ASTM E3177-18

This international standard was developed in accordance with internationally recognized principles on standardization established in the Decision on Principles for the
Development of International Standards, Guides and Recommendations issued by the World Trade Organization Technical Barriers to Trade (TBT) Committee.
Designation: E3177 − 18
Standard Guide on
Sampling for Process Analytical Technology
This standard is issued under the fixed designation E3177; the number immediately following the designation indicates the year of
original adoption or, in the case of revision, the year of last revision. A number in parentheses indicates the year of last reapproval. A
superscript epsilon (´) indicates an editorial change since the last revision or reapproval.
1. Scope on/in-line applications in solids, liquids, and gases (that is, in
situ PAT measurements), many of the considerations also apply
1.1 This document is to be used as a guide to Process
to at-line and off-line applications in which a sample is
Analytical Technology (PAT) instrument sampling, and covers
withdrawn from the process and subsequently presented for
both the sample from which PAT data is collected and the
analysis.
sample that is taken for reference assay. The ASTM definition
1.3 This international standard was developed in accor-
of a guide is a compendium of information or series of options
dance with internationally recognized principles on standard-
that does not recommend a specific course of action. The
ization established in the Decision on Principles for the
intention of a guide is to increases the awareness of informa-
Development of International Standards, Guides and Recom-
tion and approaches in a given subject area, as such this guide
mendations issued by the World Trade Organization Technical
should serve as a collation of points to consider when deter-
Barriers to Trade (TBT) Committee.
mining a sample practice for PAT instruments. It is not
intended to serve as a practice to be followed. As a first step,
2. Referenced Documents
one should define the overall goal of the PAT measurement.
Once defined, this guide describes various considerations as
2.1 ASTM Standards:
they relate to the specific requirements that must be met to
D4177 Practice for Automatic Sampling of Petroleum and
achieve the overall PAT goal, including the attributes to be
Petroleum Products
measured, impact of the scale of the process, and interfacing of
E105 Guide for Probability Sampling of Materials
the measurement system to manufacturing equipment (includ-
E122 Practice for Calculating Sample Size to Estimate, With
ing sampling system reliability). Additionally, it discusses the
Specified Precision, the Average for a Characteristic of a
estimation and validation of the effective sample size and the
Lot or Process
overall contribution to the measurement. Related aspects of
E456 Terminology Relating to Quality and Statistics
data collection and data processing as well as the use of risk
E1402 Guide for Sampling Design
assessments to optimize sampling and to understand the impact
E2363 Terminology Relating to Manufacturing of Pharma-
of potential sampling errors are also covered. Furthermore,
ceutical and Biopharmaceutical Products in the Pharma-
considerations for process control and aspects pertaining to
ceutical and Biopharmaceutical Industry
sample withdrawal and retention are also included. Lastly,
2.2 ASME Standard:
continuous manufacturing processes require special consider-
ASME BPE Bioprocessing Equipment
ations due to the time dependency associated with continuous
operations as compared to batch manufacturing and special
3. Terminology
considerations are needed for sampling of such processes.
3.1 Definitions—For an extensive list of terminology related
1.2 This guide is limited to a high level overview of
to pharmaceutical manufacturing, refer to Terminology E2363.
sampling considerations for PAT applied to any type of
pharmaceutical manufacturing (for example, active pharma-
4. Significance and Use
ceutical ingredient (API), solid oral dosage form, etc.). It is not
4.1 Application of this guidance should enable PAT method
intended to provide technology- or application-specific sam-
developers to design and implement reliable PAT applications
pling guidance, or both. Instead, the intent is to evoke a thought
process around sampling when developing a PAT application.
While the focus is mainly on sampling considerations for
For referenced ASTM standards, visit the ASTM website, www.astm.org, or
contact ASTM Customer Service at service@astm.org. For Annual Book of ASTM
This guide is under the jurisdiction of ASTM Committee E55 on Manufacture Standards volume information, refer to the standard’s Document Summary page on
of Pharmaceutical and Biopharmaceutical Products and is the direct responsibility of the ASTM website.
Subcommittee E55.14 on Measurement Systems and Analysis. Available from American Society of Mechanical Engineers (ASME), ASME
Current edition approved Sept. 1, 2018. Published September 2018. DOI: International Headquarters, Two Park Ave., New York, NY 10016-5990, http://
10.1520/E1377-18. www.asme.org.
Copyright © ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States
E3177 − 18
that avoid many common sources of error around sampling. 5.2.4 Interfacing of measurement systems to manufacturing
Sampling is a key element of method and process validation equipment (see Section 9):
plans. • Locations of sensors,
4.1.1 Many ASTM standards discuss sampling; however, • Numbers of sensors,
almost all are very specific to a certain field or application. For • Rationale for position of sensors,
example, the “Standard Practice for Automatic Sampling of • Mechanical interfacing:
Petroleum and Petroleum Products” (D4177) specifically cov- • Effect of sample interface/probe on the process, and
ers information for the design, installation, testing, and opera- • Cleaning of sensors.
tion of automated equipment for the extraction of representa- • Effect of time/temperature/other parameters on the
tive samples of petroleum and petroleum products from a sample interface.
flowing stream and storing them in a sample receiver. 5.2.4.1 The key objective is to establish how representative
4.1.2 Other useful ASTM standards include: E105 (Practice the sampling schedule is of the process under investigation,
for Probability Sampling of Materials), E122 (Standard Prac- that is, does the sampling plan ensure that the pertinent
tice for Calculating Sample Size to Estimate, With a Specified variability in the process is captured. Also, there is a need to
Precision, the Average for a Characteristic of a Lot or Process), establish that the sampling interface is stable to changes in the
process and material characteristics of the sample that may be
E1402 (Standard Guide for Sampling Design), and E456
(Terminology Relating to Quality and Statistics). These stan- encountered during normal operation. Furthermore, it has to
be ensured that the sample interface itself has no impact on the
dards review similar considerations as those addressed in this
guidance and can be consulted for additional insight on how to manufacturing process and product itself.
5.2.5 Rationalization of the contribution of a sample to a
deal with specific sample types or situations. However, such
standards should be carefully reviewed for relevance to phar- measurement (see Section 10):
• Sample mass contributing to a single measurement;
maceutical applications.
• Heterogeneity of the sample material at the microscopic
level;
5. Summary of Practice
• Speed of analysis, data transfer rate, and relative
5.1 Representative sampling is a key aspect of successful
displacement of the sample;
PAT measurements. There are many aspects to be considered to
• Measurement reliability; and
develop a suitable sampling approach. Scientific and statistical
• How representative the measured sample is of the
principles should be used in combination with appropriate risk
process or product, or both.
assessment tools to ensure that the sampling approach is
5.2.5.1 The key objective is to ensure that the validation of
suitable for the application.
a PAT sampling system is focused on the appropriate param-
5.2 This guide is organized into sections each of which
eters.
describes a particular aspect of sampling practices for PAT
5.2.6 Measurement cycle time (see Section 11):
applications. Presented below is a brief description of each of
• Frequency of measurement, and
the sampling aspects as well as the key objective to be
• Numbers of measurements to be averaged, etc.
addressed.
5.2.6.1 The key objective is to establish that the timescale of
5.2.1 Attribute to be measured (see Section 6):
the measurement is appropriate relative to the timescale of the
• Attribute(s) of interest,
process.
• Scale or physical characteristic of the attribute: macro-
5.2.7 Risk assessment (see Section 12):
scopic versus microscopic, and
• Use of appropriate risk assessment tools.
• Direct or indirect measurement.
5.2.7.1 The key objective is to ensure that the risks of
5.2.1.1 The key objective is to clearly define the attribute
making a sampling error are assessed and mitigated.
that is being measured.
5.2.8 Process control (see Section 13):
5.2.2 Process scale and nature (see Section 7):
• Impact of sampling on the ability to control a process.
• Scale, and
5.2.8.1 The key objective is to establish the sample size that
• Dynamics.
has the ability to reliably separate signal from noise for the
5.2.2.1 The key objective is to understand the impact of the
purpose of process control.
scale and dynamics of the process on sample size, frequency of
5.2.9 Sample withdrawal and retention prior to reference
sampling, and sampling locations.
analysis (see Section 14):
5.2.3 Estimation of the mass of sample investigated (‘effec-
• Time between PAT measurement and reference
tive sample size’) (see Section 8):
analysis, and
• What is the area or volume under scrutiny?
• Procedure for sample withdrawal.
• Depth of penetration?
5.2.9.1 The key objective is to consider the impact of sample
• Numbers of replicate measurements to achieve the
withdrawal and time between PAT measurement and reference
required signal to noise ratio and capability of the measurement
system?
In this guide, reference analysis is defined as the (chemical or physical, or both)
5.2.3.1 The key objective is to establish that the effective
analysis of a sample withdrawn from a process, typically after a PAT measurement
sample size and the level of scrutiny (degree of examination)
has been performed on it, to establish the reference value for the PAT measurement.
are appropriate. This analysis is often done in a laboratory using conventional analytical techniques.
E3177 − 18
analysis. This covers the stability of the sample between the may be required (see also Section 10). Note though that a larger
time of removal from the process until time of analysis such manufacturing scale does not always automatically necessitates
that the sample analyzed is representative. an increase in number of sensors, a change in location, or a
5.2.10 Continuous processing (see Section 15): different sampling plan; this will depend on the process,
• Time dependency of continuous processes. system, and PAT measurement.
5.2.10.1 The key objective is to recognize that continuous
processes require special considerations due to their time-
8. Estimation of the Amount of Sample Which is Being
dependent nature. Investigated (‘Effective Sample Size’)
8.1 On-line and in-line PAT measurement applications typi-
6. Attribute to be Measured
cally do not involve removal of samples from the system or
6.1 When devising a sampling interface, device, or plan for
process. Measurements are generally made using sensors or
any PAT method, one of the first aspects that has to be
probes that are in direct contact with, or inserted into the
considered is the attribute of interest, that is, what is it
system or process.
specifically that is going to be measured.
8.1.1 However, even though there may be no physical
6.1.1 The physical scale of the attribute is of significant
removal of samples from the system or process, all such PAT
importance as the sampling strategy may change depending on
measurement techniques are effectively evaluating a sub-set of
whether the attribute to be measured is microscopic (for
the material under investigation. This derives from the fact that
example, excipient distribution, morphology) or macroscopic
such techniques have a limited field of view or operation; for
(for example, crystal or granule properties such as density,
example, they will penetrate a sample matrix or process to a
size/distribution, etc.) in nature; this ties with the physical
finite depth and can only make measurements at a finite rate.
properties of the material(s) being examined.
8.1.2 It is recognized that estimating or calculating an
6.1.2 Additionally, the type of measurement has to be taken
effective sample size for analysis by the PAT system may be
into account because the sampling requirements for a direct
difficult. For powders or solids it may be possible to approxi-
measurement, that is, attribute of interest is measured directly,
mate the effective sample size for a spectroscopic technique
can be different as compared to those for an indirect
using some reasonable assumptions. In such cases, for
measurement, that is, attribute of interest is derived from the
example, the effective sample size can be a function of
measurement of another (set of) attribute(s) or process param-
illumination area, average penetration depth, material density,
eters.
sampling frequency and other factors depending on the type of
6.2 If multiple attributes are to be determined by means of
analyzer and material characteristics. However, in many liquid
a single measurement process or system, then the sampling and gas phase applications this can be significantly more
plan has to cover requirements associated with all the indi-
difficult depending on the measurement technique and the
vidual attribute measurements. The goal is to implement the system under investigation.
appropriate PAT measurement system(s) and associated sam-
8.1.2.1 When possible, as a general principle, the effective
pling plan with the appropriate sensitivity for the attribute of sample size should be calculated (or, at least, estimated) based
interest and ruggedness/insensitivity with respect to interfer-
on the contributions from the factors discussed above, that is,
ences from other factors. volume or size of the system or process being monitored (and
this, in turn, may need to be estimated based on the area of
7. Impact of Scale of the Process
examination and depth of penetration). Matrix properties of the
7.1 The scale of the manufacturing process may have an system or process being monitored should be understood. This
may change during the measurement cycle, so an average value
impact on the sampling requirements.
7.1.1 During development at small scale, the sampling or estimate may be needed.
frequency may be higher than at full commercial scale as
8.2 Frequency/Averaging of Measurement—Where multiple
product and process knowledge and understanding are the
measurements are averaged, or the output from several sensors
focus. At commercial scale a lower frequency of sampling may
is combined, these factors should also be considered:
be appropriate if the process is well characterized, understood,
• The relevance of a single point or multiple point
predictable, and controlled.
measurement to assess the matrix properties of a large mass of
7.2 The fact that commercial scale manufacturing may be (moving) material.
subject to an increased likelihood of subpopulations (substrata) • The signal to noise characteristics of the measurement
which would increase sample-to-sample variations should be system at the sampling size and sampling mass used in the
considered. Sample heterogeneity would have to be taken into application; in other words, the fundamental capability of the
account in this case. Further, depending on the size and instrument to perform the required measurement.
physical structure of the manufacturing equipment used, a 8.2.1 Once the effective sample size is established or
different number of s
...