ASTM E2629-20

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: E2629 − 20
Standard Guide for
Verification of Process Analytical Technology (PAT) Enabled
Control Systems
This standard is issued under the fixed designation E2629; 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 subsystems. This guide does not cover the requirements for
continuous quality verification of the overall process, which
1.1 This guide describes the verification of process analyti-
are covered in Guide E2537, or for validation of PAT methods,
cal technology (PAT) enabled control systems using a science-
which is covered in Guide E2898.
and risk-based approach. It establishes principles for determin-
ing the scope and extent of verification activities necessary to
1.5 For information on science- and risk-based approaches
ensure that the PAT-enabled control system is fit for purpose, in the pharmaceutical industry, reference should be made to
properly implemented, and functions as expected.
ICH Q8(R2), ICH Q9, and ICH Q10. For guidance on PAT
systems in the pharmaceutical industry, reference should be
1.2 In this guide, a PAT-enabled control system is consid-
made to FDA Guidance for Industry—PAT and FDA Guidance
ered to be the system that adjusts the manufacturing process
for Industry—Process Validation, as well as EU Guidelines for
using timely measurements (that is, during processing) of
Good Manufacturing Practice for Medicinal Products for
attributes of raw and in-process materials to determine re-
Human and Veterinary Use and EU Guideline on Process
sponses that assure the process remains within specified
Validation for Finished Products.
boundaries and minimizes variability in the output material.
The overall aim of the PAT-enabled control system is to ensure
1.6 This standard does not purport to address all of the
product quality. The PAT-enabled control system of a manu-
safety concerns, if any, associated with its use. It is the
facturing process provides the capability to determine the
responsibility of the user of this standard to establish appro-
current status of the process and drive the process to ensure the
priate safety, health, and environmental practices and deter-
output material has the desired quality characteristics. The
mine the applicability of regulatory limitations prior to use.
control system should be able to respond to process variations 1.7 This international standard was developed in accor-
in a timely manner, providing corrections that ensure that the
dance with internationally recognized principles on standard-
process follows the desired process trajectory to reach the ization established in the Decision on Principles for the
desired outcome. PAT-enabled control systems may use pro-
Development of International Standards, Guides and Recom-
cess models based on first principles understanding or empiri- mendations issued by the World Trade Organization Technical
cal models derived from experimental investigations or both.
Barriers to Trade (TBT) Committee.
In addition to automated controls, a PAT-enabled control
2. Referenced Documents
system may include components where there is manual inter-
vention.
2.1 ASTM Standards:
1.3 Principles described in this guide may be applied E122 Practice for Calculating Sample Size to Estimate, With
regardless of the complexity or scale of the PAT-enabled Specified Precision, the Average for a Characteristic of a
control system or whether applied to batch or continuous Lot or Process
E2363 Terminology Relating to Manufacturing of Pharma-
processing, or both. The intention of this standard is to describe
and support the implementation of a PAT enabled Control ceutical and Biopharmaceutical Products in the Pharma-
ceutical and Biopharmaceutical Industry
Strategy, as described in ICH Q8(R2).
E2476 Guide for Risk Assessment and Risk Control as it
1.4 The principles described in this guide are applicable to
Impacts the Design, Development, and Operation of PAT
a PAT-enabled control system and also to its component
Processes for Pharmaceutical Manufacture
This guide is under the jurisdiction of ASTM Committee E55 on Manufacture
of Pharmaceutical and Biopharmaceutical Products and is the direct responsibility of
For referenced ASTM standards, visit the ASTM website, www.astm.org, or
Subcommittee E55.13 on Process Evaluation and Control.
contact ASTM Customer Service at service@astm.org. For Annual Book of ASTM
Current edition approved Aug. 1, 2020. Published August 2020. Originally
approved in 2011. Last previous edition approved in 2019 as E2629 – 19. DOI: Standards volume information, refer to the standard’s Document Summary page on
10.1520/E2629-20. the ASTM website.
Copyright © ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States
E2629 − 20
E2500 Guide for Specification, Design, and Verification of to operate in the desired manner.
Pharmaceutical and Biopharmaceutical Manufacturing Perry’s Handbook of Chemical Engineering
Systems and Equipment
3.1.4 measurement system, n—system of sensors,
E2537 Guide for Application of Continuous Process Verifi-
instruments, and/or analyzers that collects signals generated by
cation to Pharmaceutical and Biopharmaceutical Manu-
passive or active interaction with process material or process
facturing
equipment and converts those signals into data.
E2898 Guide for Risk-Based Validation of Analytical Meth-
3.1.5 parameter, n—measureable or quantifiable character-
ods for PAT Applications
istic of a system or process. E2363
2.2 Regulatory Guidance and Other Documents:
3.1.6 process model, n—mathematical expression (algo-
ICH Q2(R1) Validation of Analytical Procedures: Text and
rithm) that uses data from the measurement system(s) (inputs
Methodology
to the process model) to calculate the value of one or more of
ICH Q8(R2) Pharmaceutical Development
the process material attributes (outputs from the process
ICH Q9 Risk Management
model) at the time the measurement was taken.
ICH Q10 Pharmaceutical Quality System
3.1.6.1 Discussion—The process model typically will have
FDA Guidance for Industry—PAT A Framework for Inno-
to handle sets of orthogonal or nonorthogonal attributes. The
vative Pharmaceutical Development, Manufacturing and
mathematical algorithm will ideally represent first-principle
Quality Assurance
understanding of the process being modelled. However, when
FDA Guidance for Industry—Process Validation General
sufficient first-principles understanding is unavailable, an em-
Principles and Practices
pirical model may also be used.
EU Guidelines for Good Manufacturing Practice for Medici-
3.2 Acronyms:
nal Products for Human and Veterinary Use Annex 15:
3.2.1 CCP—Critical control parameter
Qualification and Validation
3.2.2 CPP—Critical process parameter
EU Guideline on Process Validation for Finished Products
3.2.3 CQA—Critical quality attribute
3. Terminology
3.2.4 CQV—Continuous quality verification
3.1 Definitions—See also Terminology E2363 for other PAT
3.2.5 FDA—Food and Drug Administration
terms.
3.2.6 ICH—International Conference on Harmonization of
3.1.1 attribute, n—characteristic or inherent quality or
Technical Requirements for Registration of Pharmaceuticals
feature. E2363
for Human Use
3.1.2 control model, n—procedure or mathematical expres-
3.2.7 ISA—International Society of Automation
sion (algorithm) that uses the outputs of the process model
3.2.8 LOD—Limit of detection
combined with any other data inputs required to calculate
3.2.9 MBC—Model-based control
values for the critical control parameters for the process; it uses
3.2.10 MVA—Multivariate analysis
input data from the process to generate an actionable command
or commands that are issued to the control system.
3.2.11 PAT—Process analytical technology
3.1.2.1 Discussion—The control model may define what
3.2.12 PID—Proportional integral derivative
actions to take when specific attribute values are detected. The
3.2.13 PP—Process parameter
control model may be complex or simple, for example, it may
3.2.14 QA—Quality attribute
be predictive, as in the case of model-based control (MBC) in
which it is desired to manage the operation of the process along
4. Summary of Practice
a particular trajectory; it may be a single proportional integral
derivative (PID) loop controller; or it may be anything in 4.1 To aid reader understanding, a diagram of the data flows
between. in a PAT-enabled control system is shown in Fig. 1. The
diagram shows how process and control models can be used in
3.1.3 control system, n—system that responds to inputs
a closed loop control paradigm (with decisions being made
signals from the process, its associated equipment, other
based on action limits set in the control model) but also for
programmable systems or an operator or both, and generates
feed-forward control to downstream process steps/operations.
output signals causing the process and its associated equipment
4.2 Fig. 2 shows how the quality attributes (QAs), noncriti-
cal as well as critical, are fed into the control model via the
process model. Each process has process parameters (PPs).
Available from International Conference on Harmonisation of Technical
Based on process understanding, some PPs are held static and
Requirements for Registration of Pharmaceuticals for Human Use (ICH), ICH
Secretariat, c/o IFPMA, 15 ch. Louis-Dunant, P.O. Box 195, 1211 Geneva 20, others are subject to dynamic adjustment. Some of the PPs
Switzerland, http://www.ich.org.
directly or indirectly impact critical quality attributes (CQAs)
Available from Office of Training and Communication, Division of Drug
Information, HFD-240, Center for Drug Evaluation and Research, Food and Drug
Administration, 5600 Fishers Lane, Rockville, MD 20857, http://www.fda.gov.
5 6
Available from the European Commission (European Union (EU)), https:// Perry’s Handbook of Chemical Engineering, see BPCS–Basic Process Control
ec.europa.eu. System, McGraw Hill, 2007.
E2629 − 20
FIG. 1 Data Flows for a PAT-Enabled Control System
FIG. 2 Relationship Between Quality Attributes and the Control System
and these PPs are called critical process parameters (CPPs). environmental factors over time. Control strategy implemen-
When the CPPs (which may be fixed or adjustable) are tations generally can be categorized into three types:
dynamically adjusted as a result of information generated by
4.3.1.1 Level 1: Quality Assurance by Means of Application
the process and control models, they are called critical control
of Dynamic or Adaptive Process Control System:
parameters (CCPs). Revised CCP settings are transmitted in
(1) A Level 1 control strategy utilizes Dynamic or Adaptive
real time to the manufacturing equipment where they change
Process Control System to monitor and control the quality
the conditions of manufacture for the product.
attributes of materials in real-time.
4.3 Control Strategy:
4.3.1 The control strategy should be designed to control the
quality of the product in response to potential variations in the
“Modernizing Pharmaceutical Manufacturing: From Batch to Continuous
process, equipment conditions, incoming raw materials, or Production,” Journal of Pharmaceutical Innovation, Vol 10, No 3, September 2015.
E2629 − 20
(2) In Dynamic or Adaptive Process Control, system pro- 5. Significance and Use
cess parameters are monitored and may be adjusted in response
5.1 This guide supports the principles of Guide E2500 and
to disturbances to ensure that the quality attributes consistently
extends these principles to the verification of PAT-enabled
conform to the established acceptance criteria.
control systems.
(3) The successful application of a Dynamic or Adaptive
5.2 This guide clarifies what is important for verification of
Process Control system represents a high degree of product and
PAT-enabled control systems. Such systems are often complex
process understanding as the design of an engineering control
and require multidisciplinary and cross-functional teams to
system entails expressing the dynamic relationships among
achieve optimum results. This guide provides a common basis
process parameters, raw material and product attributes in a
for understanding requirements for all involved disciplines
quantitative and predictive manner.
such as control engineering, development, manufacturing, and
(4) The ability of a Dynamic or Adaptive Process Control
process validation.
System to compensate for variation in the raw material
attributes or external disturbances to the process condition
6. Principles To Be Considered for Verification of PAT-
significantly reduces the risk of producing of out of specifica- Enabled Control Systems
tion material and hence the requirement for routine
6.1 Verification should be science and risk based. Quality
segregation/diversion of out-of-specification is also reduced.
risk management should drive the verification process. Practice
(5) Statistical monitoring tools, for example Univariate or
E2476 provides additional guidance on risk assessments for
Multivariate SPC, may be used to demonstrate that the Dy-
PAT systems.
namic or Adaptive Process control system is ensuring that the
6.2 Verification should use the most efficient and effective
process is operating in a State of Control where there is a very
method available to achieve the specified results, choosing
low probability of out of specification being produced.
from, for example, simulation, testing, first principle modeling,
(6) Successful implementation of a Dynamic or Adaptive
or other approaches or combinations of these.
Process Control system directly supports a real-time release
6.3 Verification should cover the design space of the manu-
strategy.
facturing process. This will include all those ranges in which it
4.3.1.2 Level 2: Quality Assurance by Means of Operation
is necessary that the control system will be able to bring the
Within an Established Design Space and Confirmatory End
process back into its intended operating range. The verification
Product and In-Process Material Testing:
can occur during Process Performance Qualification or prior
(1) Product Quality may be assured by combination of
(during development phase), or both, given the process system
appropriate end product testing together with appropriate
is in a qualified state.
monitoring of controlled raw material attributes and process
6.4 Verification of the control systems should always in-
parameters.
clude verification of the system as a whole. It may also include
(2) The product and process understanding obtained
verification of individual system components.
through the establishment of a multivariate design space
facilitates the identification of potential sources of raw material
6.5 The verification process should confirm that relevant
and process variability that can impact product quality.
quality attributes will be controlled concurrently.
(3) Understanding the impact that variability from these
6.6 Verification should ensure that the control system is
sources has on in-process materials, downstream processing,
stable throughout the range of operation.
and drug product quality provides an opportunity to shift
6.7 Each component of the PAT-enabled control system
controls upstream and to reduce the reliance on end-product
should generate outputs with sufficient frequency, accuracy,
testing.
and precision to make the necessary level of process control
(4) The absence of real time corrective action within the
practical, meaningful and value-added.
control system increases the probability for production of out
of specification material and hence requires appropriate mecha-
6.8 Process and control models and the control system
nisms for ensuring rejection/diversion of any out-of-
should be verified as applicable to the scale of manufacture at
specification product.
which they will be used.
4.3.1.3 Level 3: Quality Assurance by Means of Operation
6.9 All stages of the verification should be appropriately
Within a Validated and Tightly Constrained Material Attributes
demonstrated and clearly documented in accordance with
and Process Parameters and Release Based on End Product
relevant requirements.
Testing:
7. Verification Process for PAT-Enabled Control Systems
(1) A Level 3, Control Strategy does not use PAT for either
feedforward or feedback control and is therefore outside t
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