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ASTM E3326-22

(Guide)

Standard Guide for Application of Continuous Manufacturing (BioCM) in the Biopharmaceutical Industry

Standard Guide for Application of Continuous Manufacturing (BioCM) in the Biopharmaceutical Industry

SIGNIFICANCE AND USE
4.1 This guide focuses on upstream and downstream processes for biopharmaceutical products with a particular focus on antibody production processes. For further information, see Appendix X1 and Refs (1-3).  
4.2 Bioprocesses traditionally consist of discrete unit operations labeled as upstream, downstream, and fill/finish operations. The objectives at each stage are significantly different, as are the operating parameters and control processes, that can make complete integration impractical initially (Appendix X1). This guide does not imply that complete integration is a prerequisite. A higher degree of integration may be possible over time as a better understanding of the dynamics of processes become established.  
4.2.1 Upstream Processes—The purpose of upstream processes is to generate sufficient product to meet patient requirements preferably in the fewest number of batches. This starts with increasing biomass (cell-line expansion from working cell bank to production inoculation) to a production bioreactor in which the focus shifts to producing product. The material within a bioreactor during extended growth is heterogenous, for example, cells will differ in age, there may be genetic drift, secreted product can differ in the residence time spent in the bioreactor, and cell debris accumulates throughout the process.  
4.2.2 Downstream Processes—The purpose of downstream processes is to harvest product and purify it from process- and product-related impurities (for example, cell debris, nucleic acids, and misfolds) to the desired level. Solids are first separated from solutes; solutes are then separated from each other in the process of purification. Certain processes may at best be semi-continuous, and some steps may be prone to fouling, which may require manual intervention.  
4.2.3 Fill/Finish Operations—The purpose of fill/finish operations is to formulate the purified product in a form that ensures stability and sterility and provides a dosage form consis...
SCOPE
1.1 This guide is intended as a complement to Guide E2968. It provides key concepts and principles to assist in the appropriate selection, development, and operation of continuous processing technologies for the manufacture of biologically derived products.  
1.2 Several of the principles covered in Guide E2968 are applicable to biomanufacturing. However, processes for biologically derived products differ from those for synthetic drugs in a number of fundamental ways in addition to their source (for example, format: aqueous liquids versus powders; scope: genesis to final formulation). This guide is intended to provide greater clarity for biomanufacturing. It does not imply that topics in Guide E2968 that are not covered here do not apply to continuous manufacturing (CM) for biologics.  
1.3 Biologically derived products also differ widely from each other in terms of modalities, source materials, and the manufacturing technologies used, not all of which are equally amenable to operating in a continuous mode.  
1.4 Opportunities do exist for the introduction of continuous technologies, for example, efforts are ongoing to adapt processes for large-scale manufacture of broadly applicable modalities such as monoclonal antibodies to a continuous format. This guide is intended to provide guidance to the design and implementation of antibody processes.  
1.5 The principles can be applicable to unit operations or processes or both for other modalities but may not be applicable to all bioprocesses.  
1.6 Particular consideration should be given to the development and application of the appropriate scientific understanding and engineering principles that differentiate CM from traditional batch manufacturing.  
1.7 Since much of the processing is done under conditions amenable to microbial growth, maintaining process streams free from external biological impurities and microbial contamination (for example, bioburden, viruses, ...

General Information

Status
Published
Publication Date
31-Aug-2022
ICS
11.120.01 - Pharmaceutics in general
Technical Committee
E55 - Manufacture of Pharmaceutical and Biopharmaceutical Products
Drafting Committee
E55.12 - Process Applications
Current Stage
Ref Project

Relations

Refers
ASTM E2898-20 - Standard Guide for Risk-Based Validation of Analytical Methods for PAT Applications
Effective Date
15-May-2020

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ASTM E3326-22 - Standard Guide for Application of Continuous Manufacturing (BioCM) in the Biopharmaceutical IndustryASTM E3326-22 - Standard Guide for Application of Continuous Manufacturing (BioCM) in the Biopharmaceutical Industry
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ASTM E3326-22 - Standard Guide for Application of Continuous Manufacturing (BioCM) in the Biopharmaceutical Industry
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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: E3326 − 22
Standard Guide for
Application of Continuous Manufacturing (BioCM) in the
1
Biopharmaceutical Industry
This standard is issued under the fixed designation E3326; 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 free from external biological impurities and microbial contami-
nation (for example, bioburden, viruses, and mycoplasma) is
1.1 This guide is intended as a complement to Guide E2968.
critical.
It provides key concepts and principles to assist in the
appropriate selection, development, and operation of continu- 1.8 This guide is intended to apply in both the development
ous processing technologies for the manufacture of biologi- of a new process or the redesign of an existing one.
cally derived products.
1.9 A manufacturer may choose to implement continuous
1.2 Several of the principles covered in Guide E2968 are manufacturing for discrete unit operations in stages as they
applicable to biomanufacturing. However, processes for bio- develop process understanding before implementing a fully
logically derived products differ from those for synthetic drugs connected or continuous manufacturing process.
in a number of fundamental ways in addition to their source
1.10 Units—The values stated in SI units are to be regarded
(for example, format: aqueous liquids versus powders; scope:
as the standard. No other units of measurement are included in
genesis to final formulation). This guide is intended to provide
this standard.
greater clarity for biomanufacturing. It does not imply that
1.11 This standard does not purport to address all of the
topics in Guide E2968 that are not covered here do not apply
safety concerns, if any, associated with its use. It is the
to continuous manufacturing (CM) for biologics.
responsibility of the user of this standard to establish appro-
1.3 Biologically derived products also differ widely from
priate safety, health, and environmental practices and deter-
each other in terms of modalities, source materials, and the
mine the applicability of regulatory limitations prior to use.
manufacturing technologies used, not all of which are equally
1.12 This international standard was developed in accor-
amenable to operating in a continuous mode.
dance with internationally recognized principles on standard-
ization established in the Decision on Principles for the
1.4 Opportunities do exist for the introduction of continuous
Development of International Standards, Guides and Recom-
technologies, for example, efforts are ongoing to adapt pro-
mendations issued by the World Trade Organization Technical
cesses for large-scale manufacture of broadly applicable mo-
Barriers to Trade (TBT) Committee.
dalities such as monoclonal antibodies to a continuous format.
This guide is intended to provide guidance to the design and
2. Referenced Documents
implementation of antibody processes.
2
2.1 ASTM Standards:
1.5 The principles can be applicable to unit operations or
E2363 Terminology Relating to Manufacturing of Pharma-
processes or both for other modalities but may not be appli-
ceutical and Biopharmaceutical Products in the Pharma-
cable to all bioprocesses.
ceutical and Biopharmaceutical Industry
1.6 Particular consideration should be given to the develop-
E2475 Guide for Process Understanding Related to Pharma-
ment and application of the appropriate scientific understand-
ceutical Manufacture and Control
ing and engineering principles that differentiate CM from
E2537 Guide for Application of Continuous Process Verifi-
traditional batch manufacturing.
cation to Pharmaceutical and Biopharmaceutical Manu-
1.7 Since much of the processing is done under conditions
facturing
amenable to microbial growth, maintaining process streams
E2888 Practice for Process for Inactivation of Rodent Ret-
rovirus by pH
1
This guide is under the jurisdiction of ASTM Committee E55 on Manufacture
2
of Pharmaceutical and Biopharmaceutical Products and is the direct responsibility of For referenced ASTM standards, visit the ASTM website, www.astm.org, or
Subcommittee E55.12 on Process Applications. contact ASTM Customer Service at service@astm.org. For Annual Book of ASTM
Current edition approved Sept. 1, 2022. Published October 2022. DOI: 10.1520/ Standards volume information, refer to the standard’s Document Summary page on
E3326-22. the ASTM website.
Copyright © ASTM International, 100 Barr Harbor Drive, PO Box C700, West Co
...

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ASTM E2363-23(Terminology)
Standard Terminology Relating to Manufacturing of Pharmaceutical and Biopharmaceutical Products in the Pharmaceutical and Biopharmaceutical Industry

SCOPE
1.1 This standard covers terminology used by the E55 Committee relating to pharmaceutical and biopharmaceutical industry for manufacture of pharmaceutical and biopharmaceutical products. Terms that are generally understood and in common usage or adequately defined in other readily available references are not included except where particular delineation to pharmaceutical and biopharmaceutical manufacturing may be more clearly stated.  
1.2 This terminology is, therefore, intended to be selective of terms used generally in the manufacture of pharmaceutical and biopharmaceutical products and published in a number of documents such as those listed in the succeeding section. The listing is also intended to define terms that appear prominently within other related ASTM International standards and do not appear elsewhere.  
1.3 The definitions are substantially identical to those published by regulatory agencies such as the U.S. Food and Drug Administration, European Medicines Agency, Pharmaceutical and Medical Devices Agency (Japan), other and national competent authorities (human) as well as other authoritative bodies, such as ICH, ISO, and national standards organizations.  
1.4 This terminology supplements current documents on terminology that concentrate on the manufacture of pharmaceutical and biopharmaceutical products.  
1.5 An increasing number of product designations and designations for chemical, physical, mechanical, analytical, and statistical tests and standards are coming into common usage in the literature, regulatory environment, and commerce associated with the manufacture of pharmaceutical and biopharmaceutical products.  
1.6 Units—The values stated in SI units are to be regarded as the standard. No other units of measurement are included in this standard.  
1.7 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.  
1.8 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.

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Standard Guide for Application of Continuous Manufacturing (CM) in the Pharmaceutical Industry

SIGNIFICANCE AND USE
4.1 Although some CM is used in the pharmaceutical industry (for example, purified water production), and some processes are 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 CM operation. The FDA Guidance for Industry PAT document specifically identifies that the introduction of continuous processing (now redefined as CM) 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 CM is suitable for the manufacture of all pharmaceutical products.  
4.2.2 Provide guidance on issues related to the safe operation of a CM 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 CM.  
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 CM technologies for the manufacture of pharmaceutical products. Athough selected concepts covered here can be applied to biopharmaceutical CM (BioCM), the focus of this guide is on non-biopharmaceutical applications.  
1.2 Particular consideration is given to the development and application of the appropriate scientific understanding and engineering principles that differentiate CM 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 to 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 solid 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 new processes, or the redesign of existing ones.  
1.5 All values are stated in SI units. 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, 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.

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ASTM E3263-22e1(Practice)
Standard Practice for Qualification of Visual Inspection of Pharmaceutical Manufacturing Equipment and Medical Devices for Residues

SIGNIFICANCE AND USE
4.1 Application of the approach described within this practice applies the science-based, risk-based, and statistics-based concepts and principles introduced in Guides E3106 and E3219.  
4.2 Application of the approach described within this practice provides a science-, risk-, and statistical-based approach for qualifying the inspection of equipment for cleanliness in accordance with 21 CFR 211.67(b)(6) and is in accordance with FDA Process Validation Guidance Life Cycle approach.  
4.3 Application of the approach described within this practice provides a science-, risk-, and statistical-based approach for qualifying the visual inspection of equipment for cleanliness in accordance with European Medicines Agency (EMA) Annex 15.  
4.4 Application of the approach described within this practice provides a science-, risk-, and statistical-based approach for qualifying the visual inspection of equipment for cleanliness in accordance with the EMA’s Q&A Guidance (Q&A’s #7 and #8) (2).  
4.5 Visual Inspection used as described in 4.4 should only be used in situations where there is a suitable safety margin between the VRL and MSSR and robust detectability at the VRL.  
4.6 Application of the approach described within this practice applies the risk-based concepts and principles introduced in ICH Q9. As stated in ICH Q9, the level of effort, formality, and documentation for validation (including cleaning validation) should also be commensurate with the level of risk.  
4.7 Application of the approach described within this practice provides a science-, risk-, and statistical-based approach for releasing manufacturing equipment and manufactured medical devices or cleanliness that is compatible with the U.S. FDA Guidance for Industry, PAT – A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance.  
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SCOPE
1.1 This practice provides statistically valid procedures for determining the visual detection limit of residues and the qualification of inspectors to perform the visual inspection of pharmaceutical manufacturing equipment surfaces and medical devices for residues.  
1.2 This practice applies to pharmaceuticals (including active pharmaceutical ingredients (APIs); dosage forms; and over-the-counter, veterinary, biologics, and clinical supplies) and medical devices following all manufacturing and cleaning. This practice is also applicable to other health, cosmetics, and consumer products.  
1.3 This practice applies to many types of chemical residues (including APIs, intermediates, cleaning agents, processing aids, machining oils, and so forth) that could remain on manufacturing equipment surfaces or medical devices that have undergone all manufacturing steps including cleaning.  
1.4 This practice applies only to equipment or devices that have been justified through a Quality Risk Management program to have an acceptable hazard analysis, have cleaning processes that are repeatable and validated and where Visual Inspection can be relied upon to determine the cleanliness of the equipment at the residue limit justified by the HBEL.  
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ASTM E2891-20(Guide)
Standard Guide for Multivariate Data Analysis in Pharmaceutical Development and Manufacturing Applications

SIGNIFICANCE AND USE
4.1 A significant amount of data is 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). MVDA may be particularly appropriate for exploring and handling large sets of heterogenous data, mapping data of high dimensionality onto lower dimensional representations, exposing significant correlations among multivariate variables within a single data set or significant correlations among multivariate variables across data sets. MVDA may extract statistically significant information which may enhance process understanding, decision making in process development, process monitoring and control (including product release), product life-cycle management, and continuous improvement.  
4.2 MVDA is widely used in various industries including the pharmaceutical industry. To achieve a valid outcome, an MVDA model/application should incorporate the following:  
4.2.1 A predefined risk-based objective incorporating one or more relevant scientific hypotheses specific to the application;  
4.2.2 Sufficient relevant data of requisite quality covering the variance space encountered during intended use, that is, pharmaceutical development, or pharmaceutical manufacturing, or both;  
4.2.3 Appropriate data analysis and model utilization practices including considerations on testing, validation, and qualification of all new data prior to using a model to analyze it;  
4.2.4 Appropriately trained staff;  
4.2.5 Appropriate standard operating procedures; and  
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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 after being validated appropriately using a science and risk-based approach.  
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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, model testing, and validation;  
1.2.4 Qualified and competent personnel; and  
1.2.5 Life-cycle management of MVDA model.  
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5.1 These methods are intended to determine whether a material, product, or part of a product has the degree of radiopacity desired for its application as a medical device in the human body. This method allows for comparison with or without the use of a body mimic. Comparisons without the use of a body mimic should be used with caution as the relative radiopacity can be affected when imaging through the human body.  
5.2 These methods allow for both qualitative and quantitative evaluation in different comparative situations.
SCOPE
1.1 These test methods cover the determination of the radiopacity of materials and products utilizing X-ray based techniques, including fluoroscopy, angiography, CT (computed tomography), and DEXA (dual energy X-ray absorptiometry), also known as DXA, The results of these measurements are an indication of the likelihood of locating the product within the human body.  
1.2 Radiopacity is determined by (a) qualitatively comparing image(s) of a test specimen and a user-defined standard, with or without the use of a body mimic; or (b) quantitatively determining the specific difference in optical density or pixel intensity between the image of a test specimen and the image of a user-defined standard, with or without the use of a body mimic.  
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ASTM E2363-23(Terminology)
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1.1 This standard covers terminology used by the E55 Committee relating to pharmaceutical and biopharmaceutical industry for manufacture of pharmaceutical and biopharmaceutical products. Terms that are generally understood and in common usage or adequately defined in other readily available references are not included except where particular delineation to pharmaceutical and biopharmaceutical manufacturing may be more clearly stated.  
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1.5 An increasing number of product designations and designations for chemical, physical, mechanical, analytical, and statistical tests and standards are coming into common usage in the literature, regulatory environment, and commerce associated with the manufacture of pharmaceutical and biopharmaceutical products.  
1.6 Units—The values stated in SI units are to be regarded as the standard. No other units of measurement are included in this standard.  
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SIGNIFICANCE AND USE
4.1 Although some CM is used in the pharmaceutical industry (for example, purified water production), and some processes are 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 CM operation. The FDA Guidance for Industry PAT document specifically identifies that the introduction of continuous processing (now redefined as CM) 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 CM is suitable for the manufacture of all pharmaceutical products.  
4.2.2 Provide guidance on issues related to the safe operation of a CM 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 CM.  
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 CM technologies for the manufacture of pharmaceutical products. Athough selected concepts covered here can be applied to biopharmaceutical CM (BioCM), the focus of this guide is on non-biopharmaceutical applications.  
1.2 Particular consideration is given to the development and application of the appropriate scientific understanding and engineering principles that differentiate CM 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 to 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 solid 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 new processes, or the redesign of existing ones.  
1.5 All values are stated in SI units. 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, 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.

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ASTM E3263-22e1(Practice)
Standard Practice for Qualification of Visual Inspection of Pharmaceutical Manufacturing Equipment and Medical Devices for Residues

SIGNIFICANCE AND USE
4.1 Application of the approach described within this practice applies the science-based, risk-based, and statistics-based concepts and principles introduced in Guides E3106 and E3219.  
4.2 Application of the approach described within this practice provides a science-, risk-, and statistical-based approach for qualifying the inspection of equipment for cleanliness in accordance with 21 CFR 211.67(b)(6) and is in accordance with FDA Process Validation Guidance Life Cycle approach.  
4.3 Application of the approach described within this practice provides a science-, risk-, and statistical-based approach for qualifying the visual inspection of equipment for cleanliness in accordance with European Medicines Agency (EMA) Annex 15.  
4.4 Application of the approach described within this practice provides a science-, risk-, and statistical-based approach for qualifying the visual inspection of equipment for cleanliness in accordance with the EMA’s Q&A Guidance (Q&A’s #7 and #8) (2).  
4.5 Visual Inspection used as described in 4.4 should only be used in situations where there is a suitable safety margin between the VRL and MSSR and robust detectability at the VRL.  
4.6 Application of the approach described within this practice applies the risk-based concepts and principles introduced in ICH Q9. As stated in ICH Q9, the level of effort, formality, and documentation for validation (including cleaning validation) should also be commensurate with the level of risk.  
4.7 Application of the approach described within this practice provides a science-, risk-, and statistical-based approach for releasing manufacturing equipment and manufactured medical devices or cleanliness that is compatible with the U.S. FDA Guidance for Industry, PAT – A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance.  
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SCOPE
1.1 This practice provides statistically valid procedures for determining the visual detection limit of residues and the qualification of inspectors to perform the visual inspection of pharmaceutical manufacturing equipment surfaces and medical devices for residues.  
1.2 This practice applies to pharmaceuticals (including active pharmaceutical ingredients (APIs); dosage forms; and over-the-counter, veterinary, biologics, and clinical supplies) and medical devices following all manufacturing and cleaning. This practice is also applicable to other health, cosmetics, and consumer products.  
1.3 This practice applies to many types of chemical residues (including APIs, intermediates, cleaning agents, processing aids, machining oils, and so forth) that could remain on manufacturing equipment surfaces or medical devices that have undergone all manufacturing steps including cleaning.  
1.4 This practice applies only to equipment or devices that have been justified through a Quality Risk Management program to have an acceptable hazard analysis, have cleaning processes that are repeatable and validated and where Visual Inspection can be relied upon to determine the cleanliness of the equipment at the residue limit justified by the HBEL.  
1.5 The values stated in International System of Units (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, 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 Recommend...

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Standard Guide for Multivariate Data Analysis in Pharmaceutical Development and Manufacturing Applications

SIGNIFICANCE AND USE
4.1 A significant amount of data is 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). MVDA may be particularly appropriate for exploring and handling large sets of heterogenous data, mapping data of high dimensionality onto lower dimensional representations, exposing significant correlations among multivariate variables within a single data set or significant correlations among multivariate variables across data sets. MVDA may extract statistically significant information which may enhance process understanding, decision making in process development, process monitoring and control (including product release), product life-cycle management, and continuous improvement.  
4.2 MVDA is widely used in various industries including the pharmaceutical industry. To achieve a valid outcome, an MVDA model/application should incorporate the following:  
4.2.1 A predefined risk-based objective incorporating one or more relevant scientific hypotheses specific to the application;  
4.2.2 Sufficient relevant data of requisite quality covering the variance space encountered during intended use, that is, pharmaceutical development, or pharmaceutical manufacturing, or both;  
4.2.3 Appropriate data analysis and model utilization practices including considerations on testing, validation, and qualification of all new data prior to using a model to analyze it;  
4.2.4 Appropriately trained staff;  
4.2.5 Appropriate standard operating procedures; and  
4.2.6 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 detai...
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 after being validated appropriately using a science and risk-based approach.  
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, model testing, and validation;  
1.2.4 Qualified and competent personnel; and  
1.2.5 Life-cycle management of MVDA model.  
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, health, and environmental practices and determine the applicability of regulatory limitations prior to use.  
1.4 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.

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ASTM
ASTM A370-23(Test Method)
Standard Test Methods and Definitions for Mechanical Testing of Steel Products

SIGNIFICANCE AND USE
4.1 The primary use of these test methods is testing to determine the specified mechanical properties of steel, stainless steel, and related alloy products for the evaluation of conformance of such products to a material specification under the jurisdiction of ASTM Committee A01 and its subcommittees as designated by a purchaser in a purchase order or contract.  
4.1.1 These test methods may be and are used by other ASTM Committees and other standards writing bodies for the purpose of conformance testing.  
4.1.2 The material condition at the time of testing, sampling frequency, specimen location and orientation, reporting requirements, and other test parameters are contained in the pertinent material specification or in a general requirement specification for the particular product form.  
4.1.3 Some material specifications require the use of additional test methods not described herein; in such cases, the required test method is described in that material specification or by reference to another appropriate test method standard.  
4.2 These test methods are also suitable to be used for testing of steel, stainless steel and related alloy materials for other purposes, such as incoming material acceptance testing by the purchaser or evaluation of components after service exposure.  
4.2.1 As with any mechanical testing, deviations from either specification limits or expected as-manufactured properties can occur for valid reasons besides deficiency of the original as-fabricated product. These reasons include, but are not limited to: subsequent service degradation from environmental exposure (for example, temperature, corrosion); static or cyclic service stress effects, mechanically-induced damage, material inhomogeneity, anisotropic structure, natural aging of select alloys, further processing not included in the specification, sampling limitations, and measuring equipment calibration uncertainty. There is statistical variation in all aspects of mechanical testin...
SCOPE
1.1 These test methods2 cover procedures and definitions for the mechanical testing of steels, stainless steels, and related alloys. The various mechanical tests herein described are used to determine properties required in the product specifications. Variations in testing methods are to be avoided, and standard methods of testing are to be followed to obtain reproducible and comparable results. In those cases in which the testing requirements for certain products are unique or at variance with these general procedures, the product specification testing requirements shall control.  
1.2 The following mechanical tests are described:    
Sections  
Tension  
7 to 14  
Bend  
15  
Hardness  
16  
Brinell  
17  
Rockwell  
18  
Portable  
19  
Impact  
20 to 30  
Keywords  
32  
1.3 Annexes covering details peculiar to certain products are appended to these test methods as follows:    
Annex  
Bar Products  
Annex A1  
Tubular Products  
Annex A2  
Fasteners  
Annex A3  
Round Wire Products  
Annex A4  
Significance of Notched-Bar Impact Testing  
Annex A5  
Converting Percentage Elongation of Round Specimens to
Equivalents for Flat Specimens  
Annex A6    
Testing Multi-Wire Strand  
Annex A7  
Rounding of Test Data  
Annex A8  
Methods for Testing Steel Reinforcing Bars  
Annex A9  
Procedure for Use and Control of Heat-cycle Simulation  
Annex A10  
1.4 The values stated in inch-pound units are to be regarded as standard. The values given in parentheses are mathematical conversions to SI units that are provided for information only and are not considered standard.  
1.5 When these test methods are referenced in a metric product specification, the yield and tensile values may be determined in inch-pound (ksi) units then converted into SI (MPa) units. The elongation determined in inch-pound gauge lengths of 2 in. or 8 in. may be report...

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