In the design, control, and regulation of the manufacturing and supply of microbiologically controlled devices (including sterile devices) and drug products (including cleaning, disinfection, and sterilization processing and/or aseptic process manufacturing), different terms and/or definitions are often used for similar processes or applications internationally. With product innovations (including combination products and cell-based therapy) and global regulatory influences, there is a growing need to harmonize these definitions. The objective of the Kilmer Regulatory Innovation microbiological quality and sterility assurance glossary is to clarify and harmonize the practical use of terms employed by the different parts of regulated healthcare product industries internationally and by regulators of the manufacturing and supply of microbiologically controlled healthcare products internationally. The glossary is expected to continue to evolve, and further industry, academic, and regulatory input is encouraged.

The Kilmer Conference is a meeting of microbiological quality and sterility assurance professionals from industry, academia, and regulatory authorities hosted by Johnson & Johnson. The event has been periodically held since 1976. The most recent event was held in Dublin, Ireland, in 2019. It brought together over 300 individuals representing medical device and pharmaceutical companies, educational organizations, industry associations, regulatory organizations, and standards development organizations. Its purpose was to facilitate collaboration and innovation in microbiological quality and sterility assurance across healthcare products. From this event, collaboration teams were assembled to address issues related to sterilization modalities, packaging, rapid microbiological methods, adoption of process analytical technologies, and regulatory innovation.

One such team is the Kilmer Regulatory Innovation Team. The team is made up of representatives with diverse experience including microbiology, sterility assurance, sterilization, manufacturing, quality assurance, validation, regulatory affairs, environmental controls, engineering, medical devices, pharmaceuticals, biologics, preserved products, and advanced therapy medicinal products (ATMP). Its objective is to identify and promote areas of cooperation and innovation between regulators and manufacturers. The team initiated a dialogue in 2019 to explore the needs and means to accomplish collaborative objectives. One opportunity was to modernize and standardize terms and definitions widely used by the pharmaceutical, medical device, and sterilization industries serving global markets. The resulting glossary ( Appendix 1) is introduced in this paper as a harmonized guide for manufacturers, suppliers, and regulators.

Establishing and maintaining microbiological control and sterility assurance throughout the manufacture and use of healthcare products is challenging. Microbiological quality can include variables that can be difficult to observe, measure, and control. Global economic, distribution, and regulatory requirements are often confounding and evolving. Further, the emergence of new therapies, healthcare advancements, and technologies pose new challenges to traditional standards and process control. International harmonization is therefore an important opportunity. The definitions and usage of key words and terms do matter. Individual and varying interpretation can lead to misuse, misunderstanding, redundant efforts, ineffective processes, and compliance issues. These can lead to confusion and to reluctance to adopt new and innovative means of ensuring the quality of microbiologically controlled product manufacturing processes.

There is a need for clarity in the use and definition of terms in microbiological quality and sterility assurance across all segments of the healthcare product industry. This is commonly expressed in the development of global quality regulations, standards, and guidance. An example was noted in the EU Annex 1 Manufacture of Sterile Medicinal Products revision.1  As the European Medicines Agency stated in its February 2015 concept paper: “The current guideline contains historical inaccuracies and areas of ambiguity; the revised guideline will correct the inaccuracies and offer more detail to remove ambiguity and to give clearer interpretation of GMP [Good Manufacturing Practice] expectations.”2 

Aside from regulatory compliance improvement, there is scientific value to a common lexicon. Companies and regulators from differing regions, jurisdictions, and healthcare product categories and technologies often use similar terms and definitions differently. There is value in sharing ideas between different segments of the healthcare product manufacturing industries (i.e., medical devices, drugs, preserved products, and biologics). The opportunity for cooperation and learning between these segments is enhanced by the common use of terms.

An objective of the Kilmer Regulatory Innovation Team is to harmonize and, if needed, modernize the practical and accurate use of microbiological quality terms employed by the different parts of regulated healthcare product industries internationally. As the glossary discussions proceeded, some interesting and at times surprising points came to light. These points often resulted in extensive discussion, debate, and eventual resolution to refine a definition. At times, a definition needed further refinement because of connections with other definitions. It was not always possible to state all the nuances and salient points in a concise and readable definition. To address this challenge, the glossary incorporates an expanded discussion of the term in italicized commentary that follows the definition. This allows the glossary also to be used as a guide for how these terms are used.

Developing a comprehensive glossary was not a simple task. To help ensure that the glossary objective was met, the team established a set of guiding principles:

  • Where possible, existing terms were used and referenced. However, the committee agreed that an alternative definition might help gain greater alignment across the industry or allow for innovation. Some established definitions might need to be revised or retired if found to be limited, redundant, or problematic.

  • Definitions were to meet the following criteria:

    • Simplicity: Definitions should not be voluminous, overly complex, or circular. In addition to the definition, commentary (given in italics) may be given to expand the explanation of the term or its usage.

    • Scientific accuracy and clarity: Definitions should be consistent with science, scientific principles, and current scientific understanding. They should not be open to individual interpretation.

    • Usefulness: Definitions should meet the objective of helping stakeholders (industry, regulators, suppliers) better understand a subject or term currently presenting them with difficulties. Definitions should be aligned with the subject of microbiological quality and sterility assurance.

    • Harmlessness: Definitions should not cause more confusion or burden to the stakeholders than existing definitions.

    • Relevance internationally: Definitions should be globally understood and translatable, avoid local phrases or terms that would mean different things outside of English-speaking countries, and not be specific to historical defined terms in specific regional areas.

  • Sub-definitions of similar terms are addressed in the commentary (in italics) for the primary term. For example, terms such as advanced aseptic processing and manual aseptic processing, or low and intermediate disinfection, are addressed in the commentary for aseptic process and disinfection.

  • The glossary should consider microbiologically controlled or low bioburden product/material manufacture, as well as sterile product/material manufacture.

  • The glossary should not define basic microbiological, chemical, or physical terms that are already accepted, such as “bacteria,” “virus,” etc. Only terms specifically used in the control of microbiological quality and sterility assurance were considered. Discussion focused on terms considered limited and used differently (depending on region or in practical application).

The final glossary ( Appendix 1) includes definitions and commentary for 165 terms. There are some common themes that resulted from the preparation of the glossary. These included the evolution of existing terms, consolidation of terms, modernization based on current usage, correction of scientific inaccuracy, and the simplification of definitions. Some of the more interesting conclusions from these discussions held during the glossary development are considered in the following sections.

Widely used terms and definitions were updated to reflect increased scientific knowledge and expand their use. One example is the use of alert levels and action levels. These terms are most used in manufacturing environments for monitoring microbiological quality indicators, such as bioburden or particulate levels, but are now also used to define some requirements in validation studies, such as with cleaning, where alert levels might indicate that further testing is needed to demonstrate the consistency of attaining cleaning (analyte) endpoints.3  This clarification is important, because it places emphasis on the evaluation of trends for alert levels as a predictor of failure, rather than a report of failure as expressed as an action level or limit.

The definitions of biofilm, endotoxin, and laminar flow are examples of terms that are no longer used correctly. Our knowledge of biofilms has developed over time and biofilms are no longer considered restricted to water systems. There is currently no standardized definition of biofilm, but a commonly cited definition is “an accumulated biomass of bacteria and extracellular material that is tightly adhered to a surface and cannot be removed easily.”4  A simpler definition in the glossary defines a biofilm as a community of microorganisms, and the commentary provides further information on wet and dry biofilms, as well as a more detailed description of biofilm structures. For endotoxin, traditional definitions focus on the lipopolysaccharide component of the cell wall of Gram-negative bacteria, but in fact a more scientifically accurate definition is that an endotoxin is a high–molecular-weight complex that contains lipopolysaccharide (LPS), protein, and phospholipid.5  A final example is the use of the term laminar flow, which is recommended not be used because it is not practically achievable in typical airflows. The recommended and more scientifically correct term is unidirectional airflow, defined as “airflow moving in a single direction in a uniform manner and at sufficient speed for particulate control.”

In other cases, it is recommended that the definitions stay consistent with their initial intention and remain applicable to different applications in microbiological quality requirements. An example is the F value and the associated term FBIO. FBIO is commonly used to express the delivered lethality calculated based on the inactivation of microorganisms (e.g., in the case of biological indicators). Yet, the current International Organization for Standardization (ISO) definition of FBIO value is “expression of the resistance of a biological indicator calculated as the product of the logarithm of the initial population of microorganisms and the D value.”6, 24  This definition needs to be clarified to reflect the original and true scientific use of the term: an F value being a measure of lethality, not resistance.

Similarly, the working group considered the original intended use of terms such as sterility assurance level (SAL) and probability of a non-sterile unit (PNSU). These terms are at times used synonymously and are often misrepresented in discussion and in the literature, despite the clarification of the correct usage of these terms in recent guidance documents.7  An example is the use of aseptic process simulation results to determine a numeric sterility assurance level of aseptic processing; this is clearly misleading. The committee has contemplated establishing risk of a non-sterile unit (RNSU) as a more accurate term to distinguish between quantitative and qualitative risk factors associated with sterility assurance, such as what might be used in aseptic processing.

Risk management is fundamental in any quality system and throughout a product life cycle. The risks of microbiological contamination are central to many of the definitions outlined in the glossary, such as worst case, sterile barrier system, sterility, intervention, and aseptic technique. But in many cases the risks or the impact of microbial contamination is focused on a final process (e.g., sterilization), product, or product determination method (e.g., sterile testing). Terminally sterilized products are good examples where a poor understanding of microbiological risks during design and manufacturing might not consistently lead to a product of expected quality. Examples include excursions in product bioburden levels outside of expected qualitative and quantitative microbial expectations, presence of high levels of Gram-negative bacteria in raw materials or water as a source of endotoxin, and lapses in package sealing that can allow for microbial ingress over time. Therefore, an important consideration is a return to basic principles in microbiological quality, centralized on an end-to-end philosophy. End-to-end is therefore defined as “the consideration of all processes that are required in the development, manufacture, and delivery of a microbiologically controlled or sterile labelled product for its intended use.” It is a key principle in the glossary and is not meant to apply only to traditional methods of ensuring sterile-labelled products but to any microbiologically controlled product. Allied to this concept are other terms such as assurance of sterility as a qualitative concept comprising all activities that provide confidence that product is sterile, and contamination [or microbiological] control strategy as an integrated set of controls, planned actions, and conditions that are designed to limit product contamination to defined criteria. These terms are not only important to existing products but are fundamental to the development of new products that cannot be terminally sterilized and are obtained from non-sterile sources (e.g., ATMPs, vaccines, and products that deliberately include microorganisms).

These definitions also allowed the team to further consider definitions and risks directly related to microorganisms themselves. A good example is the term pathogen, clearly and historically defined as a disease-causing microorganism. But the commentary reminds us that microorganisms vary in their pathogenicity and therefore vary in their risks to patients or consumers. Many pathogens are only considered opportunistic and might only lead to infection in particularly vulnerable recipients but are unlikely to have a patient impact in healthy individuals. An example is the use of the term objectionable microorganism in preserved products, which is proposed to be defined as a “microorganism that under certain conditions unique to a product and the associated manufacturing process poses a risk to cause disease, degrade the quality or impact the therapeutic efficacy of a product.” The concept of risk (and risk/benefit) in these cases is fundamental.

A new term has been proposed, [microbiological quality] indicator, which is any “test system that indicates by measuring, recording, or detecting.” These indicators can include parametric, chemical, or microbiological test systems linked to microbiological quality, including the traditional terms for biological indicators, chemical indicators, and dosimeters. But it is also proposed that the term indicator microorganism be used to describe the detection of types of microorganisms from manufacturing processes, environments, raw materials, or finished products that require further assessment to determine if by their species, their nature, and location recovered, they pose a risk or potential risk to product quality. Such microorganisms can be indicators of potential lapses in control and provide a signal for control improvement. An example in the glossary is the detection of a Gram-negative bacteria in a purified water system; but, overall, the risk is dependent on the associated manufacturing process.

Established definitions for aseptic processing are often linked to sterile product manufacture. The current ISO definition for aseptic processing notes that it involves “. . . the handling of sterile product, containers, and/or devices in a controlled environment in which the air supply, materials, equipment, and personnel are regulated to maintain sterility.”6  Although the U.S. FDA aseptic processing guidance8  and the proposed revision of EU Annex 11  do not specifically define aseptic processing, they do provide a definition of asepsis that is close. Again, this definition is linked to sterility, stating that asepsis is “. . . a state of control attained by using an aseptic work area and performing activities in a manner that precludes microbiological contamination of the exposed sterile product.”

These definitions are accurate, as used in the manufacturing of sterile products. But many companies use aseptic processing principles to control other microbiologically sensitive processes, as might be case with certain ATMP and cell/gene therapy applications. Current definitions of aseptic processing that are only linked to sterility do not take into account the use of the process for other microbiologically controlled products, such as low-bioburden intermediates or ATMPs. By linking the definition to sterility, control and validation measures must demonstrate that a process achieves a level of control that is not necessary or in many cases attainable. These control and validation requirements to prove sterility on such processes are burdensome and of little true benefit. The proposed definition is “manufacturing process used to prevent microbiological contamination of a product to achieve a defined microbiological quality appropriate for its intended use.” Note that the exclusive link to sterility has been replaced with a more inclusive link to microbiological quality, which could include sterility but which also could include low-bioburden products. This is close to a Parenteral Drug Association definition, which states that aseptic processing is: “. . . handling sterile materials in a controlled environment, in which the air supply, facility, materials, equipment and personnel are regulated to control microbial and particulate contamination to acceptable levels.”9  Another change is the replacement of language suggesting the means to achieve the aseptic state with a statement of the objective of the aseptic process, that being prevention of microbiological contamination. This change simplifies the definition and removes potentially prescriptive and limiting language, thus allowing for new and innovative approaches.

There was discussion within the team of the definitions of controlled environments, including cleanroom, isolators, and restricted access barrier system (RABS). The existing ISO definition of cleanroom remains unchanged but the definition can equally apply to any division of a facility, area, or space.10  For this reason, it did not seem necessary to apply unique definitions to similar terms that have been used in recent years, such as clean space, critical zone, or critical area. But the definition of isolator is modified to align with other definitions and to provide commentary on the differences between open and closed isolator designs. Similarly, a harmonized definition of RABS was needed, with commentary on the differences between open, closed, active, and passive designs. Lack of clarity regarding open and closed barrier systems and spaces deemed to be critical can result in individual interpretation of contamination control strategy and compliance requirements, which can lead to potential lapses in microbiological controls and compliance.

Although the term critical is often mentioned in regulatory guidance, it is almost always linked as an adjective or descriptor to other terms, such as critical space, critical zone, critical process, critical water, and so on. Defining the term as an aspect or condition that has an impact on the desired quality attributes of a product or process will help manufacturers and regulators assign requirements to areas or functions that meet this definition. By defining the term critical, a better understanding of its use with other terms is achieved. This is also valid in the other usage of the term, as in the case of critical or noncritical devices because the quality aspect of the product is related to the risk of infection associated with the intended use of the device in clinical practice.

The terms decontamination, sanitization, and disinfection are often used synonymously, despite having different regional or manufacturing environment meanings, which can result in misunderstandings within different manufacturing and clinical environments.

Although the definition of sterilization is already widely accepted and harmonized, the same cannot be said for disinfection and how the term is used in various manufacturing and clinical areas, as well as in regulatory documents. The agreed-upon definition of disinfection is proposed to be a “process to inactivate viable microorganisms to a level previously specified as being appropriate for a defined purpose” and aligns with current ISO documents.6  Other terms used internationally to describe different types of disinfection processes include sanitization, germicidal, fumigation, pasteurization, sterilant, and biodecontamination. Disinfection is independent of the method used (e.g., spray and wipe, use of a gas as in the case of fumigation of microbiological safety rooms, the common use of bio-decontamination in aseptic isolator applications, sanitization of walls/floors in food-handling or cleanroom applications). It is also independent of the level of disinfection considered applicable in different situations, but it does ensure an accurate description of the desired endpoint, which is the inactivation of microorganisms to a desired level. The specified levels are generally defined based on a risk assessment of various applications and with recognition of regulatory requirements (such as various levels of disinfection and sterilization). There is an opportunity internationally to agree on these desired levels, based on a risk approach.

For clarification, the team concluded that it was useful to harmonize these definitions by clarifying the root definition of contamination and contaminant. For the glossary definition, “introduced” has been replaced with “presence of” material (e.g., chemical, biochemical, or microbiological) not intended to be part of a product or process. It was important to remove action terms such as “introduced” because, in general, contamination is not a deliberate event. From this, the other definitions are easier to consider and align. For example, microbiological contamination risks can be reduced by physical removal (considered as cleaning) and/or the use of an antimicrobial process such as disinfection or sterilization. Microbiological decontamination (or biodecontamination) is therefore the removal of contaminants (in this case, microbiological contaminants) to specified levels.

The definition of sterile does not need to change and is a statement of fact: “being free from viable microorganisms.” This is a quality attribute of a product or entity, but it does not imply other product safety aspects, such as the presence of microbial toxins below acceptable levels. The definition of sterility is recommended to be modified as the “state of being sterile, based on the probability of the presence of viable microorganisms.” The regulatory expectation for a sterile label claim is related to a validated process and available methodology.

Sterility has been traditionally determined using a validated direct test method and/or a predictive, statistical analysis with a probability level that is based on specified requirements. It is widely recognized that available microbiological test methodology is limited to verifying the sterility of an entity: only a proportion of an entity can be tested, there are limitations in culturing conditions to detect the range of microorganisms, and there are risks of environmental contamination during laboratory handling. Therefore, traditional tests of sterility are not sufficient or effective to ensure a sterility claim.

The glossary proposes a single definition of a sterility test: “microbiological test to determine the presence or absence of viable, culturable microorganisms.” Sterility tests are traditionally performed as a release criterion for certain types of sterile products (e.g., aseptically manufactured products) or entities (e.g., biological indicators). Other glossary standards differentiate between a test for sterility, which is specified in a pharmacopoeia and performed on product following an aseptic process or exposure to a sterilization process, and a test of sterility, which as part of development, validation, or requalification is used to determine the presence or absence of viable microorganisms on product or portions thereof. It is well understood that an end-product sterility test is limited in its ability to detect microbiological contamination because, first, it utilizes only a small number of samples in relation to the overall batch size, and second, culture media and conditions might only stimulate growth of some, but not all, microorganisms. Therefore, an end-product sterility test only provides an opportunity to detect major failures in the sterility assurance system (i.e., a failure that results in contamination of many product units and/or that results in contamination by the specific microorganisms whose growth is supported by the prescribed media).

Overall, sterility assurance should not be based on direct detection methods for microorganisms but rather on the probability of the presence of microorganisms and on risk assessment. This applies to manufacturing processes (e.g., aseptic processing, products terminally sterilized) that take into account end-to-end microbiological quality and that render a product essentially free of the risk of viable microorganisms. In such processes, data derived from in-process controls (e.g., pre-sterilization product bioburden, environmental monitoring) and from monitoring relevant sterilization or aseptic processing parameters can provide more accurate and relevant information to support the sterility assurance of a product.

The committee also agreed that to accommodate new types of products and innovations, the traditional labeling of sterile products based on tests of sterility should be evolved to describe microbiologically controlled products that are considered safe for use based on a risk management process to ensure microbiological quality. Aligned to these definitions is the previous discussion on the use and misuse of sterilization and sterile-associated terms, such as SAL and PNSU. In addition, to ensure the correct use and understanding of these terms, it was overall agreed that there is an opportunity for establishing a more accurate term, such as the RNSU, to allow for clarity, accuracy, and innovation.

There are several reasons why the harmonization of the definition and use of microbiological control and sterility assurance terms would be of benefit to our industry and the patients we serve:

  • Ambiguous, inaccurate, unharmonized definitions can lead to confusion, individual interpretation, unnecessarily burdensome and redundant efforts, ineffective application, additional cost, and non-compliance.

  • Some terms are not used properly, or their definitions often do not align with usage. Some terms need to be modernized, simplified, removed, and evolved.Some that have been around for decades are now outdated.

  • Definitions can differ across industry segments/locations, which hamper cooperative efforts.

The proposed establishment of a harmonized and modern glossary with unambiguous, harmonized definitions will assist manufacturers in understanding the global guidance, scientific standards, and compliance required to implement effective, end-to-end microbiological quality control strategies. It will also allow global regulators and health authorities to clearly express their expectations for risks associated with the microbiological quality of products. It is also intended to encourage sharing of best practices, methods, and information among medical device, drug product, preserved product, clinical, and sterilization organizations. This will allow for easier and more efficient assimilation of new technologies. An example might be the development of a future harmonized definition of RNSU, as a replacement for terms such as SAL and PNSU. Other examples might be the use of terms such as colony-forming unit (CFU) and auto-fluorescent unit (AFU) that, if defined, can accelerate the acceptance of alternative detection technologies as superior to classical microbiological culturing techniques. CFU is an example of a microbiological term used to describe the ability to detect a single bacterial or fungal cell by traditional culture methods. But these methods are well known to be limited and could be replaced with new chemical, immunological, or molecular biological methods that can indicate microbiological quality, such as the AFU as a particulate detection method that can reflect the size and fluorescence of particles.

To be accurate, inclusive, and utilized, the glossary needs more industry, academic, and regulatory input. The Kilmer Regulatory Innovation Team is publishing the proposed glossary along with this position paper. We encourage the submission of comments and suggestions and further dialog within the industry and with health authorities. We are also encouraging participation in the team to continue to evolve the glossary and the concepts identified in this paper to support innovation in microbiological quality and sterility assurance.

Appendix 1. Glossary

This glossary of terms provides definitions of common terms in microbiological quality and sterility assurance and is recommended to be used to ensure consistency in the use of these terms internationally. The glossary was developed based on essential standards, including existing glossary documents, guidance, and references.1,6, 8, 9, 1113  Some of these documents are provided in the references (but this should not be considered a full list of those utilized) and were discussed in detail by a cross-functional committee for harmonization. The proposed definitions are summarized below, with text in italics intended as commentary, based on committee discussions and proposals.

In the design, control, and regulation of the manufacturing and supply of microbiologically controlled (including sterile) devices and drug products (including the use of cleaning, disinfection, and sterilization processing and/or aseptic process manufacturing), different terms and/or definitions are often used for similar processes or applications internationally. Because of product innovations (including combination products and cell-based therapy) and global regulatory influences, there is a benefit to harmonizing these definitions. The objective of this glossary is to clarify and harmonize the practical use of terms employed by the different parts of regulated healthcare product industries internationally and by regulators in the manufacturing and supply of microbiologically controlled healthcare products.

The glossary is expected to continue to evolve, and additional industry, academic, and regulatory input is encouraged. We encourage the submission of comments and suggestions to the corresponding author and further dialog within the industry and with health authorities. We are also encouraging participation in the Kilmer Regulatory Innovation Team to continue to evolve the glossary and the concepts identified to support innovation in microbiological quality and sterility assurance.

Action level (orlimit): value [from monitoring] that necessitates immediate intervention.6 When exceeded, the action level (or limit) should trigger appropriate investigation and corrective action based on the investigation. Examples include microbial, analyte, and airborne particulate limits.

Aeration: removal of volatile chemical residuals to a predetermined level. Modified from the current definition,6 because it is limited to sterilization. The term is defined as “part of the sterilization cycle during which the sterilizing agent and/or its reaction products desorb from the health care product until predetermined levels are reached.”6 But, aeration can also apply to disinfection applications (e.g., fumigation or biodecontamination).

Alert level (orlimit): value [from monitoring] providing early warning of deviation from specified conditions.6 An alert level is a warning of potential drift from normal operating conditions and validated state, which does not necessarily give grounds for corrective action but triggers appropriate scrutiny and follow-up to address the potential problem. Alert levels are established based on historical and qualification trend data and periodically reviewed. The alert level can be based on a number of parameters, including adverse trends, individual excursions above a set limit, and repeat events.

Analyte: chemical substance that is the subject of chemical analysis.6 

Antimicrobial: ability to inactivate or suppress the growth of microorganisms.11 Antimicrobials can be based on physical and/or chemical entities such as heat, radiation, preservatives, and other chemicals (e.g., aldehydes, oxidizing agents, phenolics, and alcohols).

Antisepsis: inactivation or inhibition of microorganisms in or on living tissues.11,14 

Antiseptic: chemical, product, or process used for antisepsis.11,14 Antiseptics are typically formulated products that contain antimicrobial chemicals such as alcohols, chlorhexidine, and iodine. For skin applications, they can include hand soaps (used with water), hand rubs (no water), and surgical scrub and preoperative skin preparation products. Other applications include wound treatments and specific treatments of skin/mucous membrane infections.

Asepsis: prevention from contamination with microorganisms.11 Generally, asepsis is a state of control attained within a work area by performing activities in a manner that reduces the risks of microbiological contamination. Asepsis applications can be part of best practices in the manufacturing of products (e.g., sterile products) and in the clinical application of products (e.g., in surgery).

Aseptic manipulation: activity performed during an aseptic process that may be part of a defined intervention.

Aseptic presentation: transfer of products, materials, etc. using conditions and procedures that minimize the risk of microbial contamination at the point of use. Modified from the current definition6 to include the point of use. Aseptic presentation is a term typically used in the clinical use of a sterile or microbiologically controlled product or products.

Aseptic processing [or manufacturing]: manufacturing process used to prevent microbiological contamination of a product to achieve a defined microbiological quality appropriate for its intended use. Current definitions are considered limited.1,6,8,11,12 “Aseptic processing” is currently defined as “handling of sterile product, containers, and/or devices in a controlled environment in which the air supply, materials, equipment, and personnel are regulated to maintain sterility.” This may not always be limited to the requirement of a “sterile” state, but rather a state that is maintained to an acceptable, defined microbiological level. The goal of an aseptic process is often a “sterile” endpoint, but the demonstration of a “sterile” product is based on the appropriate manufacturing process validation and not on a direct microbiological test for sterility. Some terms have become more widely used in the literature to describe categories of aseptic processing. These have not been harmonized but include “advanced aseptic processing” (an aseptic process in which direct intervention with open product containers or exposed product contact surfaces by operators wearing conventional cleanroom garments is not required or permitted), and “manual aseptic processing” (manual interventions in aseptic situations with little to no automation). Others include “manual aseptic process” (all or nearly all of the process is performed manually with little or no automation), “manual aseptic operations” (individual aseptic process steps, activities, functions, and/or operations that are predominately performed manually with little or no automation), and “manual aseptic filling” (an aseptic filling process in which the operator or operators perform the placement, orientation, filling, and/or sealing of each container manually with little or no automation).

Aseptic process simulation: simulation using culture medium, and/or a surrogate, as a means of verifying the control of parts of an aseptic process that pose a risk to product sterility and are not otherwise tested. The purpose of the simulation is to test the ability of the manufacturing process to prevent microbiological contamination of a product and identify potential process variance that could result in contamination.1,9,15 It is considered an important part of the aseptic process validation, but not the only part. Also known as a “media fill,” the process simulation is usually performed with a microbiological growth medium to challenge the combination of all aspects of the aseptic process that are deemed to pose a risk of microbiological contamination of a product and are not otherwise adequately addressed in separate validation studies.

Aseptic process validation: collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that an aseptic process is capable of consistently delivering a product of defined microbiological quality. This is a modification of current definitions.1,12,15 Aseptic process validation is not limited to the performance of aseptic process simulations. The validation of the entire aseptic process, individually and in combination, includes validation and qualification of all process steps and conditions that can affect and pose a risk to the sterility of the product and the performance of the aseptic process. See Contamination control strategy.

Aseptic technique: activities designed to limit the risk of the introduction of microbial contamination. Modified from current definitions.6,11 Note that risk can never be completely “prevented” but only minimized or mitigated. The traditional requirements for aseptic technique focused on reducing the introduction of viable microorganisms (particularly pathogens), but best practices can also include consideration of particulates and other contaminants that impact product quality and safety.

Assurance of sterility: qualitative concept comprising all activities that provide confidence that product is sterile.6 Also referred to as “sterility assurance.” Assurance of sterility implies an end-to-end concept that considers all processes that are required in the development, manufacture, and delivery of a microbiologically controlled or sterile labeled product for its intended use.

Autochthonous [microorganisms]: indigenous or inhabitants of a particular environment or niche. These microorganisms exist by adapting their physiologies to their environments, permitting proliferation or simply survival in those environments. The term is used to distinguish microorganisms that inhabit and proliferate within locations using available resources to self-sustain. It is particularly important in the context of cleanrooms because most recovered microorganisms are introduced primarily from personnel and are incapable of self-sustaining in that environment.

Bactericidal: ability to inactivate bacteria.11,14 This term typically applies to any agent or product that can kill vegetative bacteria (both pathogenic and nonpathogenic), but not necessarily bacterial spores. See Sporicide.

Bacteriostatic: ability to inhibit the growth of bacteria.11 The ability of a product or process to inhibit growth might not necessarily lead to cell death or loss of viability.

Bioburden: population of viable (or detectable) microorganisms on or in a product or other material. Modified from the current definition6 to refer to “detectable” microorganisms. The term “bioburden” can refer to the estimated number of viable (or culturable) microorganisms associated with any specific item, including personnel, manufacturing environments (air and surfaces), equipment, product packaging, raw materials (including water), in-process materials, products prior to sterilization, and finished products. Note that not all viable microorganisms are detectable using standard microbiological techniques. Bioburden refers to detectable microbiological contamination from any source, including microorganisms from biofilms, but does not include byproducts of microbial growth, such as toxins (e.g., endotoxins).

Biocide: chemical or physical agent that can inactivate living organisms.11,16 “Microbiocide” or “microbicide” refers to an agent that inactivates microorganisms. The term “biocide” is used in certain jurisdictions to apply only to chemical agents, and there might be regulatory requirements that apply to their use within those areas. An example is the EU Biocidal Products Regulation.16 

Biocompatibility: condition of being compatible with living tissue or a living system by not being toxic, injurious, or causing an immunological reaction.

Biocontamination: contamination of items, environments, or surfaces by biological material or entities, including microorganisms and their associated toxins. Toxins include exotoxins, endotoxins, and mycotoxins, as well as cells or biological entities other than components intended to be present in a product.

Biodecontamination: removal and/or reduction of biological contamination to an acceptable level.6,11 Biodecontamination typically includes cleaning (physical removal of soiling and microorganisms) and/or subsequent antimicrobial (e.g., disinfection) steps to achieve a target or defined level. See Decontamination.

Biodeterioration: deterioration of valuable materials due to biologic activity.11 

Biofilm: community of microorganisms. Biofilms can consist of single or multiple types of microorganisms, which can be multiplying, dormant, or generally associated with the biofilm structure. Biofilms can be “wet” (associated with water) or “dry” and typically develop on or are associated with surfaces or interfaces (e.g., water lines or storage systems). Biofilms are microbially derived communities characterized by cells that are irreversibly associated with a substratum, interface, or each other; they are often embedded in a matrix of extracellular polymeric substances (EPSs) that they produce and exhibit mixed phenotypes with respect to growth rate, gene transcription, and resistance mechanisms.

Biofouling: accumulation and subsequent deleterious effects of biological contaminants on products or processes. Biofouling is also referred to as biological fouling.

Biological contaminant: cell or biological entity other than the intended components present in product.6 

Biological indicator (BI): test system containing viable microorganisms providing a defined resistance to a specified sterilization or disinfection process. Modified from the current definition.6 Biological indicators can also be used to test disinfection processes.

Chemical indicator (CI): test system that reveals change in one or more pre-specified process variables based on a chemical or physical change resulting from exposure to a process.6 These test systems are widely used in disinfection and sterilization applications.

Clean: visually free of soil and quantified as being below specified levels of analytes.6,11,17 Soil can refer to any unwanted contaminant(s), including product residues, process residues, and environmental contaminants. Analytes can include any chemical substance that is the subject of chemical analysis, such as parenteral product residues, process residues, detergents, human or animal tissue components (e.g., protein, hemoglobin), and environmental contaminants removed to an acceptable level. In many applications, a visually clean endpoint might be acceptable and might not require the quantification of specified analytes, depending on the use or reuse of the target surface, device, or equipment.

Cleaning: removal of soil to the extent necessary for further processing or for intended use. Modified from the current definition6,17 to replace “contamination” with “soil.” “Soil” can include single or various forms of contaminants. Note that cleaning alone can provide a sufficient level of decontamination in many situations by physical removal and can also be a prerequisite to effective disinfection or sterilization. Contaminants can include unwanted materials between product batches, such as product residues.

Clean-in-place (CIP): cleaning of internal surfaces of parts of equipment or an entire process system, without, or with minimal, disassembly.6 Internal surfaces generally refer to product-contacting surfaces.

Cleanroom: room within which the number or concentration of airborne particles is controlled and classified, and which is designed, constructed, and operated in a manner to control the introduction, generation, and retention of particles inside the room.18 A cleanroom can also be a defined division of a facility, area, or space. Other terms include “clean space,” “clean zone,” “critical zone,” and “critical area” and might apply to the same levels of airborne particle concentrations. Particles can include microbial and non-microbial particulates of various size, and the classification of cleanroom is defined based on the limits of airborne particulates (of certain sizes) detected in an area/room. See Critical surface.

Clean zone: defined space within which the number or concentration of airborne particles is controlled and classified, and which is constructed and operated in a manner to control the introduction, generation, and retention of contaminants inside the space.18  See Cleanroom.

Closed system: controlled system that incorporates a physical barrier that prevents the ingress and egress of contamination. Closed systems are those that use physical aspects to separate the applicable contents in a system from the external environment. For example, a closed vessel that is hermetically sealed during aseptic processing would be a closed system. A vessel with a vent filter might also be a closed system if the filter removes contaminants from the air between the interior of the vessel and the outside environment. An isolator that only allows materials to move into or out of the isolator through specialized rapid transfer ports can be considered a closed system, depending on its intended use and design; however, an isolator that relies on positive air pressure alone to keep out contaminants would not be a closed system because the means of separation is not a physical barrier. The risk and ability of other means, such as aseptic transfer and connecting devices, to prevent contamination from entering or leaving the system should be assessed to determine if it can be considered a closed system.

Conditioning: treatment of product or process prior to the exposure phase to attain a specified temperature, relative humidity, or other process variable throughout the load.6 Conditioning is often referred to as preconditioning. The exposure phase typically refers to a part of a cleaning, disinfection, or sterilization process. For example, the exposure cycle stage of a disinfection or sterilization process occurs between the introduction of the sterilizing or disinfecting agent into the chamber and the removal of the agent.

Containment: combination of buildings, engineering functions, equipment, and work practices that allow safe handling of hazardous biological or chemical substances and prevent unwanted release of these substances to the external environment. Modified from the current definition6 to indicate that containment methods can include methods such as physical separation, airflow, or differential pressure.

Contaminant: material (e.g., chemical, biochemical, or microbiological) not intended to be part of a product or process. Examples of contaminants include soils, protein, dirt, detergents, product residuals, particulates, and microorganisms.

Contamination: presence of material (e.g., chemical, biochemical, or microbiological) not intended to be part of a product or process. Contamination or the presence of unwanted contaminants can derive from a variety of sources including raw materials, the environment, and handling. The risks associated with contamination should be considere d during the design, manufacture, delivery, and use of a microbiologically controlled product. See End-to end and Contamination control strategy.

Contamination [or microbiological] control strategy: integrated set of controls, planned actions, and conditions that are designed to limit product contamination to defined criteria. The strategy is designed to assure process performance and product quality. The planned set of controls can include parameters and attributes related to active substances, excipients, drug product materials and components, in-process controls, and finished product specifications; parameters for facility and equipment operating conditions; and the associated methods and frequency of monitoring and control. The strategy should take into account end-to-end microbiological quality and follow the principles of quality risk management. Controls can include exclusion technologies, cleaning, disinfection, sterilization, aseptic handling, training, etc.

Critical: aspect or condition that has an impact on the desired quality attributes of a product or process. Examples include manufacturing conditions where a microbiologically controlled product is exposed to environmental or contact surfaces, or any condition that could pose a risk to the sterility or microbiological quality of the product. Other examples include critical process conditions for parametrically released products or loads. See, for example, Critical processing zone, Critical surface, and Critical water.

Critical processing zone: location within the aseptic processing area in which product and critical surfaces are exposed to the environment.6 Also referred to as “critical zone,” ”critical area,” or ”critical space.” A critical zone, area, or space in an aseptic process or bioburden-controlled process is a space where product and direct or indirect product contact surfaces are exposed to the environment.

Critical surface: surface that might directly affect or come into direct contact with a product, including its containers or closures, or other material posing a risk of contamination.6 A critical surface is a surface that contacts product or a surface that contacts something that will contact product (e.g., stopper).1,8 

Critical water: water that is extensively treated to ensure that microorganisms and inorganic/organic materials are removed to meet a defined specification.11,19 Different levels of water purity can be defined in different pharmacopeia (e.g., purified water or water for injection), standards, or guidance documents.

Death rate curve: See Survivor curve.

Decontamination: removal of contaminants to specified levels. A decontamination process can include a cleaning (physical removal) and/or an antimicrobial (e.g., disinfection) process, depending on the defined level previously specified as being appropriate for a defined purpose, and is often a combination of these processes.1,8, 11, 12 

Deodorizer: any chemical, product, or process used to prevent or delay the growth of odor-producing microorganisms, or to mask, chemically destroy, or neutralize odors.

Depyrogenation: process used to remove or deactivate pyrogenic substances to a specified level.6 

Disinfectant: chemical and/or physical agent used for disinfection. Modified from the current definition.6,11 Methods include the use of chemicals, combinations of chemicals, and/or non-chemical disinfectant modalities such as radiation and heat. Chemicals can include liquids and gases. Different “levels” of disinfectants and disinfection have been defined for specific applications, such as high-, intermediate-, and low-level disinfection. A low-level disinfectant is expected to inactivate vegetative bacteria (except mycobacteria), enveloped (lipid) viruses, and fungi, but not necessarily fungal or bacterial spores. An intermediate-level disinfectant is expected to inactivate all vegetative bacteria, including tubercle bacilli, lipid and some nonlipid viruses, and fungal spores, but not bacterial spores. A high-level disinfectant is expected to inactivate all forms of microbial life except for large numbers of bacterial spores, when used in sufficient concentration and under suitable exposure conditions.

Disinfection: process to inactivate viable microorganisms to a level previously specified as being appropriate for a defined purpose.6,11 Other terms are used internationally to describe disinfection processes, including “sanitization,” “germicidal,” “fumigation,” “pasteurization,” “sterilant,” and “biodecontamination.” These terms can have different regulatory requirements, depending on the jurisdiction.

Disinfestation: extermination or removal of insects, rodents, or other animal forms that cause harm or transmit disease, which may be on a person or his or her belongings, clothing, or surroundings.11 

Dosimeter: device having a reproducible, measurable response to radiation that can be used to measure the absorbed dose in a given system.6 

D value: time or dose required under stated conditions to achieve inactivation of 90% of a population of the test microorganisms.6,11 Also referred to as “D10 value” or “decimal reduction time” (DRT).

Endotoxin: high–molecular-weight complex that contains lipopolysaccharide (LPS), protein, and phospholipid originating from the outer membrane of Gram-negative bacteria.5 To clarify existing definitions of endotoxin, including that given in ISO 11139,6 it is now recognized that the lipopolysaccharide component of the cell wall of Gram-negative bacteria is only part of the endotoxin complex that is responsible for eliciting an inflammatory response/cytokine cascade in animals and humans. Bacterial endotoxins can be pyrogens (pyrogenic substances) under certain conditions.

End-to-end [microbiological quality]: consideration of all processes that are required in the development, manufacture, and delivery of a microbiologically controlled or sterile labeled product for its intended use.

Environmental control: application of engineering and/or procedural systems to maintain conditions in a defined space within specified limits.6 

Environmental isolate: microorganism isolated from processing or manufacturing environments.6 

Excipient: chemical or biological component other than an active ingredient that is included in a formulation.11 Excipients can include formulation components that aid in the delivery, control, preservation, optimization, etc., of a product used for cleaning, antisepsis, disinfection, or sterilization. Examples include buffers, thickeners, solvents, and chelating agents.

Exotoxin: toxin produced and secreted from a microorganism.

Filling: [for microbiologically controlled products,] controlled process by which a sterile or microbiologically defined product or material is dispensed into a final or next-process-stage container.

First air: filtered air that has not been interrupted with the potential to add contamination to the air prior to reaching exposed product or product contact surfaces.

Fomite: inanimate object or material that may transmit microorganisms. Often used to describe inanimate surfaces that can contain pathogens in different environments.

Formulation: combination of chemical ingredients, including active and other ingredients, into a product for its intended use.11 

Fractional cycle: equipment operating cycle in which the exposure phase is reduced compared with that specified for the normal cycle. Modified from the current definition.6 A fractional cycle is typically used for cycle development and validation studies. The equipment operating cycle can include a cleaning, disinfection, or sterilization cycle, and the exposure phase can include a defined antimicrobial reduction phase of a cycle.

Fumigation: delivery of an antimicrobial process that is applied indirectly to an area.11 Fumigation implies a non-manual application of the antimicrobial agent and can include the aerosolized, gaseous, or vaporous distribution of antimicrobial agents into an environment with the purpose of disinfecting the surfaces within the area.

Fungicidal: ability to inactivate fungi.11,14 

Fungistatic: agent that inhibits but does not necessarily inactivate fungi.

F value: measure of lethality delivered by a heat process expressed in terms of the equivalent time, in minutes, at a specified temperature with reference to microorganisms with a specified z value. Modified from the current definition.6 For heat-based processes, the F value is given as F (T/z) and is therefore specified at a reference temperature (T) and z value; z is the change in temperature that produces a tenfold change in the D value. A specific example of a widely used F value is the F0, which specifies reference conditions of T=121.1°C and z=10°C to calculate an equivalent lethality for a moist heat process. Another example is the FBIOor Fbiologicalterm that is used to express the delivered lethality calculated based on the inactivation of microorganisms (e.g., biological indicators). In this case, the FBIOis calculated as DTx LR, where DTis the D value of the test microorganism at the reference temperature (T) and LR is the actual logarithmic reduction (log N0– log NF) of the microbial population achieved during the cycle. The current definition of FBIO value in ISO 11139 is “expression of the resistance of a biological indicator calculated as the product of the logarithm of the initial population of microorganisms and the D value,”6 but it is recommended that this definition be updated or further developed (potentially as a new specific term) to reflect the true scientific use of the term because an F value is a measure of lethality, not resistance.

Germicidal: ability to or agent used to inactivate microorganisms.11 The term “germicide” therefore refers to the ability of an agent to kill microorganisms. The term “germ” generically applies to all microorganisms. Traditionally, “germicidal” was used to refer to effectiveness against pathogenic microorganisms, most often vegetative bacteria. Regulatory requirements for this label claim can vary internationally, and therefore it should be inspected carefully when used. It is suggested that this term be replaced by disinfection or defined disinfection against certain target microorganisms.

Gowning or gowning procedure: specified actions for putting on protective garments in a manner commensurate with the cleanliness level of the room.6 Protective clothing is used to reduce the risks of contamination from people entering and working in a defined area.

Growth promotion test: test performed to demonstrate that a growth medium will support microbial multiplication. Modified from the current definition.6 This test is often used to confirm the ability of growth media to support the growth of low levels of microorganisms during microbiological studies, such as bioburden assessments and sterility testing.

Healthcare acquired infection (HAI): infection acquired during treatment within a healthcare setting.

Holding time: [for an equipment operating cycle,] period during which process parameters are maintained within their specified tolerances.6 Holding time can include a controlled, qualified, or validated activity or set of conditions designed to maintain the microbiological quality of microbiologically sensitive materials stored prior to use in a process.

Hygiene: conditions and practices that help to maintain health and prevent the spread of diseases, particularly those caused by pathogenic microorganisms.

Inactivation: to make microorganisms unable to grow or multiply. This term refers to the growth or multiplication of microorganisms.

[Microbiological quality] Indicator: test system that indicates by measuring, recording, or detecting. Microbiological quality indicators can include parametric (e.g., mechanical or electrical sensors), chemical, or microbiological test systems. Examples include biological indicators, chemical indicators, and dosimeters. When the term is used as “indicator microorganism,” it describes the detection of types of microorganisms from manufacturing processes, environments, raw materials, or finished products that require assessment to determine if by their species, their nature, and the location from which they are recovered, they pose a risk or potential risk to product quality. Such microorganisms can be indicators of potential lapses in control and provide a signal for control improvement. Examples include the identification of fungal contamination in a controlled environment and the detection of Gram-negative bacteria in a purified water system, depending on the associated manufacturing process.

Infection: invasion and multiplication of microorganisms in a host. The presence of microorganisms does not necessarily imply an infection risk. Infection will depend on factors such as the strain (or type) of microorganism, the infectious dose, the susceptibility of the host, etc.

Inoculated carrier: supporting material on, or in, which a defined number of viable test microorganisms has been deposited.6  See Biological indicator.

Inorganic load: naturally occurring or artificial contamination containing inorganic contaminants.

Intervention: manipulation, activity, or combination thereof planned during an aseptic process within a critical area or other area that might pose a risk of contamination. Interventions are typically planned within a critical area or other areas associated with the aseptic process. They can be corrective/non-routine (an allowable activity that might or might not occur during the aseptic process and is performed to correct/adjust an aseptic process during its execution) or inherent/routine (an activity that is an integral part of the aseptic process and is required for routine operation). An intervention can be robotic or human. Deviations can be planned or not planned, but interventions are considered qualified events.1,8,9,12 

Isolator: enclosure capable of preventing ingress of contaminants by means of physical separation of the interior from the exterior that is capable of interior biodecontamination, and where personal and exterior environments remain separated from the interior of the enclosure by means of a physical barrier. Modified from the current definition.6 Note that in some cases an isolator might also need to take into account the risk of egress of contaminants (microbiological or chemical). In aseptic processing, isolators typically are designed to meet Grade A (ISO 5) conditions. Isolators can be “open” or “closed” in design. Closed isolators exclude external contamination from the isolator's interior via an aseptic connection to auxiliary equipment, rather than using openings to the surrounding environment. Closed systems essentially remain sealed throughout operations. Open isolator systems are designed to allow for the continuous or semicontinuous ingress and/or egress of materials during operations through one or more openings. Openings are engineered (e.g., by using continuous overpressure) to exclude the entry of external contamination into the isolator.

Laminar airflow:This term should no longer be used, as it is not attainable in airflow. Traditionally, “laminar airflow” has been defined as a system of unidirectional flows of air, horizontally or vertically, to reduce the opportunity for microbial contamination. The term “unidirectional air flow” should be used instead.

Lethal rate (L): measure of inactivation per unit time at a temperature, expressed in terms of a reference temperature.6 

Load: defined product, equipment, or materials to be processed together within an operating, sterilization, or decontamination cycle.6 

Master product: device or procedure set used to represent the most difficult to clean, disinfect or sterilize an item in a product family or processing category.6 

Microbial barrier: physical or procedural property of a system to minimize the risk of ingress of microorganisms. Modified from the current definition6 to include systems not just limited to sterile barrier systems. A sterile barrier is an exclusion system that essentially reduces the ingress of microorganisms under tested conditions.

Microbiocide or Microbicide: See Biocide.

Microbiostat: any chemical(s) that controls or prevents the growth of microorganisms.11 

Microorganism: entity of microscopic size, encompassing bacteria, fungi, protozoa, and viruses.6 Also called “microbes,” microorganisms include prokaryotes (e.g., bacteria), eukaryotes (e.g., fungi, protozoans, algae), and viruses.

Minimum effective concentration (MEC): lowest concentration of a chemical or product that achieves a claimed activity.6 

Minimum recommended concentration (MRC): lowest concentration of a chemical or product specified for use in a process.6 

Non-pyrogenic: not exceeding a pyrogen limit specification. A pyrogen is a substance that causes a significant rise in body temperature (“fever-producing”). Examples are bacterial endotoxins and some material-mediated chemicals that can leach from a surface. Endotoxin and pyrogen specifications can vary depending on the application (e.g., device or drug use). The terms “non-pyrogenic” or “meets pyrogen limit specifications” are recommended over other such terms as “pyrogen-free.''21 

Nosocomial: acquired or occurring in a hospital or healthcare facility.

Objectionable microorganism: microorganism that under certain conditions unique to a product and the associated manufacturing process poses a risk of causing disease, degrading the quality of a product, or impacting the therapeutic efficacy of a product. The objectionable nature of a microorganism relates to the unique circumstances of a particular formulation, a particular ingredient, a particular method of manufacture, or the conditions found within a particular manufacturing process. Objectionable microorganisms are typically unintended or undesirable, indicating a loss of control that can lead to proliferation, harm to patient, or product degradation. They can survive or proliferate in a product, adversely affecting the chemical, physical, functional, and therapeutic attributes. Objectionable microorganisms should be characterized and, once defined, might need to be monitored and/or excluded from manufacturing areas because they could increase the risk of product contamination that could cause product degradation or patient harm/illness. The risk of objectionable microorganisms should be considered as part of an end-to-end process.21,22  See End-to-end, Contamination control strategy, and Assurance of sterility.

Operating cycle: complete set of stages of a process that is carried out in a specified sequence.6 

Organic load: naturally occurring or artificial contamination containing organic contaminants.

Packaging system: combination of a sterile barrier system and protective packaging.

Parametric release: declaration that product has reached a desired microbiological quality state based on records demonstrating that the process variables were delivered within specified tolerances. Modified from the current definition6,24 to apply to a wider range of processes than sterilization.

Pasteurization: heat disinfection process used to reduce levels of pathogenic and spoilage microorganisms to a level previously specified as being appropriate for a defined purpose.11  See Disinfection.

Pathogen: disease-causing microorganism.11 Microorganisms vary greatly in their true pathogenic potential, based on pathogenic factors (e.g., infectious dose), the risk of their presence in a manufacturing process, and their impact on the final product user (e.g., immune state of the patient, application of the product). Some microorganisms can opportunistically cause adverse effects on specific vulnerable recipients within a patient population but not others.

PNSU: See Probability of a non-sterile unit.

Preconditioning: treatment of product, prior to an operating cycle, to attain specified values, such as temperature, relative humidity, and/or other process variables.6 Preconditioning is generally conducted prior to and separate from a full operating cycle (e.g., a sterilization cycle). See Conditioning.

Preservation: control of the multiplication of microorganisms or prevention of microbial contamination.

Preservative: antimicrobial agent or mechanism used for preservation.

Prion: transmissible agent that is composed entirely of protein material and that does not appear to have a unique, associated nucleic acid.

Probability of a non-sterile unit (PNSU): probability of one or more microorganisms being present on (or in) a product item in a population of items.7,11 Note: It is expressed as the negative exponent to the base 10. Traditionally, the terms “PSNU” and “SAL” were used synonymously, but they are now typically used to describe mathematical probabilities of sterility in different situations. The SAL is the probably of sterility based on the extrapolation of an applied antimicrobial (sterilization) process to a product, whereas the PSNU term has often been used incorrectly based on the sampling of a proportion of product for sterility testing (in comparison to its initial definition7, 25 ). Both terms are used to give a mathematical confidence of sterility, but sterility can only be assured by an end-to-end approach for microbiological quality and sterility assurance. The working group has deliberated on definitions for PNSU and SAL, and it is recommended that a new definition be evolved to focus on an end-to-end, risk-based process for the assurance of microbiological quality. This is proposed to be the “risk of a non-sterile unit (RNSU).” See SAL.

Process challenge device (PCD): item providing a defined resistance to a cleaning, disinfection, or sterilization process and used to assess the performance of a process.6 

Processing: activity to prepare a new or used healthcare product for its intended use.6 Processing (or reprocessing) is used to describe steps such as cleaning, disinfection, and/or sterilization as well as other steps (e.g., inspection, maintenance) for the preparation of a new or used medical device for patient use. Processing steps are commonly conducted at a healthcare facility prior to patient use and in accordance with the manufacturer's instructions for use. The term “processing” was often used to describe the required steps for the first preparation of a medical use, and the term “reprocessing” was used for the steps involved in preparing the device for subsequent reuse with another patient. These definitions have been harmonized.

Process parameter: specified value for a process variable.6 A process parameter can be a process setting or a process condition, by which the process will perform in an intended manner. The specified value of a process parameter can be given as a range or as a set-point with tolerances.

Process variable: chemical or physical attribute within a microbiologically controlled process, changes in which can alter its effectiveness. Modified from the current definition6 to cover a wider range of activities. Process variables can include exposure time, temperature, pressure, concentration, and humidity as examples. This definition will cover process variables in cleaning, disinfection, sterilization, and aseptic manufacturing processes.

Product family: group or subgroup of product characterized by similar attributes determined to be equivalent for evaluation and processing purposes.6 Processing in this case can include any cleaning, disinfection, sterilization, or aseptic manufacturing process, as applicable.

Protective packaging: configuration of materials designed to prevent damage to the sterile barrier system and its contents from the time of their assembly until the point of use.6 

Pyrogen: substance that causes fever reactions at sufficient amounts.5,21 “Pyrogen” essentially means “fever-producing.” Technically, a fever in a human is defined as any body temperature above the normal of 98.6 °F (37 °C), but in practice a person is usually not considered to have a significant fever until the temperature is above 100.4 °F (38 °C).

Qualification: activities undertaken to demonstrate that utilities, equipment, or methods are suitable for their intended use and perform properly.6 

RABS: See Restricted access barrier system.

Reagent: substance or compound added to a system to cause a chemical reaction, or added to test if a reaction occurs. For cell-based health care products, ISO 11139 defines “reagent” as “material used for cellular growth, differentiation, selection, purification, or other critical manufacturing steps, but that is not intended to be part of the final product.”6 

Reference microorganism: microbial strain obtained from a recognized culture collection.6 A recognized culture collection depository authority is recognized under the Budapest Treaty on The International Recognition of the Deposit of Microorganisms for the Purposes of Patent and Regulation.

Reference standard: measurement standard designated for the calibration of other measurement standards for quantities of a given kind in a given organization or at a given location.6 

Reprocessing: See Processing.

Resistance: inability of an antimicrobial agent to be effective against a target microorganism.11 Resistance can be an innate or acquired attribute of the target microorganism. See Tolerance.

Resistometer: test equipment designed to create defined combinations of the physical and/or chemical parameters of a process. Modified from the current definition6 to apply to sterilization and other processes.

Restricted access barrier system (RABS): system that provides an enclosed, but not sealed, environment meeting defined cleanroom conditions. “Open” RABSs are open to and share the air from the surrounding environment during the aseptic process and might not have or depend on a positive pressure between the RABS interior and the surrounding environment. “Closed” RABSs produce and contain their own environment independent of air from the surrounding environment and usually depend on a positive pressure between the RABS interior and the surrounding room environment to maintain environmental conditions. “Active” RABSs have an integral HEPA-filtered air supply. “Passive” RABSs have an air supply from ceiling mounted HEPA-filters.1,8,12,20 

Reusable [medical] device: device designated or intended by the manufacturer as suitable for processing and reuse.6 

Risk assessment: systematic process of organizing information to support a risk decision to be made within a risk management process. Risk assessment consists of the identification of hazards and the analysis and evaluation of risks associated with exposure to those hazards.12 

Safety data sheet (SDS): document specifying the properties of a substance, its potential hazardous effects for humans and the environment, and the precautions necessary to handle and dispose of the substance safely.6 A substance can include a specific chemical or combination of chemicals in a product.

SAL: See Sterility assurance level.

Sanitization: removal, reduction, or inactivation of microorganisms.11 The preferred term should be “disinfection,” as it generally applies to the reduction of microorganisms on inanimate surfaces to an acceptable level. Historically, “sanitization” was often used in the food and pharmaceutical industries to refer to surface or liquid/water-line disinfection applications. The term has often been used for applications in the disinfection of microorganisms that pose a threat to public health.

Sanitizer: antimicrobial product or process used for the purpose of sanitization. See Disinfectant.

Self-contained biological indicator (SCBI): biological indicator presented such that the primary package intended for incubation contains the incubation medium required for incubation and recovery of the test organism.6 

Single-use component (SUC): See Single-use system.

Single-use [medical] device: [medical] device labeled or intended to be used on one individual during a single procedure.6 

Single-use system (SUS): disposable system or unit operation designed for one-time use. SUSs are typically those that are used in manufacturing processes and are typically made up of disposable components such as bags, filters, tubing, connectors, storage bottles, and sensors.

Soil: natural or artificial contamination on a device or surface following its use or simulated use.6 

Spore: dormant stage in the life cycle of certain bacteria and fungi. Bacterial and fungal spores can survive under adverse conditions and microbial distribution/dispersion. There are many types produced, including asexual and sexual spores. Bacterial spores (endospores) are widely considered to be some of the more resistant forms of microorganisms to inactivation.

Spore log reduction (SLR): negative exponent to the base 10, expressed as a logarithm, describing the decrease in the number of spores.6 

Sporicide: agent that inactivates microbial spores.11,17 

Standard distribution of resistances (SDR): reference set of resistances of microorganisms and corresponding probabilities of occurrence.6 

Sterilant: chemical or combination of chemicals used to generate a sterilizing agent.6 Sterilants are used for disinfection or sterilization purposes.

Sterile: free from viable microorganisms.6 “Sterile” refers to a quality attribute of a product or entity. “Sterile” is a term limited to the presence or absence of living microorganisms. It might or might not imply other product safety aspects, such as toxicity caused by the presence of microbial toxins. The labeling of a sterile product is based on a regulatory requirement related to a validated process and available methodology. “Sterile” is therefore an attribute of a product or item that is free of microorganisms as determined through a validated, end-to-end process, such as the application of a terminal sterilization process and/or aseptic processing. Available test methodologies are limited in verifying the “sterile” state of a product because of limitations in microorganism culturing conditions. Therefore, traditional “sterile” tests or tests of sterility are not sufficient or effective in ensuring a “sterile” claim. A risk-based approach, based on an end-to-end assurance of sterility, is recommended. It is also recommended that traditional labeling of sterile products be evolved to labeling that indicates that microbiologically controlled products are considered safe for use based on a risk management process to ensure microbiological quality.

Sterile barrier system: minimum package that minimizes the risk of ingress of microorganisms and allows aseptic presentation of the sterile product at the point of use.6 

Sterility: state of being sterile, based on the probability of the presence of viable microorganisms. Modified from the current definition.6 Sterility is a condition representing the absence of microorganisms from an entity. Sterility has been traditionally determined through validated direct testing or by using a predictive, statistical analysis with a probability level that is based on specified safety requirements. It is widely recognized that available microbiological test methodology is limited to verifying the sterility of an entity, with only the ability to test a proportion of the entity, limitations in culturing conditions to detect the range of microorganisms, and risks of environmental contamination during laboratory handling. Therefore, traditional tests of sterility are not sufficient or effective in ensuring a sterility claim. Sterility should not be based on direct detection methods for microorganisms but rather on the probability of the presence of microorganisms and risk assessment. This will include manufacturing processes (e.g., aseptic processing or products terminally sterilized) that take into account end-to-end microbiological quality and render a product essentially free of the risk of viable microorganisms. Microbiologically controlled (including sterile) entities should be considered safe for use based on a risk management process to ensure microbiological quality.

Sterility assurance: See Assurance of sterility.

Sterility assurance level (SAL): probability of a single viable microorganism occurring on an item after sterilization. Note: It is expressed as the negative exponent to the base 10.6,7,11 Traditionally, the terms “PSNU” and “SAL” were used synonymously, but they are now typically used to describe mathematical probabilities of sterility in different situations. The SAL is the probably of sterility based on the extrapolation of an applied antimicrobial (sterilization) process to a product, whereas the PNSU term has often been used incorrectly based on the sampling of a proportion of product for sterility testing (in comparison to its initial definition25 ). Both terms are used to give a mathematical confidence of sterility but can only be assured by an end-to-end approach for microbiological quality and sterility assurance. The working group has recommended that these terms be evolved into a new definition that focuses on an end-to-end, risk-based process for the assurance of microbiological quality. This is proposed to be the “risk of a non-sterile unit (RNSU).” See PNSU.

Sterility test: microbiological test to determine the presence or absence of viable, culturable microorganisms. Note that ISO 111396 differentiates between a “testforsterility” as a technical operation typically specified in a pharmacopoeia and performed on product following an aseptic process or exposure to a sterilization process, and a “test of sterility” as a technical operation performed as part of development, validation, or requalification to determine the presence or absence of viable microorganisms on product or portions thereof. A sterility test is traditionally performed as a release criterion for certain types of sterile products (e.g., aseptically manufactured products) or entities (e.g., biological indicators). It is well understood that an end-product sterility test is limited in its ability to detect microbiological contamination because, first, it utilizes only a small number of samples in relation to the overall batch size, and, second, culture media and conditions might only stimulate growth of some, but not all, microorganisms. Therefore, an end-product sterility test only provides an opportunity to detect major failures in the sterility assurance system (i.e., a failure that results in contamination of a large number of product units and/or that results in contamination by the specific microorganisms whose growth is supported by the prescribed media). In contrast, data derived from in-process controls (e.g., sterilization parameters) and monitoring (e.g., pre-sterilization product bioburden or environmental monitoring) can provide more accurate and relevant information to support the sterility assurance of the product. See Parametric release.

Sterilization: validated process used to render product free from viable microorganisms.6 A “product” can be a component during a manufacturing processes or a final product. Sterilization is a suitably designed, validated, and controlled process that inactivates or physically removes viable microorganisms in a product until sterility is obtained. The process should meet preestablished specifications that will result in the inactivation or removal of microorganisms in a statistically reproducible manner to predefined specifications or to achieve sterility. A physical removal (filtration) process can be used, but terminal sterilization (antimicrobial) processes are defined by a probability of survival in a final product. See SAL.

Sterilization cycle: predetermined sequence of stages performed in a sterilizer to achieve product free of viable microorganisms.6 

Sterilizer: equipment designed to achieve sterilization.6 

Sterilizing agent: physical or chemical agent(s), or combination thereof, having microbicidal activity to achieve sterility under defined conditions.6 

Sterilizing-grade filter: filter that reproducibly removes microorganisms from the process stream, producing a sterile filtrate.

Surrogate product: item, component, or ingredient designed to represent a product in process simulations and is comparable with the actual product. Modified from the current definition6 to broaden the scope.

Survivor (or death rate) curve: graphical representation of the microbial death rate kinetics for a specific antimicrobial product or process on a defined microbial population.11 

Terminal process: final step of processing to render a medical device safe and ready for its intended use.6 

Terminal sterilization: process whereby a product is sterilized within its sterile barrier system.6 

Thermal death time: time required to inactivate microorganisms at a specified temperature.

Thermolabile: readily damaged by heat.6 

Tolerance: decreased effect of an antimicrobial agent against a target microorganism, requiring increased concentration or other modification to be effective.11 Tolerance can be an innate or acquired attribute of the target microorganism. See Resistance.

Total particulates: sum of all monitored solid and liquid particles of a given size suspended in air. “Total particulates” are sometimes referred to as “non-viable particulates,” although “total particulates” is a more accurate term because the viability or microbiological nature of the particles is unknown at the time of discovery. In reference to ISO 14644-1,18 particle sizes of 0.5 microns and 5.0 microns are typically used as limits in total particle estimates and are reported quantitatively as particulates up to 0.5 microns and up to 5.0 microns. Both data sets include particles below the set particle size.

Toxicity: quality of being toxic or poisonous.

Toxin: foreign substance that is capable of inflicting damage on a host cell. Most toxins are generated by microorganisms.

Unidirectional airflow: Airflow moving in a single direction in a uniform manner and at sufficient speed for particulate control. Unidirectional airflow is used to remove particulates away from or to retain particulates within an area. This is a more accurate term than “laminar air flow.”

Utility water: water as it comes from a potable source.19 The quality or purity of the water could be sufficient for certain applications but generally further treatment is required to achieve a desired and consistent specification.

Validation: confirmation process, through the provision of objective evidence that the requirements for a specific intended use or application have been fulfilled.6 A manufacturing process typically includes the collection and evaluation of data, from the process design stage through commercial production, that establish scientific evidence that a process is capable of consistently delivering quality product. Process validation involves a series of activities taking place over the life cycle of the product and process.9,15 

Verification: provision of objective evidence that specified requirements have been fulfilled.6 For manufacturing, verification is a systematic approach to verify that systems, acting singly or in combination, are operating correctly over time. Ongoing assurance is gained during routine production that the process remains in a state of control.

Viable: alive and capable of reproduction under favorable circumstances.

Virucide: agent that inactivates viruses to make them noninfective.

Worst case: condition or set of conditions within the specified operating range that pose the greatest risk(s) of process or product failure. “Worst case” does not mean working outside of normal or desired operating ranges or conditions, nor should it necessarily mean those parameters or conditions that pose a high risk(s) of product or process failure. It is important that when high-risk parameters and conditions are identified, steps are taken to mitigate those risks, rather than just including them in the validation studies. Therefore, ”worst case” implies conditions that might have the highest potential to uncover any unaddressed process weakness or variability. As such, it might mean working at the extremes of (but still within) the acceptable operating range or design space, including such parameters and conditions as exposure time, temperature, system configuration, container and closure design opening, operator presence and activity, etc.1,8,9 

z value: change in temperature of a thermal sterilization or disinfection process that produces a tenfold change in D value.6,11,25 The D value and z value will be specific for a particular microorganism type.

The authors would like to acknowledge the members of the Kilmer Regulatory Innovation Team: H. Baseman, D. Blumenthal, T. Carlson, E. Claverie-Williams, L. Cordie-Bancroft, G. Gori, M. Jornitz, B. Lambert, J. McDonald, G. McDonnell, C. Murray, M. Sadowski, D. Singer, M. Sinha, E. Tidswell, J. Walker, J. Williams.

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Author notes

Gerald McDonnell, BSc, PhD, is a senior director in microbiological quality & sterility assurance at Johnson & Johnson in Raritan, NJ. Email: gmcdonne@its.jnj.com.

Hal Baseman is the COO and a principal at ValSource, Inc., in Jupiter, FL. Email: hbaseman@valsource.com.

Lena Cordie-Bancroft is the president/principal consultant at Qualitas Professional Services, LLC, in Minneapolis, MN. Email: lena.cordie@qualitasproserv.com.