Printed on: Fri Jan 05 2024, 06:32:12 AM(EST) Status: Currently Official on 05-Jan-2024 DocId: GUID-35D7E47E-65E5-49B7-B4CC-4D96FA230821_2_en-US

Printed by: USP NF Official Date: Official as of 01-May-2022 Document Type: GENERAL CHAPTER @2024 USPC
Do Not Distribute DOI Ref: 46nba DOI: https://doi.org/10.31003/USPNF_M10975_02_01
1

Add the following:

▲
á1220ñ ANALYTICAL PROCEDURE LIFE CYCLE
INTRODUCTION
This general chapter holistically considers the validation activities that take place across the entire life cycle of an analytical
procedure and provides a framework for the implementation of the life cycle approach.
The analytical procedure life cycle approach described here is consistent with the quality by design concepts described in
International Council for Harmonisation (ICH) guidelines. The procedure life cycle approach emphasizes the importance of
sound scientific approaches and quality risk management for the development, control, establishment, and use of analytical
procedures. Total error is used in this chapter; however, measurement uncertainty can also be used.
The procedure life cycle approach is applicable to all types of analytical procedures, and the extent of effort should be consistent
with the complexity of the procedure and the criticality of the quality attribute to be measured. The life cycle approach can
be considered optional, and any of the elements can be applied on the basis of how the procedure is used. Elements of the
life cycle approach can also be applied retrospectively if deemed useful or in early stages of development with the appropriate
modifications.
Elements of life cycle management of analytical procedures are also discussed in Analytical Procedures and Methods Validation
for Drugs and Biologics (Guidance for Industry, FDA 2015).
Validation of an analytical procedure is the process by which it is established, through laboratory studies, that the performance
of the procedure meets the requirements for the intended analytical applications. Validation, or demonstration that a
procedure is suitable for the intended purpose, takes place during the entire procedure life cycle, beginning during the initial

al
procedure design activities and extending through routine use. These activities include the formal procedure validation,
verification, and transfer of procedures, as well as establishing and assuring adherence to an appropriate set of procedure
controls and system suitability requirements.
The procedure life cycle is comprised of the analytical target profile (ATP) and three stages, which are introduced below and
shown in Figure 1.
The ATP defines the criteria for the procedure performance characteristics that are linked to the intended analytical application
ci
and the quality attribute to be measured. It applies to all stages of the procedure life cycle. For quantitative procedures, the
ATP describes the required quality of the reportable value since the reportable value generated using a qualified analytical
procedure provides the basis for key decisions regarding compliance of a test article with regulatory, compendial, and
manufacturing limits. The acceptable level of risk of making an incorrect decision can also be considered when establishing
ATP criteria.
ffi
Stage 1: Procedure design encompasses procedure development, which consists of the analytical technology and sample
preparation. It includes understanding gained through knowledge gathering, systematic procedure development
experiments, and risk assessments and associated lab experiments. The output of Stage 1 includes:
1. A set of procedure conditions that minimizes procedure bias to a suitable level, can provide acceptable precision,
and can meet the ATP criteria
O

2. An understanding of the effect of procedure parameters (e.g., temperature, wavelength, flow rate, etc.) on
procedure performance
3. Optimization of performance characteristics of the analytical procedure such as accuracy, precision, the
appropriateness of any calibration model, specificity and limit of quantitation (as far as applicable); this includes a
preliminary replication strategy for samples and standards
4. An initial analytical control strategy (ACS), which is a set of controls (system suitability tests [SSTs] and other
procedure-specific controls) needed to ensure proper performance
Stage 2: Procedure performance qualification consists of studies designed to demonstrate that the procedure is suitable for
its intended purpose. This involves confirmation that the reportable values generated by application of the analytical
procedure meet the ATP criteria as well as confirmation of procedure performance characteristics through the traditional
validation, verification, or transfer studies. Data generated during Stage 1 can be used if available and suitable. At the end
of Stage 2, the replication strategy and the performance of the procedure is confirmed to meet the ATP and other criteria.
Stage 3: Ongoing procedure performance verification involves monitoring the analytical procedure during routine use and
confirming that the performance continues to meet ATP criteria. Monitoring ensures that the performance of the
procedure is maintained at an acceptable level over the procedure lifetime. It can also provide an early indication of
potential performance issues or adverse trends and aid in identifying required changes for the analytical procedure.
Confirming procedure performance after changes ensures that the modified procedure will produce reportable values that
meet the criteria defined in the ATP.
More details about the procedure life cycle are described in the subsequent sections.

https://online.uspnf.com/uspnf/document/1_GUID-35D7E47E-65E5-49B7-B4CC-4D96FA230821_2_en-US 1/12
Printed on: Fri Jan 05 2024, 06:32:12 AM(EST) Status: Currently Official on 05-Jan-2024 DocId: GUID-35D7E47E-65E5-49B7-B4CC-4D96FA230821_2_en-US
Printed by: USP NF Official Date: Official as of 01-May-2022 Document Type: GENERAL CHAPTER @2024 USPC
Do Not Distribute DOI Ref: 46nba DOI: https://doi.org/10.31003/USPNF_M10975_02_01
2

al
ci
ffi
O

Figure 1. The three stages of the analytical procedure life cycle.

ANALYTICAL TARGET PROFILE (ATP)

A fundamental component of the life cycle approach is the definition of the analytical target profile (ATP) for the analytical
measurement. The ATP is a prospective description of the desired performance of an analytical procedure that is used to
measure a quality attribute, and it defines the required quality of the reportable value produced by the procedure, aligned
with the quality target product profile (QTPP). The ATP is based on the intended use for the procedure and, for quantitative
or semi-quantitative procedures, should include upper limits on the precision and accuracy (bias) of the reportable value.
The ATP focuses the design goals for a new analytical procedure, serves as a basis for procedure qualification criteria, and
provides a guide for monitoring of the procedure during its life cycle. Ideally, the ATP should be specified in way that is
independent of the measurement technology; however, in some cases it may be necessary to link it directly to a measurement
technology. The ATP can be defined in many ways, but the overall focus of having a procedure with acceptable bias and
precision should be part of the ATP.
Some examples of ATPs are shown below. The first example has separate criteria for accuracy and precision.
Example 1: The procedure must be able to accurately quantify [drug] in a range from [A units] to [B units] in the [description
of test article] in the presence of [x, y, z] with an accuracy = 100% ± [D%] and a precision ≤ [E%] for the reportable value.
The second example specifies that the combined accuracy and precision, or the distribution of the total analytical error
(TAE), must fall within the desired level.
Example 2: The procedure must be able to quantify [analyte] in a range from [A units] to [B units] in the [description of test
article] in the presence of [x, y, z] so that the distribution of the total analytical error of the reportable value falls within
the total allowable analytical error range of ± [C%].

https://online.uspnf.com/uspnf/document/1_GUID-35D7E47E-65E5-49B7-B4CC-4D96FA230821_2_en-US 2/12
Printed on: Fri Jan 05 2024, 06:32:12 AM(EST) Status: Currently Official on 05-Jan-2024 DocId: GUID-35D7E47E-65E5-49B7-B4CC-4D96FA230821_2_en-US
Printed by: USP NF Official Date: Official as of 01-May-2022 Document Type: GENERAL CHAPTER @2024 USPC
Do Not Distribute DOI Ref: 46nba DOI: https://doi.org/10.31003/USPNF_M10975_02_01
3

These two examples are not exhaustive and other approaches to defining an ATP can be utilized.
BIAS AND PRECISION
Procedure design, qualification, and performance verification often focus on specific procedure performance characteristics.
For example, traditional procedure development is focused on achieving targets for accuracy, precision (repeatability and
intermediate precision), detection/quantitation limit, and robustness. A close examination of these performance
characteristics reveals that they focus on two primary aspects of the measurement:
1. Bias (accuracy): how close the measurement is, on average, to the true value that is being measured
2. Precision: how much the measurement will vary randomly under routine use
The link between specific procedure performance characteristics and the overall bias and precision should be considered during
development. This can lead to a better understanding of the aspects that affect the bias and precision and to a better
assessment and control of the risks associated with using the procedure.
Procedures should be developed to have levels of bias that are consistent with the ATP criteria, and the impact of bias on the
reportable value should be considered. Appropriate limits for bias and precision in the ATP can be determined based on
several factors, including:
• The criticality of the quality attribute being measured
• The risk that an unacceptable error could occur
• The width of the specification acceptance range for the quality attribute measured by the procedure
• The potential clinical safety or efficacy impact (if known) that an analytical error can have
After considering those factors, a maximum allowable combined bias and precision can be determined that provides appropriate
performance for the procedure (see Statistical Tools for Procedure Validation á1210ñ). Once this has been determined, the
distribution of the reportable value should be within that combined range. This approach expands the bias and precision

al
into a combined range for likely values for the measurement (Figure 2).

ci
ffi
O

Figure 2. Relationship between the bias, precision, and the maximum allowable combined bias and precision.

SPECIFICATION AND DECISION RULES

Deciding if a material conforms to specification relies on the use of a decision rule. A decision rule provides the acceptable level
of the probability of making a wrong decision which can be used to define the maximum allowable combined bias and
precision. There are several types of decision rules with the most common being the simple decision rule, where the material
meets specification if the reportable value is within an acceptance range, and otherwise it does not meet specification (Figure
3).

https://online.uspnf.com/uspnf/document/1_GUID-35D7E47E-65E5-49B7-B4CC-4D96FA230821_2_en-US 3/12
Printed on: Fri Jan 05 2024, 06:32:12 AM(EST) Status: Currently Official on 05-Jan-2024 DocId: GUID-35D7E47E-65E5-49B7-B4CC-4D96FA230821_2_en-US
Printed by: USP NF Official Date: Official as of 01-May-2022 Document Type: GENERAL CHAPTER @2024 USPC
Do Not Distribute DOI Ref: 46nba DOI: https://doi.org/10.31003/USPNF_M10975_02_01
4

al
ci
ffi
Figure 3. Use of a simple decision rule.
O

One consideration for determining the ATP criteria is understanding the impact that total analytical error has on the risk
associated with the decision that a material conforms to specification. Total analytical error is used in this chapter; however,
measurement uncertainty can also be used (see Analytical Data—Interpretation and Treatment á1010ñ). The primary risk is
that the decision rule produces the wrong decision; that is, that the material tested is determined to conform (or not conform)
to specification limits when in fact the opposite is true. This risk may be strongly impacted by the procedure variability. The
following are examples of risks associated with a specification that has an upper acceptance limit (Ua) under four scenarios
(Figure 4):
Scenarios 1 and 4: In these scenarios, the decision is clear. The reportable value (RV1 and RV4) is well above or below the upper
acceptance limit relative to the distribution of the total analytical error.
Scenarios 2 and 3: In these scenarios, it is less clear that the true quality characteristic is actually above or below the upper
acceptance criterion and there is probability that the true value of the quality characteristic is actually inside (Scenario 2) or
outside (Scenario 3) the specification acceptance range.
For Scenario 1 and Scenario 4, the simple decision rule produces an outcome with very low risk of making the wrong decision.
However, for Scenario 2 and Scenario 3, the reportable value is close enough to the acceptance criterion to create some risk
that the wrong decision could be made.

https://online.uspnf.com/uspnf/document/1_GUID-35D7E47E-65E5-49B7-B4CC-4D96FA230821_2_en-US 4/12
Printed on: Fri Jan 05 2024, 06:32:12 AM(EST) Status: Currently Official on 05-Jan-2024 DocId: GUID-35D7E47E-65E5-49B7-B4CC-4D96FA230821_2_en-US
Printed by: USP NF Official Date: Official as of 01-May-2022 Document Type: GENERAL CHAPTER @2024 USPC
Do Not Distribute DOI Ref: 46nba DOI: https://doi.org/10.31003/USPNF_M10975_02_01
5

al
ci
ffi
O

Figure 4. The four possible scenarios when a reportable value (RV) is compared to the specification acceptance criteria. Each
outcome shows a normal distribution curve with the reportable value at the center of the TAE distribution. (Adapted from
EURACHEM/CITAC Guide: Use of uncertainty information in compliance assessment, First Edition, 2007.)

In all of these scenarios, what ultimately needs to be considered is the use of the material being tested and how the specifications
are established. If the specification acceptance criteria are well within a safe and efficacious range, using the simple decision
rule that the reportable value must be within the specification acceptance range provides adequate protection. However,
the closer the acceptance range is to the safe and efficacious range, the larger the impact the distribution of the total analytical
error can have on decision rule risks. Managing these risks may be achieved by altering the type of decision rule that is used.
In the situation where the safe and efficacious range is accurately known, guard bands can be applied to that range, based on
the distribution of the total analytical error, to determine the acceptance range (Figure 5). In situations where additional risk
reduction is desired, a multistage testing approach could be used with an indecision zone (Figure 6) for the initial stage of
testing. When the reportable value is within the indecision zone, a predetermined supplementary sampling and testing plan
and decision rule are used to determine conformance.

https://online.uspnf.com/uspnf/document/1_GUID-35D7E47E-65E5-49B7-B4CC-4D96FA230821_2_en-US 5/12
Printed on: Fri Jan 05 2024, 06:32:12 AM(EST) Status: Currently Official on 05-Jan-2024 DocId: GUID-35D7E47E-65E5-49B7-B4CC-4D96FA230821_2_en-US
Printed by: USP NF Official Date: Official as of 01-May-2022 Document Type: GENERAL CHAPTER @2024 USPC
Do Not Distribute DOI Ref: 46nba DOI: https://doi.org/10.31003/USPNF_M10975_02_01
6

al
ci
Figure 5. Decision rule using guard bands based on the total analytical error.
ffi
O

Figure 6. Decision rule using indecision zones based on the total analytical error.

STAGE 1: PROCEDURE DESIGN

Preparation for Analytical Procedure Development
When possible, ATPs should be established for quality attributes that require analysis and established before starting
procedure design activities. Any technique that is capable of meeting the ATP criteria can be selected. Relevant prior
knowledge can assist with the procedure development activities, which can include the physical and chemical properties
of the analytes, information in the scientific literature, and any existing procedures for the analysis of the same material
type or for similar material attributes. The availability of any relevant analytical technology and/or platform analytical
procedures (applicable to materials of similar type) can also be considered, which may expedite procedure development
activities.
Once the technology has been selected, and if development of a new analytical procedure is required, relevant information
should be gathered prior to conducting development activities. Such information may include:
• Known chemical structures and their physical and chemical properties
• Reference standards, reagents, likely instrumentation and systems
• Any other relevant information linked to the operational requirements, such as instrumentation type/setup and
sample preparation
Analytical Procedure Development
The main purposes of procedure development are to identify conditions that minimize or avoid bias, to optimize variability,
and to establish robust operating parameters that have the potential to meet the ATP. This can be carried out through

https://online.uspnf.com/uspnf/document/1_GUID-35D7E47E-65E5-49B7-B4CC-4D96FA230821_2_en-US 6/12
Printed on: Fri Jan 05 2024, 06:32:12 AM(EST) Status: Currently Official on 05-Jan-2024 DocId: GUID-35D7E47E-65E5-49B7-B4CC-4D96FA230821_2_en-US
Printed by: USP NF Official Date: Official as of 01-May-2022 Document Type: GENERAL CHAPTER @2024 USPC
Do Not Distribute DOI Ref: 46nba DOI: https://doi.org/10.31003/USPNF_M10975_02_01
7

the systematic screening and/or optimization of instrumental and sample preparation conditions when appropriate.
This work begins with the process of understanding the influence of analytical procedure parameters on performance
and their impact (directly or indirectly) on the ATP.
It is important to define the objective of development in terms of the desired levels of robustness to be achieved and the
risks associated with the use of the procedure. This ultimately dictates the level of development needed in terms of the
extent of experimentation and any modeling that may be used to optimize procedure performance.
The output of the procedure development process provides procedure operating conditions that represent the desired
level of robustness.
Quality Risk Management (QRM) and the Analytical Procedure
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 life cycle of the analytical procedure.
The aim of the QRM process is to assess the proposed procedure conditions and identify appropriate controls on the
analytical procedure parameters and material attributes that will ensure the procedure meets the ATP. All variables
associated with the analytical procedure should be considered, including sample and standard preparations,
instrumental and equipment parameters, and environmental variables (e.g., laboratory temperature, humidity, etc.).
QRM activities can be applied during procedure development either formally or informally and major sources of bias and
variability can be identified, reduced or even eliminated by ensuring the appropriate technology and procedure
conditions.
The first step in the QRM process is the risk assessment, which starts with risk identification. To facilitate risk identification,
the analytical procedure can be described using a process flow, map, or summary, and each part of the procedure can
be broken down into detailed sub-steps. It is important to consider all steps, from sample and standard preparation to
analyte testing to quantitation. The procedure process map can then be used to identify variables associated with the
analytical procedure. Tools such as Ishikawa diagrams can be used in conjunction with the process maps to identify

al
potential variables associated with each step in the analytical procedure. Prior knowledge related to the analytical
technology can accelerate this step (e.g., generic Ishikawa diagrams and process maps may exist for common analytical
techniques). Figure 7 illustrates a range of potential variables associated with the sample preparation step from an HPLC
analysis. ci
ffi
O

Figure 7. Ishikawa diagram used to identify potential variables.

Once potential variables have been identified, the risk associated with each variable can be estimated and ranked based
on the ability to meet the ATP and other desired performance attributes. This assessment is driven by prior knowledge
and scientific expertise, but some factors with unknown influence may need to be considered higher risk until further
knowledge is available.
A heat map can be a valuable tool to support a qualitative assessment of risk. A heat map provides a visual indication of
which variables are considered to have a potentially strong, medium, or minor impact on the performance of the
analytical procedure (see Table 1).
Table 1. Example of heat map capturing a qualitative risk assessment related to sample preparation and HPLC setup
steps from an analytical procedure. Impact levels are strong (red), medium (amber), and minor (green).

https://online.uspnf.com/uspnf/document/1_GUID-35D7E47E-65E5-49B7-B4CC-4D96FA230821_2_en-US 7/12
Printed on: Fri Jan 05 2024, 06:32:12 AM(EST) Status: Currently Official on 05-Jan-2024 DocId: GUID-35D7E47E-65E5-49B7-B4CC-4D96FA230821_2_en-US
Printed by: USP NF Official Date: Official as of 01-May-2022 Document Type: GENERAL CHAPTER @2024 USPC
Do Not Distribute DOI Ref: 46nba DOI: https://doi.org/10.31003/USPNF_M10975_02_01
8

al
ci
ffi
Alternatively, each risk can be formally scored and ranked using set risk criteria, for example using failure mode and effects
analysis (FMEA).
Once the risk associated with each factor and variable has been determined, planning for how to manage those risks
occurs. The risk for those variables that are well understood may be mitigated by controlling them within a certain
O

range (control variables). Other variables will be difficult or impractical to control, and the risks associated with them
will need to be accepted (noise variables). For variables where there may be higher risk, one way to reduce risk is to
gain additional knowledge about the influence of those parameters using modeling and/or experimentation.
Experimentation is a direct way of generating data that can be used to assess the impact of procedure parameters on
performance, and the use of statistical design of experiments (DOE) is an effective way to do this. This approach is
generally useful for exploring procedure parameters and optimizing the conditions of the procedure to obtain the
desired performance. In a well-designed experiment, the way data are collected ensures that the effect of variables and
their possible interactions on the quality attributes are studied. Specific recommendations on the types of DOEs to use
are outside of the scope of this chapter; however, a design that examines combinations of factors and their possible
interactions usually can better predict procedure performance compared to one-factor-at-a-time designs.
When available, mechanistic models can be used to understand the effect of procedure parameters on performance. Use
of mechanistic models can reduce experimental work and provide a reliable estimate of the behavior of the analytes of
interest.
Some procedures may not require modeling, for example if the technology is simple or if the overall risk of not meeting
the ATP is low.
There are different modeling approaches that can be applied, including empirical and mechanistic, and either may be
appropriate depending on the intended use of the analytical procedure and the desired model accuracy.
Robustness and Method Operable Design Region (MODR)
Robustness is a measure of the capacity of a procedure to remain unaffected by small but deliberate variations in parameters
and to maintain suitability during normal usage. In some cases, it is helpful to demonstrate robustness of the procedure
by developing models that describe the effect of parameters on the performance of the procedure, either through
assessing performance against the ATP or other surrogate criteria. This knowledge also enables the determination of
robust operation regions for procedure parameters and, if desired, a method operable design region (MODR).
The MODR is the multivariate space of analytical procedure parameters that ensure the ATP is fulfilled and therefore provide
assurance of the quality of the measured value. The MODR should ideally be obtained through well-designed
experiments that consider multivariate interactions. If the MODR relates to attributes that are linked to the elimination
of bias (such as ensuring appropriate separation in chromatographic procedures) or minimization of variability (through
operating at a suitable λmax wavelength), an impact on the final performance of the reportable value is not expected.
Consequently, the validation performance characteristics do not need to be investigated completely within the MODR.
When there are a number of noise factors associated with an analytical procedure, performance can vary over time

https://online.uspnf.com/uspnf/document/1_GUID-35D7E47E-65E5-49B7-B4CC-4D96FA230821_2_en-US 8/12
Printed on: Fri Jan 05 2024, 06:32:12 AM(EST) Status: Currently Official on 05-Jan-2024 DocId: GUID-35D7E47E-65E5-49B7-B4CC-4D96FA230821_2_en-US
Printed by: USP NF Official Date: Official as of 01-May-2022 Document Type: GENERAL CHAPTER @2024 USPC
Do Not Distribute DOI Ref: 46nba DOI: https://doi.org/10.31003/USPNF_M10975_02_01
9

among laboratories or instruments or other noise factors. In these cases, the MODR reflects the knowledge at a point
in time and can be managed by the analytical life cycle (see Stage 3).
Replication Strategy for the Reportable Value
Once the target conditions and operating ranges for the procedure have been determined, an assessment can be
performed to develop an understanding of the overall sources of variation contributed by the procedure. This can be
accomplished in many ways, including propagation of error models and measurement system analysis experiments.
Sources of variation may be grouped into general categories such as run-to-run and within-run variations. Those sources
could also be broken down into component categories such as lab-to-lab, instrument-to-instrument, sample
preparation, and sample introduction. If the amount of variation from these sources can be quantified, it may allow for
the use of an optimized sample and standard replication strategy.
In general, replicating the aspects of the procedure that contribute to a large part of the overall variation followed by an
appropriate analysis to generate the reportable value will lead to improved precision. Estimating the amount of variation
associated with each step of the procedure during the procedure design phase can allow for determination of an optimal
sample and standard replication strategy, which may enable the procedure to more easily meet the criteria of the ATP
for the reportable value. Consideration should be given to including the acceptable variability among the individual
results for the factors (e.g. sample preparation, sample injection etc.) being replicated in system suitability criteria (see
Figure 8 for an example of such a criterion).
Analytical Control Strategy (ACS)
The ACS is a set of controls needed to ensure the procedure performs as expected and plays a key role in ensuring that
the ATP is realized throughout the life cycle. The preliminary ACS is identified during the procedure development
process in Stage 1 and includes SSTs and other environmental or procedure controls needed for the procedure to meet
the ATP. It is derived from an understanding of the analytical procedure as a process and the requirements defined in
the ATP. Critical procedure attributes, identified during development, should be controlled, and their acceptable

al
conditions, materials, or criteria should be explicitly specified in the procedure.
The analytical procedure with its associated initial control strategy is the input to Stage 2 of the life cycle.
STAGE 2: ANALYTICAL PROCEDURE PERFORMANCE QUALIFICATION (APPQ)
Stage 2 involves confirming (or qualifying) that the procedure meets the requirements of the ATP in the facility where the
procedure will be routinely operated. This qualification activity takes place once the initial ACS has been defined.
ci
The elements of Stage 1 described above establish the analytical procedure, preliminary ACS, and replication strategy and
conclude the initial development activities. Once the procedure is established, the procedure is ready to undergo analytical
procedure performance qualification (APPQ). APPQ occurs in Stage 2 of the life cycle and evaluates the procedure to
determine if it is capable of consistently generating a reportable value that meets the defined ATP and is suitable for its
intended purpose in the laboratory. APPQ is a term inspired by the FDA Guidance for Industry Process Validation: General
ffi
Principles and Practices in which PPQ is used for process performance qualification that confirms the commercial
manufacturing process design and performance is as expected. Here, APPQ encompasses all of the analytical procedure
activities commonly referred to as qualification, verification, validation, and transfer described in other literature and
guidances. This chapter expands these well-known activities to integrate them into the procedure life cycle and include them
in a process that incorporates the ATP.
Protocol and Study Design
O

APPQ is an important milestone in the analytical life cycle and is thus a documented activity under protocol. The extent
of the APPQ study design depends on several factors including the type of technology of the procedure being qualified.
The protocol for a qualification study generally includes (but is not limited to):
• The ATP.
• The acceptance criteria needed to meet the ATP (e.g., accuracy, precision, range) and procedure-specific
performance characteristics (e.g., specificity, calibration model, quantitation limit). Also refer to other appropriate
guidance related to procedure validation, verification, or transfer. Depending on the data collected in Stage 1, it
may be appropriate to include by reference instead of repeating the experiment.
• A description of (or reference to) the procedure and its initial analytical procedure controls, including system
suitability requirements.
• A description of the qualification experiments that will be performed and the statistical approach to be used to
analyze the data. If appropriate, the experimental design can include varying noise factors in order to demonstrate
acceptable performance under routine use.
• Acceptable performance and robustness under routine use.
• References to platform, universal, and general procedures that cross multiple products and analytes that may allow
for reduced experiments based on previous qualification studies.
• Reference to data generated during Stage 1 that will be used to demonstrate qualification (e.g., robustness).
APPQ Results and Documentation
Upon successful completion of the qualification study, an evaluation should be performed to determine if the relevant
analysis meets the criteria outlined in the ACS, including system suitability criteria, defined in Stage 1. Additional controls
or modification to system suitability criteria may be included to reduce sources of variability that are identified in the
routine operating environment.
When the qualification experiments are complete and the results meet the predefined acceptance criteria and are justified
to be acceptable, the study is documented in a report. The report summarizes the protocol study design and ATP,
presents the data and calculation results, and draws conclusions about the procedure’s suitability for intended use.
If the study did not meet predefined acceptance criteria, it may be appropriate to return to Stage 1 and perform additional
procedure development activities before re-entering Stage 2. Stage 2 may also be reinitiated when significant changes
to the analytical procedure operating conditions are needed or if there is a need to update the ATP.

https://online.uspnf.com/uspnf/document/1_GUID-35D7E47E-65E5-49B7-B4CC-4D96FA230821_2_en-US 9/12
Printed on: Fri Jan 05 2024, 06:32:12 AM(EST) Status: Currently Official on 05-Jan-2024 DocId: GUID-35D7E47E-65E5-49B7-B4CC-4D96FA230821_2_en-US
Printed by: USP NF Official Date: Official as of 01-May-2022 Document Type: GENERAL CHAPTER @2024 USPC
Do Not Distribute DOI Ref: 46nba DOI: https://doi.org/10.31003/USPNF_M10975_02_01
10

Analytical procedure transfer as well as verification of compendial procedures fall under Stage 2 and are governed by the
same documentation descriptions above. The extent of the study design for these activities should be based on the
ATP and on an assessment of the risks to the procedure performance when a procedure is transferred or a compendial
procedure is adopted.
The last steps in Stage 2 are to finalize the documented procedure (including learnings from the APPQ) and to finalize the
ACS. The replication levels (multiple sample and standard preparations, multiple injections, etc.) may be updated based
on the precision of the reportable value found during the qualification. The impact of changing the replication strategy
must consider its continued ability to meet the ATP.
After the completion of the Stage 2 activities, the procedure is released for routine use; that is, it may be utilized for its
intended purpose for testing.
STAGE 3: ONGOING PROCEDURE PERFORMANCE VERIFICATION (OPPV)
Stage 3 of the procedure life cycle ensures that the analytical procedure remains in control during routine use and thus continues
to meet the ATP criteria.
This stage includes both routine monitoring of data linked to the performance of the analytical procedure and evaluation of
the procedure’s performance after changes to determine if the analytical procedure continues to be fit for purpose. Since a
large number of analyses may be performed over time during the application of the analytical procedure, the monitoring
provides an excellent opportunity to obtain reliable performance data during the routine application. This in turn provides
the opportunity to identify unusual behavior and lack of expected performance.
Routine Monitoring
Effective monitoring of an analytical procedure provides ongoing confidence that the reportable values generated are fit
for purpose.
This stage includes an ongoing program to collect and analyze data that relate to analytical procedure performance.
Monitoring may include tracking analytical performance attributes such as SSTs including SST failures, batch data trends

al
including analytically caused out-of-specification or out-of-trend results, trends, and other attributes as appropriate.
The extent of monitoring should be based on the risk associated with the respective quality attribute and with the
analytical procedure. The monitored data and information should be evaluated periodically depending on the number
of analyses performed. If there is an indication that the procedure is not in control, an investigation should be conducted
and corrective and preventive actions taken.
Analytical Control Attributes
ci
Data related to procedure performance can be extracted from the application of the analytical procedure itself or from
additional analyses of control samples. Control samples can be those that are identical to or representative of the
samples to be analyzed, a standard check result, or a standard addition to the sample. Such additional controls may
be implemented on a risk basis, i.e., for complex procedures, or if indicated by performance failures in the monitoring
ffi
program.
The ACS can be used as a source for identifying the relevant attributes used for ongoing monitoring, for example SST
attributes such as system precision, signal-to-noise ratio, or peak symmetry. Operational attributes that are not directly
linked to the ATP may not be well suited for the performance monitoring program. However, monitoring of such
attributes, e.g., HPLC peak resolution or peak symmetry, may still provide benefits to proactively determine required
activities, such as HPLC column replacement.
O

Direct monitoring of the reportable value with comparison to the ATP is best performed by analyzing control samples that
are adequately representative of the test samples. As an alternate option, batch reportable values may be directly
monitored. Although these values are comprised of both process- and analytical procedure-related variability, assessing
their control charts allows the detection of changes and trends. Further investigations would be required to understand
the cause, whether process or procedure related.
Control Charts
The use of control charts is a recommended practice for monitoring of procedure performance attributes and control
sample results. A control chart is a plot of a response variable versus time with limits that are based on the distribution
of expected values around a mean or target value (Figure 8). This approach is based on the premise that, no matter
how well a procedure is designed, there exists a certain amount of natural variability in measurements. When the
variation is due to random causes alone, the procedure is said to be statistically in-control, and values on the chart
should generally stay within the control chart limits.
Control chart limits can be established to detect the presence of special causes of variation, sudden process shift, longer
term drift, or excessive noise. When special cause variation is detected, an investigation can be conducted to determine
the root cause and appropriate corrective actions.

https://online.uspnf.com/uspnf/document/1_GUID-35D7E47E-65E5-49B7-B4CC-4D96FA230821_2_en-US 10/12
Printed on: Fri Jan 05 2024, 06:32:12 AM(EST) Status: Currently Official on 05-Jan-2024 DocId: GUID-35D7E47E-65E5-49B7-B4CC-4D96FA230821_2_en-US
Printed by: USP NF Official Date: Official as of 01-May-2022 Document Type: GENERAL CHAPTER @2024 USPC
Do Not Distribute DOI Ref: 46nba DOI: https://doi.org/10.31003/USPNF_M10975_02_01
11

al
ci
ffi
Figure 8. Example of a control chart for an API titration content range from two replicate determinations.

In addition to the monitoring of these analytical control attributes, average (pooled) performance attributes can be
O

calculated, such as an average standard deviation, a standard deviation from duplicates, or precision of the reportable
value from control samples. Monitoring analytical control attributes over time provides data that can be used for
improved understanding of the true variation of components of the procedure and the overall procedure variation. This
improved understanding can be valuable for determining necessary improvements to the procedure and for improving
the ACS.
Changes to an Analytical Procedure
Changes to analytical procedures may be needed over the life cycle and can be prompted by several events including
needed changes identified through a routine monitoring program, the adoption of new technology, or changes to the
ATP. Such changes should be risk assessed for their impact to determine the appropriate activities required. In addition,
appropriate change management approaches and documentation should be used when making changes to a
procedure.
Depending on the degree of change made to the analytical procedure, the actions required to confirm the performance
after the change will vary. The level of activities required to confirm that a changed analytical procedure is producing
fit-for-purpose data will depend on an assessment of the risk associated with the change, the knowledge available about
the procedure, and the effectiveness of the ACS.
Examples of change
• An adjustment to a procedure parameter to a value within the range that was previously qualified (e.g., a change
within the MODR) may not require additional experimentation before implementation. However, any changes
to the routine operating conditions within the MODR should be risk assessed against the ability to meet the
ATP criteria and further studies performed as needed prior to implementation of the new operating conditions.
An adjustment of the established monitoring limits also might be required.
• A change to a procedure variable to a value outside the set point or range that was previously qualified would
require a risk assessment, which should consider the procedure performance characteristics that may be
impacted by the change. These performance characteristics should then be considered in a PPQ study to
confirm that the change does not impact the procedure’s ability to meet the ATP.
• A change to a new laboratory (i.e., analytical transfer) would require review of the risk assessment and
appropriate qualification activities to ensure that the implemented procedure meets the ATP requirements.
• A change to a new procedure/technique would require new or additional appropriate design and qualification
activities (Stage 1 and Stage 2) to demonstrate conformance of the new procedure to the ATP.

https://online.uspnf.com/uspnf/document/1_GUID-35D7E47E-65E5-49B7-B4CC-4D96FA230821_2_en-US 11/12
Printed on: Fri Jan 05 2024, 06:32:12 AM(EST) Status: Currently Official on 05-Jan-2024 DocId: GUID-35D7E47E-65E5-49B7-B4CC-4D96FA230821_2_en-US
Printed by: USP NF Official Date: Official as of 01-May-2022 Document Type: GENERAL CHAPTER @2024 USPC
Do Not Distribute DOI Ref: 46nba DOI: https://doi.org/10.31003/USPNF_M10975_02_01
12

• A change impacting the ATP, e.g., a specification acceptance limit change, would require a new ATP and review
of the existing procedure design and qualification data (Stage 1 and Stage 2) to determine whether the
procedure will still meet the requirements of the new ATP.

GLOSSARY
Analytical Control Strategy (ACS): A planned set of controls derived from current analytical procedure understanding that
ensures the analytical procedure performance and the quality of the measured results and reportable value.
Analytical Procedure Performance Qualification (APPQ): General term for all activities performed in Stage 2 of the
Analytical Procedure Life Cycle, i.e., to demonstrate that the procedure is suitable for routine application in the respective
laboratory. This may include ICH validation, verification of compendial procedures, or transfer. [NOTE—Other definitions are
also used for qualification of biological procedures, reference materials, and instrument qualification.]
Analytical Procedure Validation: All activities that confirm that a procedure is suitable for the intended purpose that take
place over the entire life of the procedure. [NOTE—This interpretation is broader and more holistic than those in ICH. Within
the context of the ICH Q2-Guidline, validation activities expected for a submission application are described. These activities
take place in the lifecycle Stage 2, which also includes verification of compendial procedures, and analytical transfer.]
Analytical Target Profile (ATP): The ATP defines the required quality of the reportable value and is a description of the
criteria for the procedure performance characteristics that are linked to the intended analytical application and the quality
attribute to be measured.
Bias: Estimate of a systematic measurement error.
Fit for purpose: Demonstration of meeting the intended use as specified in the ATP through the analytical procedure lifecycle.
Measurement Uncertainty: A parameter associated with the result of a measurement, that characterizes the dispersion of
the values that could reasonably be attributed to the measurand.1

al
Method Operable Design Region (MODR): A combination of analytical procedure parameter ranges within which the
analytical procedure performance criteria are fulfilled and the quality of the measured result is assured.
Ongoing Procedure Performance Verification (OPPV): General term for all activities performed in Stage 3 of the
Analytical Procedure Life Cycle. Assurance that an analytical procedure remains suitable during the routine application by
verification of its ongoing suitability after changes, and by monitoring of performance parameters to identify potential
ci
performance changes or adverse trends.
Platform analytical procedure: A platform analytical procedure can be defined as a multi-product method suitable to test
quality attributes of different products without significant change to its operational conditions, system suitability, and
reporting structure. This type of method would apply to molecules that are sufficiently alike with respect to the attributes
that the platform method is intended to measure.
Quality Risk Management (QRM): A systematic process for the assessment, control, communication and review of risks to
ffi
the quality of the analytical procedure over the product lifecycle.
Reportable Value: The reportable value is the end result of a completed measurement procedure, as documented. The
reportable value, which often is a summary value for several individual determinations, is compared with the acceptance
criteria (see General Notices 7.10 Interpretation of Requirements).
Total analytical error (TAE): Total analytical error (TAE) represents the overall error in a test result that is attributed to
imprecision and inaccuracy; TAE is the combination of both systematic error of the procedure and random measurement
O

error.
Transfer of analytical procedures (TAP): Documented process that qualifies a laboratory (the receiving unit) to use an
analytical test procedure that originated in another laboratory (the transferring unit), thus ensuring that the receiving unit
has the procedural knowledge and ability to perform the transferred analytical procedure as intended (USP á1224ñ).
Verification of compendial procedures: Documented assessment of whether the compendial procedure can be used for
its intended purpose, under the actual conditions of use for a specified drug substance and/or drug product matrix (USP
á1226ñ).▲ (USP 1-May-2022)

1 USP PF 44(1) Measurement Uncertainty for the Pharmaceutical Industry.

https://online.uspnf.com/uspnf/document/1_GUID-35D7E47E-65E5-49B7-B4CC-4D96FA230821_2_en-US 12/12