E55.01 - Process Understanding and PAT System Management, Implementation and Practice

SIGNIFICANCE AND USE
4.1 This guide supports the principles of Guide E2500 and extends these principles to validation of analytical methods for PAT applications. The ongoing process of method validation is graphically represented in Fig. 1, which shows the life cycle of the validation of analytical methods for PAT applications. Prerequisites for validation are the identification of the measurement requirements and development of a method to meet those requirements.  
FIG. 1 Life Cycle for the Validation of Analytical Method for PAT Applications  
4.2 The method risk assessment also takes into account the stage in the product life cycle at which the measurements are being made and how the resulting data will be used. The integration of these considerations in the risk assessment facilitates the determination of the level of validation necessary to ensure that the method is fit for purpose.  
4.3 Changes may occur during the product life cycle necessitating identification of changes to the measurement requirements and method update and revalidation. Procedures should be established to evaluate the continued suitability of the process analytical method and to make appropriate recommendations to update the process analytical method for the intended use during the product life cycle.  
4.4 Additional informative examples can be found in Practices D3764, D6122, E1655, E1790, E2056, E2617, and E2656; and Guide E2891 that address validation of methods and models. Other useful standards include ASME BPE2019, ISO 14971, ISO 15839, and USP Acoustic Emission .
SCOPE
1.1 This guide provides an overview to the risk-based validation of process analytical methods under a process analytical technology (PAT) paradigm for pharmaceuticals and biopharmaceuticals and as such includes guidance on assessing risk to product quality from inappropriate method validation.  
1.2 This guide builds on existing standards on the topic of validation concentrating on applying such standards to analytical methods for on-line analysis. In particular, it addresses the validation of at-line, on-line, or in-line PAT measurements and covers both drug substance and drug product (DP) measurements.  
1.3 The definitions of International Council for Harmonisation (ICH) validation parameters (such as specificity, precision, repeatability, etc.) apply; however, the method of demonstrating the validation parameters may vary from that described in ICH and is discussed.  
1.4 As consistent with the U.S. Food and Drug Administration (FDA) process validation guidance, this document also briefly covers ongoing assurance that the method remains in a validated state during routine use.  
1.5 Equipment and instrument qualification are out of the scope of this guide but will be referenced as inputs to validation of analytical methods for PAT applications.  
1.6 The validation of multivariate prediction models is out of scope but will be referenced as inputs to validation of analytical methods for PAT applications.  
1.6.1 The validation of any analytical model used in the PAT method is essential to the validation of the PAT method but, the details of the model validation process is out of scope. See term  model validation, 3.1.7.  
1.7 Microbiological methods are out of scope.  
1.8 This standard does not purport to address all of the safety concerns, if any, associated with its use. It is the responsibility of the user of this standard to establish appropriate safety, health, and environmental practices and determine the applicability of regulatory limitations prior to use.  
1.9 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.

SIGNIFICANCE AND USE
5.1 This guide supports the principles of Guide E2500 and extends these principles to the verification of PAT-enabled control systems.  
5.2 This guide clarifies what is important for verification of PAT-enabled control systems. Such systems are often complex and require multidisciplinary and cross-functional teams to achieve optimum results. This guide provides a common basis for understanding requirements for all involved disciplines such as control engineering, development, manufacturing, and process validation.
SCOPE
1.1 This guide describes the verification of process analytical technology (PAT) enabled control systems using a science- and risk-based approach. It establishes principles for determining the scope and extent of verification activities necessary to ensure that the PAT-enabled control system is fit for purpose, properly implemented, and functions as expected.  
1.2 In this guide, a PAT-enabled control system is considered to be the system that adjusts the manufacturing process using timely measurements (that is, during processing) of attributes of raw and in-process materials to determine responses that assure the process remains within specified boundaries and minimizes variability in the output material. The overall aim of the PAT-enabled control system is to ensure product quality. The PAT-enabled control system of a manufacturing process provides the capability to determine the current status of the process and drive the process to ensure the output material has the desired quality characteristics. The control system should be able to respond to process variations in a timely manner, providing corrections that ensure that the process follows the desired process trajectory to reach the desired outcome. PAT-enabled control systems may use process models based on first principles understanding or empirical models derived from experimental investigations or both. In addition to automated controls, a PAT-enabled control system may include components where there is manual intervention.  
1.3 Principles described in this guide may be applied regardless of the complexity or scale of the PAT-enabled control system or whether applied to batch or continuous processing, or both. The intention of this standard is to describe and support the implementation of a PAT enabled Control Strategy, as described in ICH Q8(R2).  
1.4 The principles described in this guide are applicable to a PAT-enabled control system and also to its component subsystems. This guide does not cover the requirements for continuous quality verification of the overall process, which are covered in Guide E2537, or for validation of PAT methods, which is covered in Guide E2898.  
1.5 For information on science- and risk-based approaches in the pharmaceutical industry, reference should be made to ICH Q8(R2), ICH Q9, and ICH Q10. For guidance on PAT systems in the pharmaceutical industry, reference should be made to FDA Guidance for Industry—PAT and FDA Guidance for Industry—Process Validation, as well as EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use and EU Guideline on Process Validation for Finished Products.  
1.6 This standard does not purport to address all of the safety concerns, if any, associated with its use. It is the responsibility of the user of this standard to establish appropriate safety, health, and environmental practices and determine the applicability of regulatory limitations prior to use.  
1.7 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.

SIGNIFICANCE AND USE
4.1 This guide is intended to provide guidance regarding the use of risk management in the development, day-to-day running, and continuous improvement of pharmaceutical processes incorporating Process Analytical Technology (PAT). Since PAT is defined as being “risk-based” (see FDA Guidance for Industry), it is important that a consistent approach to the use of risk methodologies is adopted, to ensure rapid transfer of process understanding within the development and manufacturing teams, and to the regulators where that is appropriate.  
4.2 This guidance only covers those aspects of risk assessment related to “risk to product quality.” Other aspects (such as “risk to patient”) should be covered in the conventional manner.
SCOPE
1.1 This document provides guidance on the assessment of risks to product quality within and related to PAT processes in the pharmaceutical industry. It addresses those risks to product quality arising from, associated with, identified by, or modified by the implementation of PAT in pharmaceutical development and manufacturing for primary, secondary, and biotech sectors of the industry. It does not replace those assessments of risk currently undertaken by pharmaceutical companies, but is, rather, an additional component focused specifically upon the evaluation and design of PAT processes. See Practice E2474, Guide E2500, and ICH Q8.  
1.2 This standard does not purport to address all of the safety concerns, if any, associated with its use. It is the responsibility of the user of this standard to establish appropriate safety and health practices and determine the applicability of regulatory limitations prior to use. Note that safety in this context refers to operational and operator safety, not to patient safety.

SIGNIFICANCE AND USE
4.1 Although some continuous processing is used in the pharmaceutical industry (for example, purified water production, inherently continuous individual unit operations such as dry granulation and compression), these operations are generally operated in isolation and do not deliver the potential benefits of an integrated continuous manufacturing operation. The FDA Guidance for Industry PAT document specifically identifies that the introduction of continuous processing may be one of the outcomes from the adoption of a science-based approach to process design.  
4.2 This guide does not:  
4.2.1 Suggest that continuous production is suitable for the manufacture of all pharmaceutical products.  
4.2.2 Provide guidance on issues related to the safe operation of a continuous process or continuous processing equipment. It is the responsibility of the user of this standard to establish appropriate health and safety practices and determine the applicability of regulatory limitations prior to use.  
4.2.3 Recommend particular designs or operating regimes for continuous manufacturing.  
4.3 Appendix X1 includes a table comparing the characteristics of continuous and discrete or batch processes.
SCOPE
1.1 This guide introduces key concepts and principles to assist in the appropriate selection, development and operation of continuous processing technologies for the manufacture of pharmaceutical products.  
1.2 Particular consideration is given to the development and application of the appropriate scientific understanding and engineering principles that differentiate continuous manufacture from traditional batch manufacturing.  
1.3 Most of the underlying concepts and principles (for example, process dynamics and process control) outlined in this guide can be applied in both Drug Substance (DS) and Drug Product (DP) processes. However it should be recognized that in Drug Substance production the emphasis may be more on chemical behavior and dynamics in a fluid phase whereas for drug product manufacture there may be a greater emphasis on the physical behavior and dynamics in a solid/powder format.  
1.4 This guide is also intended to apply in both the development of a new process, or the improvement/redesign of an existing one.  
1.5 The values stated in SI units are to be regarded as standard. No other units of measurement are included in this standard.  
1.6 This standard does not purport to address all of the safety concerns, if any, associated with its use. It is the responsibility of the user of this standard to establish appropriate safety and health practices and determine the applicability of regulatory limitations prior to use.

SIGNIFICANCE AND USE
4.1 This guide supports the principles of Guide E2500 and extends these principles to validation of analytical methods for PAT applications. The ongoing process of method validation is graphically represented in Fig. 1, which shows the life cycle of the validation of analytical methods for PAT applications. Prerequisites for validation are the identification of the measurement requirements and development of a method to meet those requirements.  
4.2 The method risk assessment also takes into account the stage in the product life cycle at which the measurements are being made and how the resulting data will be used. The integration of these considerations in the risk assessment facilitates the determination of the level of validation necessary to ensure that the method is fit for purpose.  
4.3 Changes may occur during the product life cycle necessitating identification of changes to the measurement requirements and method update and revalidation. Procedures should be established to evaluate the continued suitability of the process analytical method.  
4.4 Additional informative examples can be found in Practices D3764, D6122, E1655, E1790, E2056, E2617, and E2656 that address validation of methods and models. Other useful standards include ASME BPE2009, ISO 14971, ISO 15839, and USP Acoustic Emission  .
SCOPE
1.1 This guide provides an overview to the risk-based validation of process analytical methods under a process analytical technology (PAT) paradigm for pharmaceuticals and biopharmaceuticals and as such includes guidance on assessing risk to product quality from inappropriate method validation.  
1.2 This guide builds on existing standards on the topic of validation concentrating on applying such standards to analytical methods for on-line analysis. In particular, it addresses the validation of at-line, on-line, or in-line PAT measurements and covers both API and Drug Product (DP) measurements.  
1.3 The definitions of International Conference on Harmonization (ICH) validation parameters (such as specificity, precision, repeatability, etc.) apply; however, the method of demonstrating the validation parameters may vary from that described in ICH and is discussed.  
1.4 As consistent with the U.S. Food and Drug Administration (FDA) process validation guidance, this document also briefly covers ongoing assurance that the method remains in a validated state during routine use.  
1.5 Equipment and instrument qualification are out of the scope of this guide but will be referenced as inputs to validation of analytical methods for PAT applications.  
1.6 The validation of multivariate prediction models is out of scope but will be referenced as inputs to validation of analytical methods for PAT applications.  
1.7 Microbiological methods are out of scope.  
1.8 This standard does not purport to address all of the safety concerns, if any, associated with its use. It is the responsibility of the user of this standard to establish appropriate safety and health practices and determine the applicability of regulatory limitations prior to use.

SIGNIFICANCE AND USE
4.1 This guide supports the principles of Guide E2500 and extends these principles to validation of analytical methods for PAT applications. The ongoing process of method validation is graphically represented in Fig. 1, which shows the life cycle of the validation of analytical methods for PAT applications. Prerequisites for validation are the identification of the measurement requirements and development of a method to meet those requirements.  
4.2 The method risk assessment also takes into account the stage in the product life cycle at which the measurements are being made and how the resulting data will be used. The integration of these considerations in the risk assessment facilitates the determination of the level of validation necessary to ensure that the method is fit for purpose.  
4.3 Changes may occur during the product life cycle necessitating identification of changes to the measurement requirements and method update and revalidation. Procedures should be established to evaluate the continued suitability of the process analytical method.  
4.4 Additional informative examples can be found in Practices D3764, D6122, E1655, E1790, E2056, and E2617 that address validation of methods and models. Other useful standards include ASME BPE2009, ISO 14971, ISO 15839, and USP Acoustic Emission  .
SCOPE
1.1 This guide provides an overview to the risk-based validation of process analytical methods under a process analytical technology (PAT) paradigm for pharmaceuticals and biopharmaceuticals and as such includes guidance on assessing risk to product quality from inappropriate method validation.  
1.2 This guide builds on existing standards on the topic of validation concentrating on applying such standards to analytical methods for on-line analysis. In particular, it addresses the validation of at-line, on-line, or in-line PAT measurements and covers both API and Drug Product (DP) measurements.  
1.3 The definitions of International Conference on Harmonization (ICH) validation parameters (such as specificity, precision, repeatability, etc.) apply; however, the method of demonstrating the validation parameters may vary from that described in ICH and is discussed.  
1.4 As consistent with the U.S. Food and Drug Administration (FDA) process validation guidance, this document also briefly covers ongoing assurance that the method remains in a validated state during routine use.  
1.5 Equipment and instrument qualification are out of the scope of this guide but will be referenced as inputs to validation of analytical methods for PAT applications.  
1.6 The validation of multivariate prediction models is out of scope but will be referenced as inputs to validation of analytical methods for PAT applications.  
1.7 Microbiological methods are out of scope.  
1.8 This standard does not purport to address all of the safety concerns, if any, associated with its use. It is the responsibility of the user of this standard to establish appropriate safety and health practices and determine the applicability of regulatory limitations prior to use.

SIGNIFICANCE AND USE
4.1 A significant amount of data is being generated during pharmaceutical development and manufacturing activities. The interpretation of such data is becoming increasingly difficult. Individual examination of the univariate process variables is relevant but can be significantly complemented by multivariate data analysis (MVDA). Such methodology has been shown to be particularly efficient at handling large amounts of data from multiple sources, summarizing complex information into meaningful low dimensional graphical representations, identifying intricate correlations between multivariate datasets taking into account variable interactions. The output from MVDA will generate useful information that can be used to enhance process understanding, decision making in process development, process monitoring and control (including product release), product life-cycle management and continual improvement.  
4.2 MVDA is a widely used tool in various industries including the pharmaceutical industry. To generate a valid outcome, MVDA should contain the following components:  
4.2.1 A predefined objective based on a risk and scientific hypothesis specific to the application,  
4.2.2 Relevant data,  
4.2.3 Appropriate data analysis techniques, including considerations on validation,  
4.2.4 Appropriately trained staff, and  
4.2.5 Life-cycle management.  
4.3 This guide can be used to support data analysis activities associated with pharmaceutical development and manufacturing, process performance and product quality monitoring in manufacturing, as well as for troubleshooting and investigation events. Technical details in data analysis can be found in scientific literature and standard practices in data analysis are already available (such as Practices E1655 and E1790 for spectroscopic applications, Practice E2617 for model validation and Practice E2474 for utilizing process analytical technology).
SCOPE
1.1 This guide covers the applications of multivariate data analysis (MVDA) to support pharmaceutical development and manufacturing activities. MVDA is one of the key enablers for process understanding and decision making in pharmaceutical development, and for the release of intermediate and final products.  
1.2 The scope of this guide is to provide general guidelines on the application of MVDA in the pharmaceutical industry. While MVDA refers to typical empirical data analysis, the scope is limited to providing a high level guidance and not intended to provide application-specific data analysis procedures. This guide provides considerations on the following aspects:  
1.2.1 Use of a risk-based approach (understanding the objective requirements and assessing the fit-for-use status),  
1.2.2 Considerations on the data collection and diagnostics used for MVDA (including data preprocessing and outliers),  
1.2.3 Considerations on the different types of data analysis and model validation,  
1.2.4 Qualified and competent personnel, and  
1.2.5 Life-cycle management of MVDA.  
1.3 This standard does not purport to address all of the safety concerns, if any, associated with its use. It is the responsibility of the user of this standard to establish appropriate safety and health practices and determine the applicability of regulatory limitations prior to use.

SIGNIFICANCE AND USE
This guide supports the principles of Guide E2500 and extends these principles to the verification of PAT-enabled control systems.
This guide clarifies what is important for verification of PAT-enabled control systems. Such systems are often complex and require multidisciplinary and cross-functional teams to achieve optimum results. This guide provides a common basis for understanding requirements for all involved disciplines such as control engineering, development, manufacturing, and process validation.
SCOPE
1.1 This guide describes the verification of process analytical technology (PAT) enabled control systems using a science- and risk-based approach. It establishes principles for determining the scope and extent of verification activities necessary to ensure that the PAT-enabled control system is fit for purpose, properly implemented, and functions as expected.
1.2 In this guide, a PAT-enabled control system is considered to be the system that adjusts the manufacturing process using timely measurements (that is, during processing) of attributes of raw and in-process materials to determine responses that assure the process remains within specified boundaries and minimizes variability in the output material. The overall aim of the PAT-enabled control system is to ensure product quality. The PAT-enabled control system of a manufacturing process provides the capability to determine the current status of the process and drive the process to ensure the output material has the desired quality characteristics. The control system should be able to respond to process variations in a timely manner, providing corrections that ensure that the process follows the desired process trajectory to reach the desired outcome. PAT-enabled control systems may use process models based on first principles understanding or empirical models derived from experimental investigations or both. In addition to automated controls, a PAT-enabled control system may include components where there is manual intervention.
1.3 Principles described in this guide may be applied regardless of the complexity or scale of the PAT-enabled control system or whether applied to batch or continuous processing, or both.
1.4 The principles described in this guide are applicable to a PAT-enabled control system and also to its component subsystems. This guide does not cover the requirements for continuous quality verification of the overall process, which are covered in Guide E2537.
1.5 For information on science- and risk-based approaches in the pharmaceutical industry, reference should be made to ICH Q8(R2), ICH Q9, and ICH Q10. For guidance on PAT systems in the pharmaceutical industry, reference should be made to FDA Guidance for IndustryPAT and FDA Guidance for IndustryProcess Validation.
1.6 This standard does not purport to address all of the safety concerns, if any, associated with its use. It is the responsibility of the user of this standard to establish appropriate safety and health practices and determine the applicability of regulatory limitations prior to use.

SCOPE
1.1 The purpose of this guide is to establish a framework and context for process understanding for pharmaceutical manufacturing using quality by design (QbD) (Juran, 1992; FDA/ICH Q8). The framework is applicable to both active pharmaceutical ingredient (API) and to drug product (DP) manufacturing. High (detailed) level process understanding can be used to facilitate production of product which consistently meets required specifications. It can also play a key role in continuous process improvement efforts.  
1.2 Process Analytical Technology (PAT) is one element that can be used for achieving control over those inputs determined to be critical to a process. It is important for the reader to recognize that PAT is defined as:

SIGNIFICANCE AND USE
This guide is intended to provide guidance regarding the use of risk analysis in the development, day-to-day running, and continuous improvement of pharmaceutical processes incorporating Process Analytical Technology (PAT). Since PAT is defined as being “risk-based” (see FDA Guidance for Industry), it is important that a consistent approach to the use of risk methodologies is adopted, to ensure rapid transfer of process understanding within the development and manufacturing teams, and to the regulators where that is appropriate.
4.2 This guidance only covers those aspects of risk assessment related to “risk to product quality.” Other aspects (such as “risk to patient”) should be covered in the conventional manner.
SCOPE
1.1 This document provides guidance on the assessment of risks to product quality within and related to PAT processes in the pharmaceutical industry. It addresses those risks to product quality arising from, associated with, identified by, or modified by the implementation of PAT in pharmaceutical development and manufacturing for primary, secondary, and biotech sectors of the industry. It does not replace those assessments of risk currently undertaken by pharmaceutical companies, but is, rather, an additional component focused specifically upon the evaluation and design of PAT processes. See Practice E 2474, Guide E 2500, and ICH Q8.
1.2 This standard does not purport to address all of the safety concerns, if any, associated with its use. It is the responsibility of the user of this standard to establish appropriate safety and health practices and determine the applicability of regulatory limitations prior to use. Note that safety in this context refers to operational and operator safety, not to patient safety.

ABSTRACT
This practice covers pharmaceutical process design utilizing process analytical technology, which is integral to process development as well as post-development process optimization. It is focused on practical implementation and experimental development of process understanding. The principles in this practice are applicable to both drug substance and drug product processes. For drug products, formulation development and process development are interrelated and therefore the process design will incorporate knowledge from the formulation development. The following practices and methodologies shall be done to attain desired state: risk assessment and mitigation; continuous improvement; process fitness for purpose; intrinsic performance assessment; manufacturing strategy; data collection and formal experimental design; multivariate tools; process analyzers; and process control.
SCOPE
1.1 This practice covers process design, which is integral to process development as well as post-development process optimization. It is focused on practical implementation and experimental development of process understanding.
1.2 The term process design as used in this practice can mean:
1.2.1 The activities to design a process (the process design), and/or
1.2.2 The outcome of this activity (the designed process).
1.3 The principles in this practice are applicable to both drug substance and drug product processes. For drug products, formulation development and process development are interrelated and therefore the process design will incorporate knowledge from the formulation development.
1.4 The principles in this practice apply during development of a new process or the improvement or redesign of an existing one, or both.
This standard does not purport to address all of the safety concerns, if any, associated with its use. It is the responsibility of the user of this standard to establish appropriate safety and health practices and determine the applicability of regulatory limitations prior to use.

ABSTRACT
This practice covers pharmaceutical process design utilizing process analytical technology, which is integral to process development as well as post-development process optimization. It is focused on practical implementation and experimental development of process understanding. The principles in this practice are applicable to both drug substance and drug product processes. For drug products, formulation development and process development are interrelated and therefore the process design will incorporate knowledge from the formulation development. The following practices and methodologies shall be done to attain desired state: risk assessment and mitigation; continuous improvement; process fitness for purpose; intrinsic performance assessment; manufacturing strategy; data collection and formal experimental design; multivariate tools; process analyzers; and process control.
SCOPE
1.1 This practice covers process design, which is integral to process development as well as post-development process optimization. It is focused on practical implementation and experimental development of process understanding.  
1.2 The term process design as used in this practice can mean:  
1.2.1 The activities to design a process (the process design), or  
1.2.2 The outcome of this activity (the designed process), or both.  
1.3 The principles in this practice are applicable to both drug substance and drug product processes. For drug products, formulation development and process development are interrelated and therefore the process design will incorporate knowledge from the formulation development.  
1.4 The principles in this practice apply during development of a new process or the improvement or redesign of an existing one, or both.  
1.5 This standard does not purport to address all of the safety concerns, if any, associated with its use. It is the responsibility of the user of this standard to establish appropriate safety and health practices and determine the applicability of regulatory limitations prior to use.
WITHDRAWN RATIONALE
This practice covers process design, which is integral to process development as well as post-development process optimization.
Formerly under the jurisdiction of Committee E55 on Manufacture of Pharmaceutical and Biopharmaceutical Products, this practice was withdrawn in July 2020. This standard was withdrawn without replacement due to its limited use by the industry.