E55.13 - Process Evaluation and Control

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

SIGNIFICANCE AND USE
4.1 This guide 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 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.

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
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.