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ASTM E2968-14

(Guide)

Standard Guide for Application of Continuous Processing in the Pharmaceutical Industry

Standard Guide for Application of Continuous Processing in the Pharmaceutical Industry

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.

General Information

Status
Historical
Publication Date
30-Nov-2014
ICS
11.120.01 - Pharmaceutics in general
Technical Committee
E55 - Manufacture of Pharmaceutical and Biopharmaceutical Products
Drafting Committee
E55.01 - Process Understanding and PAT System Management, Implementation and Practice
Current Stage
Ref Project

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ASTM E2968-14 - Standard Guide for Application of Continuous Processing in the Pharmaceutical Industry
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NOTICE: This standard has either been superseded and replaced by a new version or withdrawn.
Contact ASTM International (www.astm.org) for the latest information
Designation: E2968 − 14
Standard Guide for
Application of Continuous Processing in the Pharmaceutical
1
Industry
This standard is issued under the fixed designation E2968; 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 2. Referenced Documents
2
1.1 This guide introduces key concepts and principles to 2.1 ASTM Standards:
assist in the appropriate selection, development and operation E2363 Terminology Relating to Process Analytical Technol-
of continuous processing technologies for the manufacture of ogy in the Pharmaceutical Industry
pharmaceutical products. E2475 Guide for Process Understanding Related to Pharma-
ceutical Manufacture and Control
1.2 Particular consideration is given to the development and
E2537 Guide for Application of Continuous Quality Verifi-
application of the appropriate scientific understanding and
cation to Pharmaceutical and Biopharmaceutical Manu-
engineering principles that differentiate continuous manufac-
facturing
ture from traditional batch manufacturing.
E2898 Guide for Risk-Based Validation of Analytical Meth-
1.3 Most of the underlying concepts and principles (for
ods for PAT Applications
3
example, process dynamics and process control) outlined in
2.2 FDA Documents:
this guide can be applied in both Drug Substance (DS) and
FDA Guidance for Industry PAT A Framework for Innova-
Drug Product (DP) processes. However it should be recognized
tive Pharmaceutical Development, Manufacturing, and
that in Drug Substance production the emphasis may be more
Quality Assurance (2004)
on chemical behavior and dynamics in a fluid phase whereas
3. Terminology
for drug product manufacture there may be a greater emphasis
on the physical behavior and dynamics in a solid/powder
3.1 Definitions:
format.
3.1.1 For general definitions, refer to Terminology E2363
and Guides E2537 and E2475.
1.4 This guide is also intended to apply in both the devel-
3.2 Definitions of Terms Specific to This Standard:
opment of a new process, or the improvement/redesign of an
3.2.1 back mixed process—a process with a residence time
existing one.
distribution (RTD) which is non zero and potentially significant
1.5 The values stated in SI units are to be regarded as
compared to the mean residence time.
standard. No other units of measurement are included in this
standard.
3.2.1.1 Discussion—For example, in an idealized fully back
mixed process quantities of material will be mixed into a single
1.6 This standard does not purport to address all of the
homogeneous condition such that a rapid step change in the
safety concerns, if any, associated with its use. It is the
properties of inlet material will not result in an equivalent step
responsibility of the user of this standard to establish appro-
change in the properties of the output material but will be
priate safety and health practices and determine the applica-
reflected in a more gradual change. The rate of this change will
bility of regulatory limitations prior to use.
depend on the equipment characteristics, residence volume,
1 2
This guide is under the jurisdiction of ASTM Committee E55 on Manufacture For referenced ASTM standards, visit the ASTM website, www.astm.org, or
of Pharmaceutical and Biopharmaceutical Products and is the direct responsibility of contact ASTM Customer Service at service@astm.org. For Annual Book of ASTM
Subcommittee E55.01 on Process Understanding and PAT System Management, Standards volume information, refer to the standard’s Document Summary page on
Implementation and Practice. the ASTM website.
3
Current edition approved Dec. 1, 2014. Published April 2015. DOI: 10.1520/ Available from Food and Drug Administration (FDA), 10903 New Hampshire
E2968-14. Ave., Silver Spring, MD 20993-0002, http://www.fda.gov.
Copyright © ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States
1

---------------------- Page: 1 ----------------------
E2968 − 14
and the residence time distribution/degree of mixing. A fully amount of starting material (with the option to divert certain
back mixed process may be considered and modeled as one or
amount of material taken from online control), and this is
more continuously stirred tank reactors (CSTR).
comparable to conventional discrete or batch manufacturing
3.2.2 controlled state—A process is in a controlled state
operations.
when it is: (1) Under Process Control, and (2) operating
(3) Alternatively a continuous process may be operated
normally, such that the measured critical quality attributes of
with an ‘infinite’ run-time, in which qua
...

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1.1 The purpose of this guide is to establish a framework and context for process understanding for pharmaceutical manufacturing using the principles of quality by design (QbD) (Juran, 1992;2 ICH Q8). The framework is applicable to both drug substance (DS) and 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 continual process improvement efforts.  
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Standard Terminology Relating to Manufacturing of Pharmaceutical and Biopharmaceutical Products in the Pharmaceutical and Biopharmaceutical Industry

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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.  
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.  
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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.  
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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.  
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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).  
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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.  
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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.  
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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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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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1.2.1 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);  
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4.1 Application of the approach described within this standard guide applies science-based concepts and principles introduced in the FDA’s initiative on pharmaceutical CGMPs for the 21st century.4  
4.2 This guide supports, and is consistent with, elements from ICH Q8 – Q11 and guidelines from USFDA, European Commission, Pharmaceutical Inspection Co-operation Scheme, and the China Food and Drug Administration.8  
4.3 According to FDA Guidance for Industry, PAT, “With real time quality assurance, the desired quality attributes are ensured through continuous assessment during manufacture. Data from production batches can serve to validate the process and reflect the total system design concept, essentially supporting validation with each manufacturing batch.” In other words, the accumulated product and process understanding used to identify the Critical Quality Attributes (CQAs), together with the control strategy, will enable control of the CQAs, providing the confidence needed to show validation with each batch. This is as opposed to a traditional discrete process validation approach.
SCOPE
1.1 This guide describes Continuous Process Verification as an alternate approach to process validation where manufacturing process (or supporting utility system) performance is continuously monitored, evaluated, and adjusted (as necessary). It is a science-based approach to verify that a process is capable and will consistently produce product meeting its predetermined critical quality attributes. Continuous Process Verification (ICH Q8) is similarly described as Continuous Quality Verification.  
1.2 Pharmaceutical and biopharmaceutical product manufacturing companies are required to provide assurance that the processes used to manufacture regulated products result in products with the specified critical quality attributes of strength identity and purity associated with the product safety and efficacy. Process validation is a way in which companies provide that assurance.  
1.3 With the knowledge obtained during the product lifecycle, a framework for continuous quality improvements will be established where the following may be possible: (1) risk identified, (2) risk mitigated, (3) process variability reduced, (4) process capability enhanced, (5) process design space defined or enhanced, and ultimately (6) product quality improved. This can enable a number of benefits that address both compliance and operational goals (for example, real time release, continuous process improvement).  
1.4 The principles in this guide may be applied to drug product or active pharmaceutical ingredient/drug substance pharmaceutical and biopharmaceutical batch or continuous manufacturing processes or supporting utility systems (for example, TOC for purified water and water for injection systems, and so forth).  
1.5 The principles in this guide may be applied during the development and manufacturing of a new process or product or for the improvement or redesign, or both, of an existing process.  
1.6 Continuous process verification may be applied to manufacturing processes that use monitoring systems that provide frequent and objective measurement of process data in real time. These processes may or may not employ in-, on-, or at-line analyzers/controllers that monitor, measure, analyze, and control the process performance. The associated processes may or may not have a design space.  
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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.  
1.3 The values stated in SI units are to be regarded as 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.

  • Guide
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  • Guide
    17 pages
    English language
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