E55.11 - Process Design

SCOPE
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.  
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:    
“…a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in process materials and processes, with the goal of ensuring final product quality. It is important to note that the term analytical in PAT is viewed broadly to include chemical, physical, microbiological, mathematical, and risk analysis conducted in an integrated manner. The goal of PAT is to enhance understanding and control the manufacturing process…” (USFDA PAT)  
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.

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.

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). A consistent approach to the use of risk methodologies should be 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 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, health, and environmental 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.  
1.3 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 Application of the approach described within this guide is intended to satisfy international regulatory expectations in ensuring that manufacturing systems and equipment are fit for intended use, for example, qualified, and to satisfy requirements for design, installation, operation, and performance.  
5.2 The approach described in this guide applies concepts and principles introduced in the FDA initiative, Pharmaceutical cGMPs for the 21st Century — A Risk-Based Approach.  
5.3 This guide supports, and is consistent with, the framework described in ICH Q8, ICH Q9, ICH Q10, and ICH Q11.  
5.4 This guide is designed to conform with FDA, EU, and other international regulations regarding equipment and facility suitability for use and qualification.  
5.5 This guide may be used independently or in conjunction with other Committee E55 standards published by ASTM International.
SCOPE
1.1 This guide is applicable to all elements of pharmaceutical and biopharmaceutical manufacturing systems including: good manufacturing practice (GMP) utility equipment, process equipment, supporting utilities, associated process monitoring and control systems, and automation systems that have the potential to affect product quality and patient safety.  
1.2 For brevity, these are referred to throughout the rest of this guide as manufacturing systems.  
1.3 This guide may also be applied to laboratory, information, and medical device manufacturing systems.  
1.4 This guide is applicable to both new and existing manufacturing systems. The approach may be used for implementation of changes to existing systems.  
1.5 This guide is applicable throughout the life-cycle of the manufacturing system from concept to retirement.  
1.6 This standard does not address employee health and safety, environmental, or other non-GxP regulations. 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 The proper design of low-temperature storage facilities ensures that sensitive biological materials are maintained under conditions providing maximum storage stability.  
4.2 Properly designed and operated low-temperature storage facilities ensure that the handling of sensitive biological materials at low temperatures does not compromise stability (see Guide E1565).  
4.3 Properly designed low-temperature storage facilities ensure that adequate safeguards are provided to prevent untoward events from compromising the stability of sensitive biological materials.
SCOPE
1.1 This guide covers recommended procedures for developing and maintaining low-temperature storage facilities for freezers with mechanical refrigeration.  
1.2 This guide covers recommended procedures for developing and maintaining low-temperature storage facilities for freezers cooled with liquid nitrogen.  
1.3 This guide does not cover practices for preservation by freezing which are covered in Practice E1342.  
1.4 The values stated in SI units are to be regarded as standard. No other units of measurement are included in this standard.  
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, health, and environmental practices and determine the applicability of regulatory limitations prior to use.  
1.6 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 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.  
1.7 This guide may be used independently or in conjunction with other proposed E55 standards to be published by ASTM International.

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;2 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:    
“…a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in process materials and processes, with the goal of ensuring final product quality. It is important to note that the term analytical in PAT is viewed broadly to include chemical, physical, microbiological, mathematical, and risk analysis conducted in an integrated manner. The goal of PAT is to enhance understanding and control the manufacturing process…” (U.S. FDA PAT)  
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.