E55 - Manufacture of Pharmaceutical and Biopharmaceutical Products

SIGNIFICANCE AND USE
3.1 Rodent-derived cell lines are widely used in the production of biopharmaceutical drugs such as mAbs and Fc fusion proteins. These cell lines have been shown to contain genes encoding endogenous retroviral-like particles or endogenous retrovirus. Despite the lack of evidence for an association between such rodent retroviruses and disease in humans, the potential contamination of human therapeutics raises safety concerns for biopharmaceutical drugs. Additionally, adventitious agents such as viruses can be introduced into a biopharmaceutical drug substance manufacturing process from other sources, and potential safety issues can be attributed to these potential unknowns. For these reasons, effective viral clearance is an essential aspect of an integrated approach combining safety testing and process characterization which ensures virus safety for biopharmaceutical drug products made using rodent cell lines.  
3.2 Solvent/detergent inactivation has been widely used for decades to inactivate enveloped viruses in blood plasma derived biopharmaceutical therapies (1-3).3 Solvent/detergent systems using the detergents Triton X-100 or Polysorbate 80 along with the organic solvent tri(n-butyl)phosphate (TNBP) have been used to inactivate enveloped viruses by disrupting the viral envelope thereby reducing the ability of the enveloped virus to attach to and then infect the host cell (4 and 5).  
3.3 Most manufacturers of mAbs, recombinant proteins, and Fc fusion proteins have focused on viral inactivation methods using the detergent Triton X-100 or Polysorbate 80 in the absence of TNBP (6), which can interfere with subsequent bioprocessing steps. The ability of the detergents alone to inactivate retroviruses has been demonstrated in monoclonal antibodies produced in rodent-derived cell lines (6-9). At a 2011 workshop devoted to viral clearance steps used in bioprocessing (7), investigators from one firm showed incubation with 0.2 % Triton X-100 for 60 min of hold time at a...
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1.1 This practice assures effective inactivation of ≥4 log10 of infectious rodent retrovirus (that is, reduction from 10 000 to 1 infectious rodent retrovirus or removal of 99.99 % of infectious rodent retroviruses) in the manufacturing processes of monoclonal antibodies or immunoglobulin G (IgG) Fc fusion proteins manufactured in rodent-derived cell lines that do not target retroviral antigens. Rodent retrovirus is used as a model for rodent cell substrate endogenous retrovirus-like particles potentially present in the production stream of these proteins.  
1.2 The parameters specified for this practice are clarification, Triton X-100 detergent concentration, hold time, pH, and inactivation temperature.  
1.3 This practice can be used in conjunction with other clearance or inactivation unit operations that are orthogonal to this inactivation mechanism to achieve sufficient total process clearance or inactivation of rodent retrovirus.  
1.4 This detergent inactivation step is performed on a clarified, cell-free intermediate of the monoclonal antibody or IgG Fc fusion protein.  
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, 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 methodology was originally developed (1-4)6 for use in drug content uniformity and dissolution but has general application to any multistage test with multiple acceptance criteria. Practice E2709 summarizes the statistical aspects of this methodology. This practice applies the general methodology of Practice E2709 specifically to the UDU test.  
4.1.1 While other methods can be used to estimate the probability of passing the UDU test, they are outside the scope of this practice.  
4.2 The UDU test procedure describes a two-stage sampling test, where at each stage one can pass or continue testing, and the decision to fail is deferred until the second stage. At each stage there are acceptance criteria on the test results as outlined in Table 1.    
4.3 The UDU test is a market standard. The USP General Notices include the following statement about compendial standards. “The similarity to statistical procedures may seem to suggest an intent to make inference to some larger group of units, but in all cases, statements about whether the compendial standard is met apply only to the units tested.” Therefore, the UDU procedure is not intended for inspecting uniformity of finished product for lot/batch release or as a lot inspection procedure.  
4.3.1 The UDU test defines a product requirement to be met at release and throughout the shelf-life of the product.  
4.3.2 Passing the UDU test once does not provide statistical assurance that a batch of drug product meets specified statistical quality control criteria.  
4.4 This practice provides a practical specification that may be applied when uniformity of dosage units is required. An acceptance region for the mean and standard deviation of a set of test results from the lot is defined such that, at a prescribed confidence level, the probability that a future sample from the lot will pass the UDU test is greater than or equal to a prespecified lower probability bound. Having test results fall in the acceptance r...
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1.1 This practice provides a general procedure for evaluating the capability to comply with the Uniformity of Dosage Units (UDU) test. This test is given in General Chapter  Uniformity of Dosage Units of the USP, in 2.9.40 Uniformity of Dosage Units of the Ph. Eur., and in 6.02 Uniformity of Dosage Units of the JP, and these versions are virtually interchangeable. For this multiple-stage test, the procedure computes a lower bound on the probability of passing the UDU test, based on statistical estimates made at a prescribed confidence level from a sample of dosage units.  
1.2 This methodology can be used to generate an acceptance limit table, which defines a set of sample means and standard deviations that assures passing the UDU test for a prescribed lower probability bound, confidence level, and sample size.  
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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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 Pharmaceutical Discussion:  
4.1.1 The origins for the calculation of cleaning validation limits for pharmaceuticals date back to the 1980's with the publication of an article in 1984, that stated that "limits must be safe and acceptable and in line with residual limits set for various substances in foods" (7). A second article in 1989 expanded upon these ideas adding that an "effect threshold" should be established in collaboration with toxicology and medical authorities (or alternatively, an appropriate safety factor. For example, 10× or 100× could be superimposed) and finally that limits for surface residue levels could then be calculated based on a smallest batch size/maximum dose combination. This article further mentioned that this calculation leads to many limits that could be verified through visual inspection (8). A third article in 1993, proposed the use of a combination of limits suggesting that carryover of product residues needed to meet these three criteria:  
(1) No more than 0.001 dose of any product will appear in the maximum daily dose of another product,
(2) No more than 10 ppm of a product will appear in another product, and
(3) No quantity of residue will be visible on the equipment after cleaning procedures are performed (9).  
4.1.2 In 1993, United States Food and Drug Administration (USFDA) issued a guide for its inspectors requiring that "the basis for any limits must be scientifically justifiable" (6). In 1996, USFDA proposed that, in addition to penicillin, certain "classes" of compounds would also need to be manufactured in dedicated facilities and would expect manufacturers to identify any drugs that present the risk of cross-contamination and to implement measures necessary to eliminate that risk (10). Otherwise, nothing short of dedicated facilities or equipment would be sufficient. In 2005, the European Medicines Agency (EMA) similarly announced that it would require dedicated facilities for certain medicines in addition t...
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1.1 This practice provides procedures for calculating safe and scientifically justifiable limits of residues for use in cleaning validation studies of pharmaceutical/biopharmaceutical/medical device manufacturing equipment surfaces and medical device surfaces.  
1.2 The procedures in this standard practice for calculating safe limits of chemical residues are based on Guide E3219.  
1.3 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.  
1.4 This practice applies to all types of chemical residues (including APIs; intermediates, cleaning agents, processing aids, machining oils, etc.) that could remain on manufacturing equipment surfaces or on medical devices that have undergone all manufacturing steps including cleaning. This practice does not cover extractables and leachables (see ISO 10993-17).  
1.5 This practice applies to microbiological residues that may be present on manufacturing equipment surfaces or on medical devices that have undergone all manufacturing steps including cleaning and does not cover disinfection or sterilization.  
1.6 Exclusions—Medical devices that do not make patient contact; non-product contact surfaces (which are discussed in other existing guides: Ref (1)2, PDA TR 29, USP , Guide E2614, ISO 14698, and ISO 14937).  
1.7 The values stated in SI units are to be regarded as standard. No other units of measurement are included in this standard.  
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 limit...

SIGNIFICANCE AND USE
4.1 This guide will encompass considerations for manufacturers regarding sources and potential causes of subvisible particles in biomanufacturing operations and the use of dynamic imaging particle analyzers as a suggested common method to monitor them. The guide will address the following components of particle analysis using dynamic imaging microscopy: fundamental principles, operation, image analysis methods, sample handling, instrument calibration, and data reporting.
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1.1 Biotherapeutic drugs and vaccines are susceptible to inherent protein aggregate formation which may change over the product shelf life. Intrinsic particles, including excipients, silicone oil, and other particles from the process, container/closures, equipment or delivery devices, and extrinsic particles which originate from sources outside of the contained process, may also be present. Monitoring and identifying the source of the subvisible particles throughout the product life cycle (from initial characterization and formulation through finished product expiry) can optimize product development, process design, improve process control, improve the manufacturing process, and ensure lot-to-lot consistency.  
1.2 Understanding the nature of particles and their source is a key to the ability to take actions to adjust the manufacturing process to ensure final product quality. Dynamic imaging microscopy (also known as flow imaging or flow microscopy) is a useful technique for particle analysis and characterization (proteinaceous and other types) during product development, in-process and commercial release with a sensitive detection and characterization of subvisible particles at ≥2 µm and ≤100 µm (although smaller and larger particles may also be reported if data are available). In this technique brightfield illumination is used to capture images either directly in a process stream, or as a continuous sample stream passes through a flow cell positioned in the field of view of an imaging system. An algorithm performs a particle detection routine. This process is a key step during dynamic imaging. The digital particle images in the sample are processed by image morphology analysis software that quantifies the particles in size, count, image intensity, and morphological parameters. Dynamic imaging particle analyzers can produce direct determinations of the particle count per unit volume (that is, particle concentration), as a function of particle size by dividing the particle count by the volume of imaged fluid (see Appendix X1).  
1.3 This guide will describe best practices and considerations in applying dynamic imaging to identification of potential sources and causes of particles during biomanufacturing. These results can be used to monitor these particles and where possible, to adjust the manufacturing process to avoid their formation. This guide will also address the fundamental principles of dynamic imaging analysis including image analysis methods, sample preparation, instrument calibration and verification and data reporting.  
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 This practice provides:  
4.1.1 A holistic approach to evaluate risks associated with an integrity breach in a SUS, considering its life cycle from development to disposal.  
4.1.2 An overview of physical and microbial test methods that could be applicable to SUS testing, for qualification and validation purposes, as well as for routine testing.  
4.1.3 Information on the main challenges faced when testing SUSs for integrity.  
4.2 This practice can be used by SUS suppliers and SUS end users to define an integrity assurance strategy for SUSs, with the relevant tests when appropriate.
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1.1 This practice uses quality risk management (QRM) and life-cycle approach to establish integrity assurance of single-use systems (SUSs), such as but not limited to bag assemblies and liquid transfer sets for processing, storage, and shipping of (bio)pharmaceutical products. It gives recommendations to identify failure modes and risks associated with such systems and their use-cases and how to identify the relevant leak(s) of concern. Integrity assurance in this context is limited to the barrier properties of the SUS, linked to microbial integrity and bioburden control (product quality) and liquid product loss (operator and environmental contamination). The required level of integrity assurance will depend on how critical the application is and can be interpreted in different ways. It can also vary between processes and applications used for different modalities (for example, advanced therapies). Other package barrier properties different from that, such as but not limited to gas barrier properties for gas headspace preservation, as well as porous barrier packages are not considered. Specific aspects how to address the contamination control strategy (CCS) for SUS are also described in chapters 8.131ff of the new Revision of Annex 1 (1),2 including chapter 8.137 regarding SUS integrity.  
1.2 The test method overview provides descriptions that focus on the standard test setup and the identification of challenges in combination with SUSs. Details, including specific test setups, test parameter, and result interpretation, are not discussed. For more detailed information refer to Test Method E3251 for microbial test methods, and to Test Method E3336 for physical test methods.  
1.3 This practice is not intended to apply to the use of single-use technology for primary containers, combination products (products composed of any combination of a drug, device, or biological product), or devices. Appropriate procedures related to these products are discussed in documents covering the integrity assurance for primary containers (2) or medical products (1, 3).  
1.4 Techniques and procedures for complaint management and root cause analysis related to integrity failures are also not discussed.  
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, 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 Single-use systems (SUSs) used for biopharmaceutical manufacturing must maintain sterility and product quality of the fluid inside. Such articles or systems should therefore be validated as providing an effective barrier against microbial ingress. The microbial barrier properties of a SUS may be demonstrated using deterministic physical tests that have been correlated to microbial integrity. Such physical test methods are described in Test Method E3336. Two microbial test methods (aerosol exposure and immersion exposure) are described in this test method that can be used to demonstrate microbial integrity of a SUS or determine the MALL, the maximum defect size that does not allow microbial ingress, into a SUS.  
4.2 It is important to note that the results of microbial ingress tests are heavily dependent on the conditions under which the test is performed and are not suitable for routine checking of a SUS due to the test’s destructive nature.  
4.2.1 Any size defect may be forced to fail under sufficiently aggressive conditions (including a large enough sample size, high differential pressure, or high hydrostatic pressure, for example) that would not ordinarily reflect normal use conditions. Thus, it is necessary to clearly define the relevant conditions for a test through a risk assessment of both the actual SUS claims and its final use (Practice E3244). Once that is established, the size of defect that can be detected under those conditions can be determined, if required, using defined defects.  
4.2.2 “Relevant conditions” refers to worse-case actual use conditions but does not mean that a SUS must be tested under theoretically absolute (extreme) “worst-case” conditions.  
4.2.3 Testing may be performed on individual components or entire systems. Considerations for defining “relevant conditions” and testing design should be based on a risk assessment for the SUS intended use and should include:
4.2.3.1 A channel created by a defect or breach through the...
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1.1 The microbial test method outlined in this test method applies to microbial ingress risk assessment of a single-use system (SUS) or its individual components that require integrity testing either by the assembly supplier or the end user of the assembly based on a potential risk of a breach to the product or manufacturing process.  
1.2 The aim of microbial ingress testing of sterile SUSs used in biopharmaceutical manufacturing is two-fold:  
1.2.1 Firstly, it is used to evaluate the ability of a SUS fluid path to remain sterile after a SUS has been challenged by microbial exposure. Microbial exposure is achieved either by directly placing a SUS into a container of microbial challenge solution, or by delivering an aerosolized microbial challenge onto a SUS that is placed inside a test chamber designed to generate and deliver the aerosol. The choice of the test challenge organism should be justified based on a risk assessment of the SUS and conditions of use.  
1.2.2 Additionally, microbial ingress testing can be used to determine the maximum allowable leakage limit (MALL) that does not allow microbial ingress under specific test conditions. The defect size that can be detected by specific physical integrity testing methods (see Test Method E3336) can be correlated to this MALL in order to claim microbial integrity. Test articles bearing calibrated defects over a range of dimensions, including up to a defect size expected to consistently allow microbial ingress as a positive control (defect-based positive control), may be tested to determine the MALL.  
1.3 Both purposes for microbial ingress testing as described in 1.2.1 and 1.2.2 can either be conducted by liquid immersion or aerosol exposure. For the purpose described in 1.2.2, the type of exposure should be determined according to the SUS’s use-case conditions and a risk assessment.  
1.4 The method used to create a breach, hole or defect in single-use film or...

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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.  
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.

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.
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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 Application of the approach described within this guide applies risk-based concepts and principles introduced in ICH Q9. As stated in ICH Q9, the level of effort, formality, and documentation for cleaning should also be commensurate with the level of risk.  
4.2 Application of the approach described within this guide applies many of the science-based, risk-based, and statistical concepts and principles introduced in the FDA’s Guidance for Industry Process Validation: General Principles and Practices   (3) and Quality Management Maturity for Finished Dosage Forms Pilot Program for Domestic Drug Product Manufacturers; Program Announcement.  
4.3 This guide supports, and is consistent with, elements from ICH Q8, ICH Q9, ICH Q10, ICH Q11, and ICH Q12.  
4.4 This guide supports and is consistent with the content and intent of ISO 14971.  
4.5 Key Concepts—This guide applies the following key concepts: (1) quality risk management, (2) science-based approach, (3) statistics-based approach, (4) process understanding, (5) continued improvement, and (6) life-cycle management as described in the ICH Q series.
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1.1 This guide applies the life-cycle approach to cleaning process validation, which includes the development, qualification, and verification of cleaning processes. It is applicable to pharmaceuticals (including active pharmaceutical ingredients (APIs)); all dosage forms; over-the-counter medicinal and neutraceutical products, veterinary products, biologics, clinical supplies, advanced therapy medicinal products (ATPM), medical device manufacturing; and is also applicable to other health, cosmetics, and consumer products.  
1.2 This guide is focused only on the cleaning of equipment product contact surfaces and medical device surfaces and does not cover disinfection, sterilization, or non-product contact surfaces (which are covered under other existing guides: Ref (1),2 USP , Guide E2614, ISO 14698, and ISO 14937).  
1.3 The values stated in SI units are to be regarded as standard. No other units of measurement are included in this standard.  
1.4 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.  
1.5 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.
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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
3.1 Mammalian cell lines are widely used in the production of biological therapeutics, such as monoclonal antibodies and other recombinant proteins. Some of these cell lines, like rodent cell lines, are known to contain genes encoding endogenous retroviral-like particles or produce endogenous retrovirus, but there is no evidence of an association between rodent retrovirus and disease in humans. Adventitious viruses can be introduced into a drug substance manufacturing process from other sources, and contamination of human therapeutics is a safety concern (3).  
3.2 Virus filtration, an orthogonal technology in a virus clearance platform to such steps as low pH or surfactant inactivation, has traditionally been accepted as a robust method for virus clearance when well designed. Size exclusion has been shown to be the primary mechanism of virus removal by virus retentive filtration, that is, larger viruses are more easily retained than smaller viruses such as parvoviruses (4, 5). Large virus retention has also been shown to be insensitive to process fluid characteristics such as protein type, protein concentration, pH, and ionic strength (4, 6, 7, 8, 9, 10). In contrast, for small viruses, aspects like flow pausing and/or flux decay can impact clearance (4, 6, 11).  
3.3 Large virus retentive filters, or retrovirus filters, are tested for removal of larger enveloped viruses like retrovirus or MuLV (80 nm to 100 nm) and have undetectable levels of the large bacteriophage PR772 (64 nm to 82 nm) (1). Small virus retentive filters, or parvovirus filters, are designed to remove parvovirus, like MMV (18 nm to 26 nm) (1). Since size exclusion has been demonstrated as the mechanism of virus retention, retroviruses, which are three to four times larger than parvoviruses, should be large enough to be completely retained, with undetectable levels of retrovirus in the filtrate, by all small virus retentive filters designed to remove parvovirus.  
3.4 Numerous published studies...
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1.1 This practice assures 6.0 log10 removal of retrovirus (for example, MuLV).  
1.2 This practice is applicable to monoclonal antibody (mAb), immunoglobulin G (IgG) fusion proteins, recombinant proteins, or other proteins produced using mammalian cell lines (for example, Chinese hamster ovary (CHO), murine hybridomas, murine myelomas, or human embryonic kidney (HEK) 293).  
1.3 The step is performed on cell-free intermediates.  
1.4 The log removal claim for retrovirus by small virus retentive filters can be used in conjunction with other clearance unit operations (for example, low pH inactivation, or inactivation of virus by surfactant) to assure sufficient total process clearance of potential virus contaminants, which would be supportive of early phase (clinical phase 1 or phase 2a trials) regulatory filings.  
1.5 Retrovirus removal claim by filtration is limited to small virus retentive filters, as defined in the PDA Technical Report Virus Filtration (1)2 in the context of this standard.  
1.6 The values stated in SI units are to be regarded as 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.

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...
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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.  
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, ...

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.  
4.8 Key Concepts—This practice applies the following key concepts: (1) visual inspection, (2) quality risk management, (3) science-based appr...
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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.  
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...

SIGNIFICANCE AND USE
4.1 The test methods outlined in this standard allow for suppliers and end users of SUSs in (bio)pharmaceutical manufacturing processes to detect a leak and/or confirm the barrier properties of empty, clean, and dry SUSs. Performing integrity testing can be a significant contribution to the overall integrity assurance of SUSs.  
4.2 The two types of physical test methods outlined in this standard are:  
4.2.1 Section 5, Pressure-Based Test Methods.  
4.2.2 Section 6, Tracer Gas-Based Test Methods.
Note 3: Other test methods are currently being adapted for robust, reliable, and reproducible testing SUS, for example, Vacuum Decay Test Method as described in Test Method F2338.  
4.3 Pressure-based test methods are generally less sensitive compared to tracer gas-based test methods but have a lower complexity and cost. To assist in selecting a method that will fit an application, refer to Table 1 in Practice E3244 for a more detailed comparison of the two methods.  
4.4 Both types of test methods can be used to detect leaks of any sizes in a SUS (referred to as leak testing) or confirm the barrier properties of the SUS (referred to as integrity testing).  
4.5 To ensure that integrity testing performed on SUSs is effective and accurate, the properties of the SUS (pressure capabilities, volume, material properties, etc.) must be considered. Also, a validation should be performed on the chosen test method as further described in 5.11 and 6.11.  
4.6 Practice E3244 should be referenced to determine the maximum allowable leakage limit for a SUS, along with the routine testing requirements that are suitable for each application.  
4.7 The purpose of the described test methods is not to stress the SUS until a potential defect occurs. The testing parameters, mainly test pressure, are independent from the use-case conditions. The robustness of the SUS under use-case conditions should be proven during product qualification.  
4.8 This standard test method describes the...
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1.1 The test methods described in this standard are applicable for single-use manufacturing equipment, further called Single-use Systems (SUSs), used for (bio)pharmaceutical products.  
1.2 The test methods described in this standard are not intended to be used on single-use technology for primary containers, combination products (products composed of any combination of a drug, device, or biological product), or devices. Appropriate procedures related to these products are discussed in documents covering the integrity assurance for primary containers (1)2 or medical products (2-4).  
1.3 The test methods and their validation are described to only cover testing of empty and dry SUSs. Residual liquid in the SUS can impact the test reliability and reproducibility.  
1.4 The test methods are intended to be used to confirm the barrier properties of the test article, further called integrity testing, or test the SUS for leaks of certain sizes, further called leak testing.
Note 1: To verify that an integrity test can confirm the intended barrier properties of the SUS, its detection limit must be equal or better than the respective maximum allowable leakage limit.  
1.5 The physical test methods covered by this standard are:  
1.5.1 Pressure-based test methods.  
1.5.2 Tracer gas-based test methods.  
1.6 The physical test methods described are in general non-destructive and allow further use of the SUS.
Note 2: Some variations can be used in a destructive way, for example, to perform root cause analysis of the leak.  
1.7 The standard describes the test apparatuses, operation procedures, environment requirements, and discusses specific challenges with testing SUSs, as well as how to perform robust validation of the test method.  
1.8 This standard does not include methods to determine the maximum allowable leakage limit for maintaining the barrier properties of the SUS. For that, refer to Practice E3244 and Test Me...

SIGNIFICANCE AND USE
3.1 This practice deals with recommended best practices for freeze dryer instrumentation, particularly which is used for monitoring the status of the product during freeze drying and perhaps for equipment capability testing. Temperature and pressure are both critical variables affecting heat transfer, mass transfer, process efficiency, and product quality. For this reason, particular emphasis is placed on product temperature and pressure measurement within the freeze dryer. The methods discussed in this guide are limited to techniques that are equally applicable at both laboratory and production scale.  
3.2 Finally, it is recognized that “best practice” changes over time as new technology matures and process understanding deepens.
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1.1 Recommended best practices in monitoring of product status during pharmaceutical freeze drying are presented focusing on methods that apply to both laboratory and production scale.  
1.2 With respect to product temperature measurement, sources of uncertainty associated with any type of measurement probe are discussed, as well as important differences between the two most common types of temperature-measuring instruments ― thermocouples and resistance temperature detectors (RTD). Two types of pressure transducers are discussed ― thermal conductivity type gauges and capacitance manometers, with the Pirani gauge being the thermal conductivity type gauge of choice. It is recommended that both types of pressure gauge be used on both the product chamber and the condenser for freeze dryers with an external condenser, and the reasoning for this recommendation is discussed.  
1.3 Aseptic filling and sterilization practices are outside the scope of this practice. These are recommendations to assist users in selecting best practices and they are not intended to supersede or replace regulatory requirements.  
1.4 Units—The values stated in SI units are to be regarded as the standard. No other units of measurement are included in this standard with the exception of mTorr for pressure measurement  
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
5.1 This test method is designed to assess the retentivity of a sterilizing filter under standard challenge conditions.  
5.1.1 A challenge of 107 bacteria per cm2 of effective filtration area is selected to provide a high degree of assurance that the method has sufficient sensitivity to detect oversized pores and that the filter will quantitatively retain large numbers of organisms. The model challenge organism, B. diminuta, is widely considered to be a small bacterium and is recognized as an industry standard for qualifying sterilizing filters. Other species may represent a worst-case test in terms of ability to penetrate a filter. This test does not provide assurance that filters can completely retain such bacteria.  
5.1.2 The analytical procedure utilized in this test method provides a method to assign a numerical value to the filtration efficiency of the filter being evaluated under standard filtration conditions. For the purpose of product sterility assurance, additional process-specific studies should be performed.
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1.1 This test method determines the bacterial retention characteristics of membrane filters for liquid filtration using Brevundimonas diminuta as the challenge organism. This test method can be used to evaluate any membrane filter system used for liquid sterilization.  
1.2 This test method is not intended to be used in performance of product- and process-specific validation of the bacterial retention characteristics of membrane filters to be used in pharmaceutical or biopharmaceutical sterilizing filtration, or both. Process- and product-specific bacterial retention validation should be carried out using the intended product manufacturing process parameters and the product solution or surrogate as the carrier fluid.  
1.3 The values stated in SI units are to be regarded as standard.  
1.3.1 Exception—The inch-pound values given for units of pressure are to be regarded as standard; SI unit conversions are shown in parentheses.  
1.4 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.  
1.5 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.
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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
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.
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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 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...
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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.  
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.

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 .
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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
2.1 This practice outlines a procedure for the mechanical calibration of paddle and basket dissolution units to ensure reproducibility of results.  
2.2 Once a unit meets all of the mechanical specifications included in this practice, it is considered calibrated and further calibration with dissolution calibrator tablets is not required.
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1.1 This practice covers the set-up and calibration of the paddle and basket dissolution apparatus.  
1.2 Use of this practice may be applied to apparatus that have been modified to enable automatic dissolution testing (that is, a valve in the bottom of the vessel or sampling through the shaft).  
1.3 The values stated in SI units are to be regarded as standard. No other units of measurement are included in this standard.  
1.4 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.  
1.5 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 Conventional stainless-steel process equipment for biopharmaceutical manufacturing require cleaning and sterilization prior to implementation. Single-use systems (SUS), stand-alone equipment typically composed of plastic components and assemblies, are usually assembled in cleanrooms and are usually not cleaned or rinsed prior to implementation (with the exception of filters, which are often rinsed prior to use). SUS cleanliness with respect to particulate matter depends upon the quality of the SUS manufacturing process, and also upon the care and handling of the SUS upon implementation by the end-user.  
4.2 In the process of manufacturing single-use components or assemblies, particulate matter may adhere to the interior (fluid contacting) or exterior surfaces of SUS (BPSA). Visual inspection of SUS components and assemblies for particulate matter is often limited by translucent or opaque materials which inhibit visualization, especially of interior fluid-contacting surfaces. Also in some cases, the large size of single-use assemblies significantly reduces the effectiveness of visual inspections. A more complete assessment of particulate matter load requires a method to extract particulate matter from the surfaces of single-use components or assemblies using a test liquid, which makes the particles readily available for analytical characterization using counting, sizing and chemical/physical identification methods.  
4.3 Pharmaceutical manufacturers use a wide variety of configurations and sizes of single-use components and assemblies, such as bioreactors, bioprocess containers, tubing, connectors, clamps, valves, sensors and filters. Extraction of particulate matter may be relatively easy from small components with readily accessible surfaces, however, extraction of particulate matter from large and complex assemblies with less readily accessible interior surfaces may require significantly more effort.  
4.4 The wide variety of single-use components and asse...
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1.1 This practice describes the requirements for development, qualification, and routine application of a procedure for the effective liquid extraction of particulate matter from the surfaces of single-use components and assemblies designed for use in biopharmaceutical manufacturing processes. The extraction generates a suspension of particulate matter in liquid which makes the particulate matter readily available for analytical characterization.  
1.2 The values stated in SI units are to be regarded as standard. No other units of measurement are included in this standard.  
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 Guidelines for unintended human exposure to active pharmaceutical ingredients (APIs) are required by various global regulations as part of international quality requirements, needed as good product stewardship, and are considered the industry standard.  
4.2 Application of the approach described within this guide applies a scientifically justified, data-driven, approach to deriving safe limits for unintended exposures to individual substances. These limits can then be further used to calculate cleaning limits used in quality risk assessment for the manufacture of pharmaceuticals. The HBEL approach considers substance-specific properties (type of effect, potency, pharmacology, safety profile, and so forth). Specific approaches are applicable to different categories of substances and in specific stages in drug development.  
4.3 The basis for the HBEL derivation is all available substance-specific data. Interpretation of these data considers the quantity and robustness of the database and the reliability and relevance of the data. Typically, adjustment factors (AFs) are used to address variability and uncertainty in different parameters to determine a safe human exposure limit, although alternative, purposefully conservative, approaches [for example, threshold of toxicological concern (TTC), read-across] may be used as appropriate.  
4.4 This guide supports, and is consistent with, elements of the European Commission (EU) Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use (27, 28) and guidance from the International Society of Pharmaceutical Engineers (ISPE) (29) in which it is mentioned that relevant residue limits should be based on a toxicological evaluation.  
4.5 Key Concepts—This guide applies the following steps: (1) hazard characterization, (2) identification of the critical effect(s) including dose-response assessment, (3) determination of one or several points of departure (PoD)s, (4) application of PoD-spe...
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1.1 This guide describes the scientific procedures underlying the integrative interpretation of all data concerning an active pharmaceutical ingredient (API) taking into account study adequacy, relevance, reliability, validity, and compound-specific characteristics (for example, potency, toxicological profile, and pharmacokinetics) leading to a numerical value for the API, which is used further in the quality risk management (ICH Q9) of cross contamination during the manufacture of different products in the same manufacturing facilities.  
1.2 This guide describes general guidance for calculating and documenting a health-based exposure limit (HBEL). It should serve the involved qualified experts as a reference for HBEL derivations and should harmonize the different approaches and nomenclature to the greatest extent possible.  
1.3 This guide should be used for calculating and documenting an HBEL, when required or necessary, for APIs (including biologics), intermediates, cleaning agents, excipients, and other chemicals (that is, reagents, manufacturing residues, and so forth) used for cleaning validation and verification (Guides F3127 and E3106). In scope is the cleaning and cross contamination of surfaces of manufacturing equipment and medical devices but does not include leachables/extractables (21 CFR 211.67, 21 CFR 610.11, 21 CFR 820.70, and 21 CFR 111.27).  
1.4 The principles in this guide may also be used as a basis for setting occupational exposure limits.  
1.5 The principles in this guide may be applied during the development and commercial manufacturing of small or large molecular weight medicines as well as isolated pharmaceutical intermediates.  
1.6 Subsequent-product HBEL values may be set for specific routes of exposure (for example, oral, inhalation, and parenteral) when necessary (for example, because of differences in bioavailability) and for specific patient populations (for example, children) if ...

SIGNIFICANCE AND USE
5.1 A risk-based approach must be used to determine the cell lines, test articles, and materials used for testing. An evaluation of relevant factors should be made to determine if a test article is representative of the intended use.  
5.2 Cell culture compatibility should be assessed if the material is in direct contact with cell culture medium regardless of duration of contact. Test articles can be of a single material or assembled from a multitude of materials.  
5.3 Two perspectives to single-use material cell culture compatibility assessments are the supplier and the end user perspectives. It is understood that the supplier may have better access to single-use materials and material manufacturing processes, while having limited access to representative cell lines. Supplier assessment of materials are best tested using cell lines available that have shown known material sensitivity. The end users may have more limited access to materials but access to more representative cell lines and processes. Therefore assessment of compatibility of material with a specific cell line in a process is best evaluated by the end user.  
5.4 This guide outlines best practices to establish test procedures. Appendix X1 outlines an example test procedure for a commercially available CHO cell line.
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1.1 This guide outlines best practices to consider when setting up a representative leachable test method to detect if a material is compatible with cell culture media or manufacturing processes. This guide does not replace or supersede cell growth tests like USP , USP  (plastic/elastomeric materials), or ISO 10993 (medical device materials), that are used in assessing biological reactivity in humans. Polymeric materials that have passed these tests have been found to leach compounds under normal process conditions that can inhibit cell culture growth for some cell lines. See Refs (1-5).2 Test methods that are representative of the manufacturing conditions will help identify materials that are appropriate for use during manufacturing.  
1.2 This guide may be relevant to biopharmaceutical manufacturing, cell-based therapeutics, vaccines, cell-based diagnostics, and other areas.  
1.3 The values stated in SI units are to be regarded as standard. No other units of measurement are included in this standard.  
1.4 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.  
1.5 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 The proper handling of material stored at low temperatures ensures that the stability of sensitive biological materials is not comprised.  
4.2 Properly designed inventory control systems ensure the maximum use of freezer space, that all material can be located easily, and that any item is retrieved easily without compromising the stability of other items in the freezer.  
4.3 Properly designed safety and security procedures ensure that material stored at low temperatures is not comprised during storage, and that if material is lost due to freezer failure or operational problems, replacement material is available (see Guide E1566).
SCOPE
1.1 This guide covers recommended procedures for handling material stored at low temperatures in mechanical freezers and liquid nitrogen freezers.  
1.2 This guide covers recommendations for implementing procedures for ensuring adequate inventory control.  
1.3 This guide covers recommendations for implementing procedures for safeguarding material stored at low temperatures.  
1.4 This guide does not cover the development or maintenance of equipment and facilities for low-temperature storage which are covered in Guide E1564.  
1.5 This guide does not cover practices for preservation by freezing which are covered in Practice E1342.  
1.6 The values stated in SI units are to be regarded as 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.

SIGNIFICANCE AND USE
4.1 This guide is intended for use by individuals maintaining and handling hazardous biological material in liquid nitrogen freezers.  
4.2 This guide does not cover all aspects of every situation that may be encountered in maintaining hazardous biological material in liquid nitrogen; each situation must therefore be assessed individually using these guidelines.  
4.3 This guide is not intended for use with systems other than liquid nitrogen storage.  
4.4 This guide does not cover practices for preservation by freezing which are covered in Practice E1342.
SCOPE
1.1 This guide covers recommended procedures for maintaining and handling hazardous biological materials at liquid nitrogen temperatures.  
1.2 This guide covers the safety precautions recommended when handling material stored in liquid nitrogen.  
1.3 This guide does not cover the maintenance and handling of hazardous biological materials maintained at cryogenic temperatures in systems other than liquid nitrogen.  
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.

SCOPE
1.1 This practice assures 5 log10 inactivation of non-defective C-type retroviruses, which are endogenous to murine hybridoma and CHO cells and are potentially present in the production stream of biopharmaceutical processes that use rodent derived cell culture.  
1.2 The process parameters specified in this practice consistently assure 5 log10 inactivation of murine retrovirus by adjusting the pH of a process solution after initial affinity capture chromatography purification.  
1.3 This practice is applicable to mAb, IgG fusion, or other recombinant proteins produced from rodent cell lines (for example, CHO or murine hybridoma), which do not target retroviral proteins. Additionally, the low pH step is performed on a cell-free intermediate, post initial capture using protein A chromatography.  
1.4 The 5 log10 inactivation of murine retrovirus claimed by using this practice will be utilized in conjunction with other clearance unit operations (for example, chromatography and virus retentive filtration) to assure sufficient total process clearance of murine retroviruses, which will be supportive of early phase regulatory filings.  
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 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 this guidance should enable PAT method developers to design and implement reliable PAT applications that avoid many common sources of error around sampling. Sampling is a key element of method and process validation plans.  
4.1.1 Many ASTM standards discuss sampling; however, almost all are very specific to a certain field or application. For example, the “Standard Practice for Automatic Sampling of Petroleum and Petroleum Products” (D4177) specifically covers information for the design, installation, testing, and operation of automated equipment for the extraction of representative samples of petroleum and petroleum products from a flowing stream and storing them in a sample receiver.  
4.1.2 Other useful ASTM standards include: E105 (Practice for Probability Sampling of Materials), E122 (Standard Practice for Calculating Sample Size to Estimate, With a Specified Precision, the Average for a Characteristic of a Lot or Process), E1402 (Standard Guide for Sampling Design), and E456 (Terminology Relating to Quality and Statistics). These standards review similar considerations as those addressed in this guidance and can be consulted for additional insight on how to deal with specific sample types or situations. However, such standards should be carefully reviewed for relevance to pharmaceutical applications.
SCOPE
1.1 This document is to be used as a guide to Process Analytical Technology (PAT) instrument sampling, and covers both the sample from which PAT data is collected and the sample that is taken for reference assay. The ASTM definition of a guide is a compendium of information or series of options that does not recommend a specific course of action. The intention of a guide is to increases the awareness of information and approaches in a given subject area, as such this guide should serve as a collation of points to consider when determining a sample practice for PAT instruments. It is not intended to serve as a practice to be followed. As a first step, one should define the overall goal of the PAT measurement. Once defined, this guide describes various considerations as they relate to the specific requirements that must be met to achieve the overall PAT goal, including the attributes to be measured, impact of the scale of the process, and interfacing of the measurement system to manufacturing equipment (including sampling system reliability). Additionally, it discusses the estimation and validation of the effective sample size and the overall contribution to the measurement. Related aspects of data collection and data processing as well as the use of risk assessments to optimize sampling and to understand the impact of potential sampling errors are also covered. Furthermore, considerations for process control and aspects pertaining to sample withdrawal and retention are also included. Lastly, continuous manufacturing processes require special considerations due to the time dependency associated with continuous operations as compared to batch manufacturing and special considerations are needed for sampling of such processes.  
1.2 This guide is limited to a high level overview of sampling considerations for PAT applied to any type of pharmaceutical manufacturing (for example, active pharmaceutical ingredient (API), solid oral dosage form, etc.). It is not intended to provide technology- or application-specific sampling guidance, or both. Instead, the intent is to evoke a thought process around sampling when developing a PAT application. While the focus is mainly on sampling considerations for on/in-line applications in solids, liquids, and gases (that is, in situ PAT measurements), many of the considerations also apply to at-line and off-line applications in which a sample is withdrawn from the process and subsequently presented for analysis.  
1.3 This international standard was developed in accordance with internationally recognized principles on standardizatio...

SIGNIFICANCE AND USE
5.1 Application of the approach described within this guide is intended to achieve a biopharma industry-wide standard format that will be available for electronic data transfer between Supplier and Customer for monitoring and studying variability.  
5.2 This guide supports and facilitates fast data transfer, thereby avoiding data recapture, human interaction, and transcription errors; and thus enables a more streamlined business process.  
5.3 If the eData structure does not conform to the XSD defined by this guide then it is not guaranteed to be inter-operable. Feedback or change requests should be directed to ASTM Headquarters, to the attention of the Committee E55 Staff Manager.  
5.4 Digital Signature can be adopted and used as part of the eData transfer. XML and XSD are provided in two formats: with and without digital signature configuration. User can follow either format for implmenation to ensure conforming with the ASTM eData XSD structure.
SCOPE
1.1 This guide is applicable to all elements of raw material electronic data (eData) transfer from a Supplier which provides a raw material to a Customer which receives the raw material.  
1.2 This guide is developed for pharmaceutical and biopharmaceutical manufacturers and their suppliers, but may be suitable for other industries that routinely transfer data.  
1.3 The guide may also be applicable to raw material eData transfer between companies in the supply chain.  
1.4 The guide is applicable to new and existing raw materials.  
1.5 This guide is applicable to the life-cycle of a raw material (that is, data generated throughout the processing stages of the raw material) and is not dependent on the Supplier or Customer.  
1.6 This guide describes two major areas of eData standard: the data format and the data content including the taxonomy and nomenclature.  
1.7 The guide currently only covers data content and data format in the English language. The data format shall not be translated. Use of other languages for the data content outside the scope of this guide.  
1.8 The format is based on Extensible Markup Language (XML) 1.0.  
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
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.

SIGNIFICANCE AND USE
5.1 Pharmaceutical water is the most common component or ingredient used in pharmaceutical and biopharmaceutical manufacturing. Acceptable purity of the water is important to the quality of the final pharmaceutical product. TOC concentration is a key indicator and attribute of the purity of this water and also an important monitor of the overall performance of the water purification system. TOC analysis is the measurement of all the covalently bound carbon present in the water, not including carbon in the form of carbon dioxide (CO2), bicarbonate icon (HCO3 –), or carbonate ion (CO3 2–), and is reported as the mass of organic carbon per volume.  
5.2 Application of this practice provides pertinent information to make informed decisions on the release of water meeting pharmaceutical TOC concentration specifications.
SCOPE
1.1 This practice establishes an approach to the real-time release testing (RTRT) of pharmaceutical water based on the total organic carbon (TOC) attribute using on-line total organic carbon (OLTOC) instrumentation that is in agreement with current regulatory thinking.  
1.2 This practice is harmonized with or supports the concepts of relevant ASTM International Committee E55 on Manufacture of Pharmaceutical Products standards, ICH Harmonized Tripartite Guidelines, the U.S. FDA PAT Guidance, and U.S. FDA Pharmaceutical cGMPs.  
1.3 This practice does not provide general guidance information for pharmaceutical procedures that are considered standard practice in the pharmaceutical industry. This practice provides specific guidance for non-standardized procedures.  
1.4 This practice does not address the user’s various internal procedures for risk, change, or quality management systems. The overall project effort associated with this practice shall be proportional to the overall risk of failing the pharmaceutical water’s TOC concentration specification.  
1.5 This practice does not purport to establish how to comply with pharmacopeias. The RTRT methodology selected must assure compliance with the user’s current required pharmacopeias. However, compliance with pharmacopeia TOC methods is not necessarily sufficient to meet current regulatory expectations for RTRT.  
1.6 This practice does not purport to substitute for or replace compendial bioburden testing requirements. It is strictly applicable to the TOC attribute of water quality.  
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 and health practices and determine the applicability of regulatory limitations prior to use.

SIGNIFICANCE AND USE
5.1 Application of the approach described within this guide is intended to satisfy international regulatory expectations in ensuring that SUS are fit for their intended use and to satisfy requirements for sourcing, supply, design, specification, installation, operation, and performance.  
5.2 The approach described in this guide applies concepts and principles introduced in the FDA initiative, Pharmaceutical cGMP’s for the 21st Century – A Risk-Based Approach. It supports and is consistent with the framework described in FDA Guidance for Industry, Process Validation: General Principles and Practices, in ICH Q7, ICH Q8 (R2), ICH Q9, and ICH Q10.  
5.3 This guide includes concepts developed in the PDA Technical Report No. 66.  
5.4 This guide may be used independently or in conjunction with other ASTM Committee E55 proposed standards to be published by ASTM International.  
5.5 Specific standard practices about extractables, leachables, particulate matter, and integrity testing/leak detection, biocompatibility, and raw materials as available should be used by suppliers and end users and applied to their own manufacturing process facilities.
SCOPE
1.1 This guide is intended as a complement to Guide E2500.  
1.2 This guide is applicable to the range of manufacturing systems described in Guide E2500, specifically all elements of single-use systems, or hybrids of single-use and traditional components, used for the manufacturing of pharmaceutical and biopharmaceutical products, including: materials of construction, components, assembly, manifolds, supporting utilities, associated process monitoring and control systems, automation systems, and controlled environment that have the potential to affect product quality and patient safety.  
1.3 This guide is applicable for the implementation of changes to manufacturing system design for existing systems. It may be used for continuous improvement and changes in operation from clinical through to commercial scale.  
1.4 For brevity, single-use systems are referred to as SUS throughout the rest of this guide.  
1.5 The approach may be applied by the end user, the supplier of SUS, and raw materials sub-suppliers further back in the supply chain.  
1.6 This guide is not intended to apply to the use of single-use technology for packaging, primary containers, combination products (products composed of any combination of a drug, device, or biological product) or devices.  
1.7 This guide does not address specific local requirements, which remain the responsibility of the end user.  
1.8 This guide does not address employee health and safety, environmental, nor other good engineering and manufacturing practices (GXP) requirements. 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 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.  
4.8 Key Concepts—This practice applies the following key concepts: (1) visual inspection, (2) quality risk management, (3) science-based appr...
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...

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).  
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 (2).  
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 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.  
4.6 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 on Process Analytical Technology Initiative (3).  
4.7 Key Concepts—This practice applies the following key concepts: (1) visual inspection, (2) quality risk management, (3) science-based approach, (4) statistics-based approach, and (5) process knowledge and understanding.
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 all 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 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 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
4.1 Single-use systems (SUSs) used for biopharmaceutical manufacturing must maintain sterility and product quality of the fluid inside. Such articles or systems should therefore be validated as providing an effective barrier against microbial ingress. The microbial barrier properties of a SUS may be demonstrated using deterministic physical tests that have been correlated to microbial integrity. Two test methods (aerosol exposure and immersion exposure) are described that can be used to demonstrate microbial integrity of a SUS or determine the MALL, the maximum defect size that does not allow microbial ingress, into a SUS.  
4.2 It is important to note that the results of microbial ingress tests are heavily dependent on the conditions under which the test is performed and are not suitable for routine checking of a SUS due to the test’s destructive nature.  
4.2.1 Any size defect may be forced to fail under sufficiently aggressive conditions (including a large enough sample size, high differential pressure, or high hydrostatic pressure, for example) that would not ordinarily reflect normal use conditions. Thus, it is necessary to clearly define the relevant conditions for a test through a risk assessment of both the actual SUS claims and its final use (Practice E3244). Once that is established, the size of defect that can be detected under those conditions can be determined, if required, using defined defects.  
4.2.2 “Relevant conditions” refers to worse-case actual use conditions but does not mean that a SUS must be tested under theoretically absolute (extreme) “worst-case” conditions.  
4.2.3 Testing may be performed on individual components or entire systems. Considerations for defining “relevant conditions” and testing design should be based on a risk assessment for the SUS intended use and should include:
4.2.3.1 A channel created by a defect or breach through the film thickness or through a seam or connection which must be filled with liquid to allow mic...
SCOPE
1.1 The microbial test method outlined in this document applies to microbial ingress risk assessment of a single-use system (SUS) or its individual components that require integrity testing either by the assembly supplier or the end user of the assembly based on a potential risk of a breach to the product or manufacturing process.  
1.2 The aim of microbial ingress testing of sterile SUSs used in biopharmaceutical manufacturing is two-fold:  
1.2.1 Firstly, it is used to evaluate the ability of a SUS fluid path to remain sterile after a SUS has been challenged by microbial exposure. Microbial exposure is achieved either by directly placing a SUS into a container of microbial challenge solution, or by delivering an aerosolized microbial challenge onto a SUS that is placed inside a test chamber designed to generate and deliver the aerosol. The choice of the test challenge organism should be justified based on a risk assessment of the SUS and conditions of use.  
1.2.2 Additionally, microbial ingress testing can be used to determine the maximum allowable leakage limit (MALL) that does not allow microbial ingress under specific test conditions. The defect size that can be detected by specific physical integrity testing methods can be correlated to this MALL in order to claim microbial integrity. Test articles bearing calibrated defects over a range of dimensions, including up to a defect size expected to consistently allow microbial ingress as a positive control (defect-based positive control), may be tested to determine the MALL.  
1.3 Both purposes for microbial ingress testing as described in 1.2.1 and 1.2.2 can either be conducted by liquid immersion or aerosol exposure. For the purpose described in 1.2.2, the type of exposure should be determined according to the SUS’s use-case conditions and a risk assessment.  
1.4 The method used to create a breach, hole or defect in single-use film or in a SUS test article, as ...

SIGNIFICANCE AND USE
4.1 This practice provides:  
4.1.1 A holistic approach to evaluate risks associated with an integrity breach in a SUS, considering its life cycle from development to disposal.  
4.1.2 An overview of physical and microbial test methods that could be applicable to SUS testing, for qualification and validation purposes, as well as for routine testing.  
4.1.3 Information on the main challenges faced when testing SUSs for integrity.  
4.2 This practice can be used by SUS suppliers and SUS end users to define an integrity assurance strategy for SUSs, with the relevant tests when appropriate.
SCOPE
1.1 This practice uses quality risk management (QRM) and life-cycle approach to establish integrity assurance of single-use systems (SUSs), such as but not limited to bag assemblies and liquid transfer sets for processing, storage, and shipping of (bio)pharmaceutical products. It gives recommendations to identify failure modes and risks associated with such systems and their use-cases and how to identify the relevant leak(s) of concern. Integrity assurance in this context is limited to the barrier properties of the SUS, linked to microbial integrity and bioburden control (product quality) and liquid product loss (operator and environmental contamination). The required level of integrity assurance will depend on how critical the application is and can be interpreted in different ways. Other package barrier properties different from that, such as but not limited to gas barrier properties for gas headspace preservation, are not considered.  
1.2 The test method overview provides descriptions that focus on the standard test setup and the identification of challenges in combination with SUSs. Details, including specific test setups, test parameter, and result interpretation, are not discussed.  
1.3 This practice is not intended to apply to the use of single-use technology for primary containers, combination products (products composed of any combination of a drug, device, or biological product), or devices. Appropriate procedures related to these products are discussed in documents covering the integrity assurance for primary containers (1)2 or medical products (2, 3).  
1.4 Techniques and procedures for complaint management and root cause analysis related to integrity failures are also not discussed.  
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, 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
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 The methodology was originally developed (1-4)6 for use in drug content uniformity and dissolution but has general application to any multistage test with multiple acceptance criteria. Practice E2709 summarizes the statistical aspects of this methodology. This practice applies the general methodology of Practice E2709 specifically to the UDU test.  
4.1.1 While other methods can be used to estimate the probability of passing the UDU test, they are outside the scope of this practice.  
4.2 The UDU test procedure describes a two-stage sampling test, where at each stage one can pass or continue testing, and the decision to fail is deferred until the second stage. At each stage there are acceptance criteria on the test results as outlined in Table 1.    
4.3 The UDU test is a market standard. The USP General Notices include the following statement about compendial standards. “The similarity to statistical procedures may seem to suggest an intent to make inference to some larger group of units, but in all cases, statements about whether the compendial standard is met apply only to the units tested.” Therefore, the UDU procedure is not intended for inspecting uniformity of finished product for lot/batch release or as a lot inspection procedure.  
4.3.1 The UDU test defines a product requirement to be met at release and throughout the shelf-life of the product.  
4.3.2 Passing the UDU test once does not provide statistical assurance that a batch of drug product meets specified statistical quality control criteria.  
4.4 This practice provides a practical specification that may be applied when uniformity of dosage units is required. An acceptance region for the mean and standard deviation of a set of test results from the lot is defined such that, at a prescribed confidence level, the probability that a future sample from the lot will pass the UDU test is greater than or equal to a prespecified lower probability bound. Having test results fall in the acceptance r...
SCOPE
1.1 This practice provides a general procedure for evaluating the capability to comply with the Uniformity of Dosage Units (UDU) test. This test is given in General Chapter  Uniformity of Dosage Units of the USP, in 2.9.40 Uniformity of Dosage Units of the Ph. Eur., and in 6.02 Uniformity of Dosage Units of the JP, and these versions are virtually interchangeable. For this multiple-stage test, the procedure computes a lower bound on the probability of passing the UDU test, based on statistical estimates made at a prescribed confidence level from a sample of dosage units.  
1.2 This methodology can be used to generate an acceptance limit table, which defines a set of sample means and standard deviations that assures passing the UDU test for a prescribed lower probability bound, confidence level, and sample size.  
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 Application of the approach described within this guide applies risk-based concepts and principles introduced in ICH Q9. As stated in ICH Q9, the level of effort, formality and documentation for cleaning should also be commensurate with the level of risk.  
4.2 Application of the approach described within this guide applies many of the science-based, risk-based, and statistical concepts and principles introduced in the FDA’s Guidance for Industry Process Validation: General Principles and Practices   (3).  
4.3 This guide supports, and is consistent with, elements from ICH Q8, ICH Q9, ICH Q10, and ICH Q11.  
4.4 Key Concepts—This guide applies the following key concepts: (1) quality risk management, (2) science-based approach, (3) statistics-based approach, (4) process understanding, and (5) continued improvement as described in the ICH Q series.
SCOPE
1.1 This guide applies the life-cycle approach to cleaning process validation, which includes the development, qualification, and verification of cleaning processes. It is applicable to pharmaceuticals (including active pharmaceutical ingredients (APIs); dosage forms; and over-the-counter, veterinary, biologics, and clinical supplies) and is also applicable to other health, cosmetics, and consumer products.  
1.2 This guide is focused only on the cleaning of equipment product contact surfaces and does not cover disinfection or non-product contact surfaces (which are covered under other existing guides: Ref (1),2 USP , Guide E2614, and ISO 14698).  
1.3 The values stated in SI units are to be regarded as standard. No other units of measurement are included in this standard.  
1.4 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.  
1.5 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 guide applies risk-based concepts and principles introduced in ICH Q9. As stated in ICH Q9, the level of effort, formality and documentation for cleaning should also be commensurate with the level of risk.  
4.2 Application of the approach described within this guide applies many of the science-based, risk-based, and statistical concepts and principles introduced in the FDA’s Guidance for Industry Process Validation: General Principles and Practices   (3).  
4.3 This guide supports, and is consistent with, elements from ICH Q8, ICH Q9, ICH Q10, and ICH Q11.  
4.4 Key Concepts—This guide applies the following key concepts: (1) quality risk management, (2) science-based approach, (3) statistics-based approach, (4) process understanding, and (5) continued improvement as described in the ICH Q series.
SCOPE
1.1 This guide applies the life-cycle approach to cleaning process validation, which includes the development, qualification, and verification of cleaning processes. It is applicable to pharmaceuticals (including active pharmaceutical ingredients (APIs); dosage forms; and over-the-counter, veterinary, biologics, and clinical supplies) and is also applicable to other health, cosmetics, and consumer products.  
1.2 This guide is focused only on the cleaning of equipment product contact surfaces and does not cover disinfection or non-product contact surfaces (which are covered under other existing guides: Ref (1),2 USP , Guide E2614, and ISO 14698).  
1.3 The values stated in SI units are to be regarded as standard. No other units of measurement are included in this standard.  
1.4 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.  
1.5 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 guide applies risk-based concepts and principles introduced in ICH Q9. As stated in ICH Q9, the level of effort, formality and documentation for cleaning should also be commensurate with the level of risk.  
4.2 Application of the approach described within this guide applies many of the science-based, risk-based, and statistical concepts and principles introduced in the FDA’s Guidance for Industry Process Validation: General Principles and Practices  (3).  
4.3 This guide supports, and is consistent with, elements from ICH Q8, ICH Q9, ICH Q10, and ICH Q11.  
4.4 Key Concepts—This guide applies the following key concepts: (1) quality risk management, (2) science-based approach, (3) statistics-based approach, (4) process understanding, and (5) continued improvement as described in the ICH Q series.
SCOPE
1.1 This guide applies the life-cycle approach to cleaning process validation, which includes the development, qualification, and verification of cleaning processes. It is applicable to pharmaceuticals (including active pharmaceutical ingredients (APIs); dosage forms; and over-the-counter, veterinary, biologics, and clinical supplies) and is also applicable to other health, cosmetics, and consumer products.  
1.2 This guide is focused only on the cleaning of equipment product contact surfaces and does not cover disinfection or non-product contact surfaces (which are covered under another existing guide (1)2).  
1.3 The values stated in SI units are to be regarded as standard. No other units of measurement are included in this standard.  
1.4 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.  
1.5 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 methodology was originally developed (1-4)6 for use in drug content uniformity and dissolution but has general application to any multistage test with multiple acceptance criteria. Practice E2709 summarizes the statistical aspects of this methodology. This practice applies the general methodology of Practice E2709 specifically to the UDU test.  
4.1.1 While other methods can be used to estimate the probability of passing the UDU test, they are outside the scope of this practice.  
4.2 The UDU test procedure describes a two-stage sampling test, where at each stage one can pass or continue testing, and the decision to fail is deferred until the second stage. At each stage there are acceptance criteria on the test results as outlined in Table 1.  
4.3 The UDU test is a market standard. The USP General Notices include the following statement about compendial standards. “The similarity to statistical procedures may seem to suggest an intent to make inference to some larger group of units, but in all cases, statements about whether the compendial standard is met apply only to the units tested.” Therefore, the UDU procedure is not intended for inspecting uniformity of finished product for lot/batch release or as a lot inspection procedure.  
4.3.1 The UDU test defines a product requirement to be met at release and throughout the shelf-life of the product.  
4.3.2 Passing the UDU test once does not provide statistical assurance that a batch of drug product meets specified statistical quality control criteria.  
4.4 This practice provides a practical specification that may be applied when uniformity of dosage units is required. An acceptance region for the mean and standard deviation of a set of test results from the lot is defined such that, at a prescribed confidence level, the probability that a future sample from the lot will pass the UDU test is greater than or equal to a prespecified lower probability bound. Having test results fall in the acceptance re...
SCOPE
1.1 This practice provides a general procedure for evaluating the capability to comply with the Uniformity of Dosage Units (UDU) test. This test is given in General Chapter  Uniformity of Dosage Units of the USP, in 2.9.40 Uniformity of Dosage Units of the Ph. Eur., and in 6.02 Uniformity of Dosage Units of the JP, and these versions are virtually interchangeable. For this multiple-stage test, the procedure computes a lower bound on the probability of passing the UDU test, based on statistical estimates made at a prescribed confidence level from a sample of dosage units.  
1.2 This methodology can be used to generate an acceptance limit table, which defines a set of sample means and standard deviations that assures passing the UDU test for a prescribed lower probability bound, confidence level, and sample size.  
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
5.1 Application of the approach described within this guide is intended to achieve a biopharma industry-wide standard format that will be available for electronic data transfer between Supplier and Customer for monitoring and studying variability.  
5.2 This guide supports and facilitates fast data transfer, thereby avoiding data recapture, human interaction, and transcription errors; and thus enables a more streamlined business process.  
5.3 If the eData structure does not conform to the XSD defined by this guide then it is not guaranteed to be inter-operable. Feedback or change requests should be directed to ASTM Headquarters, to the attention of the Committee E55 Staff Manager.  
5.4 Digital Signature can be adopted and used as part of the eData transfer. XML and XSD are provided in two formats: with and without digital signature configuration. User can follow either format for implmenation to ensure conforming with the ASTM eData XSD structure.
SCOPE
1.1 This guide is applicable to all elements of raw material electronic data (eData) transfer from a Supplier which provides a raw material to a Customer which receives the raw material.  
1.2 This guide is developed for pharmaceutical and biopharmaceutical manufacturers and their suppliers, but may be suitable for other industries that routinely transfer data.  
1.3 The guide may also be applicable to raw material eData transfer between companies in the supply chain.  
1.4 The guide is applicable to new and existing raw materials.  
1.5 This guide is applicable to the life-cycle of a raw material (that is, data generated throughout the processing stages of the raw material) and is not dependent on the Supplier or Customer.  
1.6 This guide describes two major areas of eData standard: the data format and the data content including the taxonomy and nomenclature.  
1.7 The guide currently only covers data content and data format in the English language. The data format shall not be translated. Use of other languages for the data content outside the scope of this guide.  
1.8 The format is based on Extensible Markup Language (XML) 1.0.  
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 Application of the approach described within this guide is intended to achieve a biopharma industry-wide standard format that will be available for electronic data transfer between Supplier and Customer for monitoring and studying variability.  
5.2 This guide supports and facilitates fast data transfer, thereby avoiding data recapture, human interaction, and transcription errors; and thus enables a more streamlined business process.  
5.3 If the eData structure does not conform to the XSD defined by this guide then it is not guaranteed to be inter-operable. Feedback or change requests should be directed to ASTM Headquarters, to the attention of the Committee E55 Staff Manager.  
5.4 Digital Signature can be adopted and used as part of the eData transfer. XML and XSD are provided in two formats: with and without digital signature configuration. User can follow either format for implmenation to ensure conforming with the ASTM eData XSD structure.
SCOPE
1.1 This guide is applicable to all elements of raw material electronic data (eData) transfer from a Supplier which provides a raw material to a Customer which receives the raw material.  
1.2 This guide is developed for pharmaceutical and biopharmaceutical manufacturers and their suppliers, but may be suitable for other industries that routinely transfer data.  
1.3 The guide may also be applicable to raw material eData transfer between companies in the supply chain.  
1.4 The guide is applicable to new and existing raw materials.  
1.5 This guide is applicable to the life-cycle of a raw material (that is, data generated throughout the processing stages of the raw material) and is not dependent on the Supplier or Customer.  
1.6 This guide describes two major areas of eData standard: the data format and the data content including the taxonomy and nomenclature.  
1.7 The guide currently only covers data content and data format in the English language. The data format shall not be translated. Use of other languages for the data content outside the scope of this guide.  
1.8 The format is based on Extensible Markup Language (XML) 1.0.  
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
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.

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.

SIGNIFICANCE AND USE
3.1 Rodent-derived cell lines are widely used in the production of biopharmaceutical drugs such as mAbs and Fc fusion proteins. These cell lines have been shown to contain genes encoding endogenous retroviral-like particles or endogenous retrovirus. Despite the lack of evidence for an association between such rodent retroviruses and disease in humans, the potential contamination of human therapeutics raises safety concerns for biopharmaceutical drugs. Additionally, adventitious agents such as viruses can be introduced into a biopharmaceutical drug substance manufacturing process from other sources, and potential safety issues can be attributed to these potential unknowns. For these reasons, effective viral clearance is an essential aspect of an integrated approach combining safety testing and process characterization which ensures virus safety for biopharmaceutical drug products made using rodent cell lines.  
3.2 Solvent/detergent inactivation has been widely used for decades to inactivate enveloped viruses in blood plasma derived biopharmaceutical therapies (1-3).3 Solvent/detergent systems using the detergents Triton X-100 or Polysorbate 80 along with the organic solvent tri(n-butyl)phosphate (TNBP) have been used to inactivate enveloped viruses by disrupting the viral envelope thereby reducing the ability of the enveloped virus to attach to and then infect the host cell (4 and 5).  
3.3 Most manufacturers of mAbs, recombinant proteins, and Fc fusion proteins have focused on viral inactivation methods using the detergent Triton X-100 or Polysorbate 80 in the absence of TNBP (6), which can interfere with subsequent bioprocessing steps. The ability of the detergents alone to inactivate retroviruses has been demonstrated in monoclonal antibodies produced in rodent-derived cell lines (6-9). At a 2011 workshop devoted to viral clearance steps used in bioprocessing (7), investigators from one firm showed incubation with 0.2 % Triton X-100 for 60 min of hold time at a...
SCOPE
1.1 This practice assures effective inactivation of ≥4 log10 of infectious rodent retrovirus (that is, reduction from 10 000 to 1 infectious rodent retrovirus or removal of 99.99 % of infectious rodent retroviruses) in the manufacturing processes of monoclonal antibodies or immunoglobulin G (IgG) Fc fusion proteins manufactured in rodent-derived cell lines that do not target retroviral antigens. Rodent retrovirus is used as a model for rodent cell substrate endogenous retrovirus-like particles potentially present in the production stream of these proteins.  
1.2 The parameters specified for this practice are clarification, Triton X-100 detergent concentration, hold time, pH, and inactivation temperature.  
1.3 This practice can be used in conjunction with other clearance or inactivation unit operations that are orthogonal to this inactivation mechanism to achieve sufficient total process clearance or inactivation of rodent retrovirus.  
1.4 This detergent inactivation step is performed on a clarified, cell-free intermediate of the monoclonal antibody or IgG Fc fusion protein.  
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.