structures, solubility, reactivity, and stability of the molecules of interest. A literature
search may also be useful to understand how the procedure has been applied or
modified by others. The intended purpose and fitness for routine use must always be
considered. Any relevant information identified during the knowledge-gathering
stage—such as the range over which the procedure will be used, criteria for run time,
equipment type, and other information—is also considered during the design and
development stage. However, this information is not captured in the ATP.
Once the knowledge-gathering phase is complete, the information is used to select an
appropriate technology and procedure likely to meet the requirements defined in the
ATP.
Risk Assessment Evaluation and Control
The objective of a risk assessment is to develop understanding of procedure variables
and their impact on the reportable value, which will assist in the development of a
control strategy.
For example, tools such as process maps and Ishikawa diagrams (fishbone diagrams)
may be used, in addition to prior knowledge, to provide structure to a brainstorming and
information-gathering exercise to identify variables. The attributes shown in Figure 2
may serve as a useful starting point. It is important to consider all steps in the analytical
procedure, including development of standard and test sample preparation. It is
important to ensure that the sample preparation step does not cause the analyte to
undergo any significant (uncontrolled or unintended) changes in its relevant properties
from the moment of sampling to the time when the actual analysis is carried out. Sample
preparation conditions are frequently a source of procedure variability and/or bias and its
influence in the performance of the procedure should be investigated. In the case of
sample preparation that involves dissolving a sample prior to analysis, systematic
extraction studies should be performed to ensure robust, rugged, and complete
extraction/dissolution. It is also important to investigate sources of variability and
systematic bias during Stage 1 so that they may be eliminated or controlled during
routine use of the procedure.
Besides accuracy (bias) and precision, which are defined in the ATP, experiments may
include other method-specific performance attributes known as traditional validation
characteristics (see Figure 2). However, these characteristics are eventually consolidated
into the ATP attributes.
Risk-assessment tools may be used to prioritize which variables should be studied to
evaluate their impact on the reportable results. Results from experiments investigating
variables can be used to develop and justify the control strategy.
Design of experiments (DOE) is a fundamental methodology for the QRM process. It is
a systematic method to determine the relationships between variables affecting a
process, and it is used to find cause-and-effect relationships. This information is needed
to manage process inputs in order to optimize the output of the procedure. Multi-factor
studies are a powerful way to develop understanding, although single-factor studies are
also appropriate in some cases. DOE also utilizes statistical data treatment, which allows
clear determinations regarding the significance of a variable and/or its interactions
towards the output.
Analytical Control Strategy

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The analytical control strategy is a planned set of controls, which is the output of the
QRM process. It is derived from an understanding of both the requirements for the
reportable value established in the ATP and the understanding of the analytical
procedure as a process.
The variables that need to be controlled and their acceptable ranges (from the risk
assessment and subsequent experiments) should be explicitly specified in the procedure.
Typical controls may include limits for variability of calibration and between replicates;
instructions for environmental controls (light, temperature, and humidity); sample
solution stability; and, for chromatographic methods, system suitability requirements
such as sensitivity, resolution, etc. In addition, the controls may include variables and
aspects related to the sample, sample preparation, standards, reagents, the facility,
equipment operating conditions, the format of the reportable value (i.e., number of
replicates), and the frequency of monitoring and control.
A replication strategy may be applied to reduce the random variability of the mean
(reportable value). It should be noted that increasing the number of replicates will only
reduce the random variability corresponding to the step that is replicated. For example,
increasing the number of injections will reduce the injection variance, whereas increasing
the number of sample preparations will reduce the variance associated with sample
preparation.
The analytical control strategy plays a key role in ensuring that the ATP is realized
throughout the lifecycle. Different control strategies may be required in different labs or
when using different equipment.
Knowledge Management
Knowledge management for analytical procedures is a systematic approach to
acquiring, analyzing, storing, and disseminating information, and is an important factor
in ensuring the ongoing effectiveness of the control strategy. Knowledge management
should include, but should not be limited to, development activities, technology transfer
activities to internal sites and contract laboratories, qualification and monitoring studies
over the lifecycle of the analytical procedure, and change management activities. The
knowledge gathered to develop the procedure understanding should be collected in a
repository and shared as needed to support implementation of the control strategy
across sites that use the analytical procedure. Changes and improvements to a qualified
analytical procedure should be made through the change control system.
Preparing for Qualification
Before beginning a qualification study, data collected during Stage 1 can be assessed to
provide supporting evidence for the absence of significant bias and a confirmation that
the precision is at an appropriate level, as well as other pertinent analytical
characteristics. Although bias and precision estimates at this stage do not guarantee that
a qualification study will be successful, they can flag a potentially problematic procedure.
As an integral part of preparation for laboratory qualification to execute a compendial
procedure or a procedure from another site, the process of QRM should be carried out,
and the control strategy of the procedure should be verified or expanded to ensure that
the requirements of the ATP are met.
STAGE 2: PROCEDURE PERFORMANCE QUALIFICATION
Once an ATP has been established and design activities are completed with appropriate
minimization of bias and uncertainty, knowledge is compiled and documented. A
procedure control strategy is proposed and the performance of the procedure is ready to
be qualified. The purpose of qualification is to confirm that the procedure generates
reportable values that meet the ATP criteria and remain appropriate for the testing of the

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product in the environment where it will be used. The laboratory that will be using the
procedure to generate results should perform the qualification study.
The protocol for the qualification study should be documented and should include (but
is not limited to) the ATP; method-specific performance attributes and acceptance
criteria; a description of or reference to the procedure including its control strategy; a
description of the experiments including the number of standards, test sample, and
series analysis that will be performed; and the statistical approach to be used to analyze
the data.
The analytical control strategy may be refined and updated as a consequence of any
learning from the qualification study. For example, further controls may be added to
reduce sources of variability that are identified in the routine operating environment in
an analytical laboratory, or replication levels (multiple preparations, multiple injections,
etc.) may be modified based on the uncertainty in the reportable value.
Qualification strategies will depend on the criteria described in the ATP and on the
intended use of the procedure.
STAGE 3: CONTINUED PROCEDURE PERFORMANCE VERIFICATION
Stage 3 of the procedure lifecycle ensures that the analytical procedure remains in
control, i.e., this stage maintains the established performance level and thus continues
to meet ATP criteria. Therefore, the ATP is used as a reference point for the performance
of the procedure during Stage 3 of the lifecycle of the analytical procedure.
This stage includes both routine monitoring and evaluation of the analytical procedure's
performance after changes to determine if the analytical procedure continues to be fit for
purpose.
Routine Monitoring
Effective monitoring of an analytical procedure provides confidence that the reportable
value generated is fit for purpose.
This stage should include an ongoing program to collect and analyze data that relate to
analytical procedure performance. Monitoring may include tracking analytical results,
system suitability failures, out-of-specification or out-of-trend investigations, stability
trends, or other parameters as appropriate. If the monitoring data indicate that the
procedure is not in control, an investigation should be performed with a goal of
identifying the root cause. Corrective and preventive action should be taken to ensure
that the analytical control strategy is updated in the analytical procedure.
A routine monitoring program therefore needs to be designed to:

• Ensure that the performance of the procedure or of appropriate steps (for

example, injection and sample preparation variability) maintains an acceptable
level over the procedure lifetime. (This is done to conclude that the reportable
values produced by the procedure continue to meet the ATP requirement.)
• Provide an early indication of potential procedure performance issues or adverse
trends.
• Identify any changes required to the analytical procedure.

Changes to an Analytical Procedure

During the lifecycle of a pharmaceutical product, both the manufacturing process and
the analytical procedure are likely to experience a number of changes because of
continued improvement activities or the need to operate the method and/or process in a
different environment (method transfer).
Depending on the degree of change, the actions required to qualify the change will be
different. Some examples are given below:

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• A change to a procedure variable to a value within the range that was previously
qualified would not require additional experimentation to qualify the change.
• A change to a procedure variable to a value outside the range that was previously
qualified to produce fit-for-purpose data would require performance of a risk
assessment. The risk assessment should consider which procedure performance
characteristics may be impacted by the change and should then perform an
appropriate procedure performance qualification study to confirm that the change
does not impact the method's ability to meet the ATP.
• A change to a new laboratory would require review of the risk assessment and an
appropriate qualification study (which might include comparability testing or a
reduced or full requalification).
• A change to a new procedure/technique would require performance of appropriate
development and qualification activities (Stages 1 and 2) to demonstrate
conformance of the new procedure to the ATP.
• A change impacting the ATP, e.g., a specification limit change or a need to apply
the procedure to measure levels of analytes not considered in the original ATP,
would require an update to the ATP and a review of the existing procedure design
and qualification data (Stages 1 and 2) to determine whether the procedure will
still meet the requirements of the new ATP.

The level of activities required to confirm that a changed analytical procedure is

producing fit-for-purpose data will depend on an assessment of 1) the risk associated
with the change, 2) the knowledge available about the procedure, and 3) the
effectiveness of the control strategy. It is recommended that for all changes, a risk
assessment should be carried out to determine the appropriate level of activities
required. The aim of the exercise is to provide confidence that the modified method will
produce results that meet the criteria defined in the ATP. This may be assessed by
considering the risk that the change in the method will have on the accuracy (bias) and
precision of the reportable value. Risk assessment tools can be used to provide guidance
on what actions are appropriate to verify that the method is performing as required.
Applying a lifecycle approach to analytical procedures should ensure that quality
objectives for the reportable values are met on a consistent basis.

a
Correspondence should be addressed to: Horacio Pappa, PhD, Director–General
Chapters, US Pharmacopeial Convention, 12601 Twinbrook Parkway, Rockville, MD,
20852-1790; tel +1.301.816.8319; e-mail: [email protected]

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