This chapter covers the principles of regulation of the development, manufacture, distribution, and use of processes, agents, and equipment for sterilization, disinfection, and preservation. This chapter discusses the nature of the controls that have been implemented with the intention of ensuring that products are safe, do not harm the environment, and perform as intended. These controls might be implemented through a variety of legal measures depending on the jurisdiction but are often generically described as regulatory requirements. When the term regulatory requirement is used, it generally encompasses requirements contained in any applicable law that might, for example, be termed statute, statutory instrument, regulation, ordinance, or directive.
Regulatory requirements often cover two separate aspects of product quality:
Intrinsic quality—receiving prior approval of the quality, safety, and performance/effectiveness/efficacy before placing on the market
Extrinsic quality—controlling that products are always manufactured and distributed so as to maintain the intrinsic quality of the approved product
Regulatory requirements, therefore, often cover both the lifecycle of the product and its supply chain; from concept, through development and manufacture, distribution, and monitoring of safety and performance in use to withdrawal at the end of product life. In addition, regulatory requirements can affect different organizations in the supply chain from manufacturers to importers and distributors.
Regulatory requirements can often be statements of principle or description of processes to be applied to obtain approval for products or processes. These are often subject to interpretation and that interpretation can evolve over time. This can be based on experience, developments in science and technology, and changes in the state of the art. The interpretation of regulatory requirements by regulatory authorities in a particular jurisdiction (eg, the US Food and Drug Administration [FDA]) can be thought of as the expression of regulatory expectations. These expectations can go beyond what is actually written in the regulations, for example, the expectations incorporated in what can be described as Current Good Manufacturing Practices (cGMPs or GMPs).1
Regulator positions on such issues are often presented at scientific conferences, in published guidance documents, and on official blogs hosted on regulatory authority websites.
Regulatory requirements can also be supported by voluntary consensus standards, for example, those developed by the International Organization for Standardization (ISO) and adopted by national or regional standards development organizations. Conformance with these standards might be formally recognized as providing a presumption of conformity with regulatory requirements or provide a quicker route through the regulatory approval process. Standards are generally developed in parallel to the regulatory process by consensus of stakeholders, including regulatory authorities. Standards can provide specifications for products or describe methods of test or procedures to demonstrate the effectiveness of a product or process. For medicinal products, many national pharmacopoeias predate medicines legislation. Pharmacopoeias may be integrated into local legislation in which case their contents can become legal public standards. Regulatory requirements and best practice can be supported by recommendations provided by professional societies on how to use products or apply processes in specific applications. Finally, and often overlooked, is the regulatory expectation that a manufacturer adheres to its own procedures.
An example of how cGMP expectations, applicable standards, and regulatory expectations can interact is the expectation within some European authorities that elements of the European Standard EN 285 for large steam sterilizers4
are applied by pharmaceutical manufacturers
when validating sterilization of equipment. EN 285 is itself an equipment standard that includes test methods and acceptance criteria for performance assessment of large steam sterilizers that use vacuum for air removal. The standard specifies the required performance to be achieved against a range of test loads. One measure of the sterilizer’s ability to remove air from a test load of cloth material is the equilibration time. This is the time difference between the coolest point of the chamber and the slowest to heat part of the load reaching sterilization temperature. If air removal, and hence steam penetration, is effective, this time difference will be small. EN 285 specifies 30 seconds for the largest sterilizer, when tested with a standard test pack of cloth material. Certain regulatory expectations apply this equilibration time to all production loads. In principle, equilibration time is a valuable measure of air removal effectiveness from any load, but the rigid application of one specification developed for a specific load type can be considered somewhat arbitrary.
It is not practical to cover the regulatory requirements applicable to each and every jurisdiction worldwide, but this chapter focuses on the principles generally included as regulatory requirements and some examples of how these are applied. This chapter describes where key requirements for preservation, disinfection, and sterilization are to be found in the regulatory requirements. It is not intended as an alternative to reference actual regulations, which are subject to change over time.
TABLE 70.1 Examples of common regulatory regimes of various applications of disinfection, preservation, and sterilization
Disinfecting medical devices
Preservation of medicinal products
Anti-infective for medical device
Sterilizer for medical devices used in health care
Sterilization of medical devices
Sterilization of medicinal product
Canning, sterilization of ingredients and foodstuffs
Antimicrobial agents and their use in methods of disinfection, preservation, and sterilization can be regulated in different ways depending on their application. Examples of regulatory regimes for different applications are summarized in Table 70.1
. The regulation of disinfection, preservation, and sterilization generally falls into three main areas depending on the application:
Health care products—medicinal products, medical devices, and combinations thereof
Environmental disinfectants or preservatives—biocides, pesticides, or germicides
Food products—canning, food sterilization, and treatment of ingredients
Sterilizing Agents, Sterilization Processes, Sterilizing Equipment, and Sterile Products
The regulatory requirements for medicinal products apply to sterile pharmaceuticals, including biologics, and would cover the method used to achieve sterility and the validation and routine control of that process. These requirements, including those for biological indicators that may be used in monitoring of sterilization processes
for medicinal products, are generally contained in pharmacopoeia.5
The regulatory requirements for medical devices are applicable for sterile medical devices and cover the methods of sterilization and the validation and routine control of the process to achieve sterility. Medical device regulations also commonly apply to sterilizing equipment used in health care facilities and frequently also encompass ancillary products for monitoring sterilization processes like biological and chemical indicators. The regulatory requirements for food cover processes used for canning and sterilization of food products such as sterilized milk and some sterile baby foods.
Disinfectants, Disinfecting Agents, Disinfection Processes, and Disinfecting Equipment
Environmental disinfectants are usually covered by environmental legislation and might be termed biocides, pesticides, or germicides. Generally, the regulations include disinfectants for use in the health care environment as well as a wide range of other commercial applications. The cGMPs can also apply to the use of disinfectants for environmental control in manufacturing facilities for medicinal products.
Medical device regulations cover disinfectants used specifically on medical devices such as contact lenses or endoscopes. Equipment for disinfection of reusable medical devices, such as anesthetic equipment tubing and facemasks, endoscopes, or bedpans in health care facilities, are also frequently regulated as medical devices.
Specific medicinal product regulations can also typically apply to the variety of antiseptics for human and veterinary use.
Food regulatory regimes cover use of pasteurization to extend the lifetime of perishable foods and preventive treatments to reduce spoilage and application of hygienic practices in food processing.
Preservative and Preservation
Medicinal product regulations cover preservatives incorporated in medicinal products, for example, multiuse ophthalmic preparations. Preservatives in environmental applications, such as treatment of wood, is generally covered by regulatory requirements for environmental disinfectants or pesticides.
Regulation of foods would include preservation by reduction in pH, lowering water content, raising the salt or sugar content, or adding preservatives content. Food safety legislation applies to additives to foods and hygienic practices in food processing.
Health Care Products
Health care products are divided into two principal categories: medicinal products, which might also be described as pharmaceuticals and biologics, and medical devices. The primary distinction is that medicinal products generally have a pharmacologic, metabolic, or immunologic action, whereas medical devices act physically. Where a product combines a physical and a pharmacologic action, for example, a prefilled syringe or a drug-eluting stent, it might be regulated either as a specific category of combination product or under the regime applicable to the principal intended purpose of the product.
It is an essential principle for health care products, and the manufacturing processes used to produce them, that they are designed in a way that eliminates, or reduces as far as possible, the risk of infection to the patient, user, and third parties. In order to achieve this, the product needs to allow ease of handling for its intended use and, where necessary, minimize contamination of the patient by a product or vice versa during use. Packaging systems are intended to prevent deterioration and maintain the level of cleanliness necessary. Products are accompanied by the information needed to use it safely and properly, taking account of the training and knowledge of the potential users.
One approach to reduce the risk of infection to the patient is to provide a product in a sterile state. When a claim of “sterile” is made, a number of regulatory principles can apply. These include that the product is designed and manufactured within the framework of a quality system; is packed in a nonreusable pack to ensure that it is sterile when placed on the market; is manufactured in appropriately controlled environmental conditions; is sterilized by an appropriate, validated method (when applicable); and is labeled “STERILE.”
For a terminally sterilized product, a claim that the product is sterile is linked to the delivery of a sterilization process that has been established, validated, and is routinely controlled to predict attainment of a specified maximal sterility assurance level (SAL). Specifying a value for that SAL is a matter for regulatory authorities. It is important to note that
A product sterilized using a validated process achieving maximally a SAL of 10-6 is generally regarded as sterile and is labeled as such.
Some jurisdictions accept a label claim of sterile for a product for certain defined applications when a sterilization process achieves maximally a SAL of 10-3.
Regulatory authorities may permit a product processed to achieve maximally a SAL greater than 10-6 (eg, 10-5) to be labeled as sterile based on individual analysis of the risk benefit of that particular product if a maximal SAL of 10-6 cannot be achieved.
Generally, a product processed to achieve maximally a SAL greater than 10-3
, such as 10-2
, is not traditionally
labeled as sterile. There might be individual situations in which such product (such as a cell-based therapy) is appropriate for a specific intended use and has regulatory approval for that use.8
When a regulatory body accepts that a maximal SAL greater than 10-6
may be used (eg, 10-5
) for a product, its consideration will also address how that product should be labeled.8
When terminal sterilization is not possible, the manufacture of sterile health care products using aseptic processing is permitted. Aseptic processing requires controls of a number of factors in order designate aseptically processed medical devices as sterile (see chapter 58
). These factors relate to controls to and/or records of
The manufacturing environment
The sterilization of components
Associated equipment used during manufacturing
The competence of personnel
Interventions in the process
The performance of process simulations
Inspections and tests of finished product
The acceptance limits and actions for occurrence of nonsterile units in process simulations in initial performance qualification and periodic requalification are specified by regulatory authorities or documented in supporting standards or guidance documents. The current expectations are that process simulations should generally not yield any contaminated units.
Most regulatory regimes for medicinal products have two separate but related aspects: a marketing authorization (product license) that considers the safety and efficacy of the product and a manufacturing license for each site of manufacture based on continued performance in accordance with GMPs. Part of the approval process is generally a pre-approval inspection (PAI) of the facility that is to make the medicinal product commercially.
The International Council for Harmonisation (ICH) was formed in 1990 by the European Union, Japan, and the United States in order to develop a harmonized format for submissions for marketing authorization of new products. This format is called the Common Technical Document (CTD).9
It should be noted that the CTD is a common structure for the presentation of data and that data requirements in different jurisdictions can vary. The part of the CTD relevant to sterilization, disinfection, and preservation is module 3, Quality. This section requires details of the active substance and the medicinal product; the method of manufacture and the manufacturing process; and its controls, validation, and container closure systems. The portion of the submission that details the procedures and methods applied to assure sterility of the product might also be referred to as the chemistry, manufacturing, and controls (CMC) section.
Marketing a medicinal product in the European Union is currently covered by Regulation (EC) No 726/2004.10
This lays down the procedures within the European Union for the authorization and supervision of medicinal products for human and veterinary use. Applications for market authorization as a medicinal product could be made by a centralized procedure through the European Agency for the Evaluation of Medicinal Products (commonly know by the shortened acronym EMA) or a decentralized procedure through national competent authorities, depending on the nature of the medicinal product and the market strategy of the applicant for market authorization. Applications are prepared in a CTD format. Directive 2001/83/EC, as amended (III Placing on the Market; Chapter 1
details the requirements for making an application for a marketing authorization. Attention is drawn to Article 23 of this directive; this requires that after a marketing authorization has been granted, the marketing authorization holder takes account of technical and scientific progress in methods of manufacture and control and introduces changes that enable their product to be manufactured and checked by “means of generally accepted methods.” This indicates that the marketing authorization holder is responsible for keeping processes up to date, whether they are performed in-house or undertaken by a contract manufacturer.
In the United States, drug products are authorized through a New Drug Application (NDA)12
or, for generics, an Abbreviated New Drug Application (ANDA).13
In the European Union, Directive 2001/83/EC as amended (IV Manufacture and Importation)11
details the requirements for holding a manufacturing authorization. Articles 40 to 45 cover the requirements for a manufacturing authorization. Article 47 of this directive requires that the principles and guidelines for GMP are detailed in a separate directive. This is Directive 2003/94/EC,14
and it contains the current basic requirements for GMP. The GMP is intended to provide assurance that each lot of approved product placed on market is of acceptable quality, safety, and efficacy and meets the marketing authorization commitment. In the European Union GMP, this is described in EudraLex Volume 4,1
whereas in the United States, it is described in the Code of Federal Regulations (CFR) 210 and 211.2
Role of Pharmacopoeia
The most influential pharmacopoeias worldwide are those of the United States (USP/NF),7
Europe (Ph. Eur.),5
and Japan (JP).6
The review of the submission for a marketing
authorization would consider the requirements in relation to the applicable monographs of the pharmacopoeia. Any submission that did not follow the pharmacopoeia’s expectation for sterilization, disinfection, and preservation would be subject to individual review. The pharmacopoeias require medicinal products for parenteral or ophthalmic administration to be provided sterile.
Different pharmacopoeias are arranged in similar formats, although section terminology may differ slightly. Broadly, pharmacopoeias are arranged into general chapters and monographs specific to individual medicinal products. The general chapters contain details of methods of manufacture such as sterilization methods, requirements for product types such as injectables, and test methods applicable to a range of products. These general chapters are informative unless cross-referenced in a product monograph. Pharmacopoeia monographs can contain information on specified excipients, active ingredients, and medicinal products. They might contain definitions and requirements for manufacture, packaging storage, labeling, and testing. The nomenclature for different sections in different pharmacopoeia varies and are presented with key relevant sections indicated in Table 70.2
The general chapters are used to compile into one location information which is applicable to many monographs. Monographs contain requirements such as the product’s official name, definition, specification, packaging, and storage requirements where appropriate requirements for sterility and preservation are included.
The Ph. Eur.5
is arranged into
General chapters containing requirements for test methods, reagents, etc
General monographs containing requirements applicable across any product or product type
Monographs on specific dosage forms
Individual monographs containing the requirements for specific medicinal products
The general texts on microbiology contain guidance and requirements on methods of preparation of sterile products. The reference conditions cited for sterilization are
Aqueous preparations—121°C for 15 minutes
Dry heat—160°C for at least 2 hours
Irradiation—absorbed dose 25 kGy
For depyrogenation by dry heat, a temperature of 220°C with demonstration of a 3 log10 reduction of heat-resistant endotoxin is specified. Substances that are the subject of an individual monograph are required to comply with the relevant applicable general monographs. It should be noted that the individual monographs do not reference applicable general monographs.
The Japanese Pharmacopoeia
General rules, containing general notices for preparations and monographs for preparations, specific to preparation types
General tests, processes, and apparatus giving requirements for tests applicable to a range of products
Individual monographs containing information on specific products
General information containing information on methods of sterilization, disinfection, and preservation
Under the general notices for preparations, terminal sterilization is defined as a process performed under the condition where the SAL of 10-6 or less is ensured by using suitable biological indicators. Aseptic processing using sterilization by filtration is defined as a “process performed under the condition to give a defined SAL in the clean areas where microbial and particulate levels are adequately maintained by using appropriate techniques.” The general notice does not specify which methods should be used preferentially.
The general tests section contains requirements relevant to sterile and preserved products. The section also contains test requirements for primary packaging materials such as glass containers, rubber closures, and plastic containers. The general information section also includes a table indicating which requirements are harmonized with the USP and Ph. Eur. Only the requirements for the sterility test and the bacterial endotoxin test are harmonized.
Role of Standards
There is no formal legislative link between International Standards and regulatory requirements for medicinal products, but they might be referenced as guidance, for
example, standards on design, construction, and classification of clean rooms (ISO 14644 series)15
are specifically mentioned in EudraLex Chapter 4
, Annex 1.1
TABLE 70.2 Compilation of relevant topics covered by the European, Japanese, and United States Pharmacopoeia
European Pharmacopoeia (8th edition, 2013)5
Japanese Pharmacopoeia (17th edition, 2016)6
United States Pharmacopeia (USP 40, 2017)7
General chapters containing requirements for test methods, reagents, etc
2.6.1—Test for Sterility
<71> Sterility Tests
4.01—Bacterial Endotoxins Test
<85> Bacterial Endotoxins Test
<161> Medical Devices—Bacterial Endotoxin and Pyrogen Tests
<151> Pyrogens Test
General monographs containing requirements applicable across any product or product type
5.1—General Texts on Microbiology
5.1.1—Methods of Preparation of Sterile Products
Sterilization and Sterilization Indicators
<1211> Sterilization and Sterility Assurance of Compendial Items
<1229.1> Steam Sterilization by Direct Contact
<1229.2> Moist Heat Sterilization of Aqueous Liquids
<1229.4> Sterilizing Filtration of Liquids
<1229.7> Gaseous Sterilization
<1229.8> Dry Heat Sterilization
<1229.10> Radiation Sterilization
<1229.11> Vapor Phase Sterilization
<1229.12> New Sterilization Methods
<1229.13> Sterilization in Place
5.1.2—Biological Indicators of Sterilization
<1229.5> Biological Indicators for Sterilization
<55> Biological Indicators—Resistance Performance Tests
<1229.9> Physicochemical Integrators and Indicators for Sterilization
5.1.3—Efficacy of Antimicrobial Preservation
<51> Antimicrobial Effectiveness Testing
5.1.9—Guidelines for Using the Test for Sterility
5.1.10—Guidelines for Using the Test for Bacterial Endotoxins
<1229.3> Monitoring of Bioburden
<1207> Package Integrity Evaluation—Sterile Products
Parametric Release of Terminally Sterilized Pharmaceutical Products
<1222> Terminally Sterilized Pharmaceutical Products—Parametric Release
Media Fill (Process Simulations)
Microbiological Environmental Monitoring Methods of Processing Areas for Sterile Pharmaceutical Products
<1116> Microbiological Control and Monitoring of Aseptic Processing Environments
Disinfection and Decontamination Methods
<1072> Disinfectants and Antiseptics
<1228.1> Dry Heat Depyrogenation
<1228.2> Depyrogenation by Filtration
<1228.5> Endotoxin Indicators for Depyrogenation
Monographs on specific dosage forms
(3) Preparations for Injection
(6) Preparations for Ophthalmic Application
Standards for the development and routine control of methods of sterilization such as radiation or ethylene oxide which are commonly employed for medical devices but less frequently employed for medicinal products might also be considered as relevant guidance. Some regulators expect certain aspects of standards to apply as cGMPs.
Generally, the regulation of medical devices is based on a system of risk classification of the device depending on its intended use. Higher risk devices have greater oversight. The extent of oversight can range from self-certification of the lowest risk devices and some form of registration of the manufacturer to premarket review of design and development information including clinical data for the highest risk classes. Additionally, manufacturers of most, if not all classes, of medical devices are required to implement a quality management system. There is a specific international standard, ISO 13485,16
that specifies requirements for a quality management system for regulatory compliance for medical device organizations. This standard includes requirements for sterile devices in relation to the validation of sterilization and sterile barrier systems.
European Union CE Marking as a Medical Device
The regulatory system for medical devices in the European Union offers a variety of routes for conformity assessment based on the risk classification of the medical device and the strategy for regulatory compliance developed by the manufacturer. The European Union regulations are in the process of transitioning from a series of three directives for active implantable devices,17
and in vitro diagnostic devices19
that came into force in the 1990s to a Medical Devices Regulation (MDR)20
and an In Vitro Diagnostic Medical Devices Regulation (IVDR) that entered into force in 2017.21
The European Union has four levels of medical device classification (I, IIa, IIb, and III) but has specific conformity assessment requirements for some categories of devices within these classifications. For the European Union, third-party review of the aspects related to achieving and maintaining sterility is required irrespective of the classification of the device.
Any device incorporating a medicinal product would be classified as a class III medical device under the most current classification rules (Rule 14 of Annex VII of the MDR20
). The manufacturer has to prepare and sign a declaration of conformity in order to CE-mark the device and place it on the market. In order to sign such a declaration for a class III device, the manufacturer would require certification from a notified body of review of a design dossier or type test. Both these approaches require
the notified body to review the manufacturer’s technical documentation. A notified body is an organization designated in the European Union country to assess the conformity of certain types of products as well as a manufacturer’s quality management system. The requirements for the technical documentation are set out in Annex II of the MDR and IVDR.
The regulations detail the technical documentation that the manufacturer has to establish and maintain. Aspects of the technical documentation relevant to claims of sterility are
Design and manufacturing information that includes
Information on design and development stages applied to the device
Information and specifications on the manufacturing processes and their validation
Identification of all sites, including suppliers and subcontractors, where design and manufacturing activities, including sterilization, are performed
Information for the demonstration of conformity with the general safety and performance requirements that are applicable to the device taking into account its intended purpose together with justification, validation, and verification of the solutions adopted to meet those requirements. The demonstration of conformity includes
The general safety and performance requirements that apply to the device and an explanation as to why others do not apply
The method or methods used to demonstrate conformity with each applicable general safety and performance requirement
The harmonized standards or other solutions applied
The documents providing evidence of conformity with the harmonized standard or other method applied to demonstrate conformity with the general safety and performance requirements
The general safety and performance requirements that apply in relation to risks of infection. All devices, irrespective of their risk classification, have to meet the general requirements for safety and performance that apply to them. In terms of sterile devices, the applicable requirements are that the device
Is designed, manufactured, and packed in a nonreusable pack and/or according to appropriate procedures to ensure that it is sterile when placed on the market and remains sterile, under the storage and transport conditions laid down, until the protective packaging is damaged or opened
Is manufactured in appropriately controlled environmental conditions
Is manufactured and sterilized by an appropriate, validated method
Is labeled with the word STERILE or an accepted symbol indicating sterility
Has packaging and/or labeling that distinguishes between identical or similar product sold in both a sterile and a nonsterile condition
indicates that devices, systems, or processes that are in conformity with relevant harmonized standards are presumed to be in conformity with those requirements of the regulation covered by those standards. References to standards that are considered to be harmonized are published in the Official Journal of the European Union
. The list of harmonized standards under the directives for medical devices17
includes standards identifying requirements for terminally sterilized medical devices to be designated sterile, EN 556-1,22
and the European adoptions of international standards for the development, validation, and routine control of sterilization by the methods of sterilization generally applied for terminal sterilization. It is expected that these same standards will be given the status of harmonized under the MDR.
United States Approval and Clearance of Medical Devices
The US regulation of medical devices also has a system of controls based on classification of devices. The Medical Device Amendments to the Federal Food, Drug and Cosmetic Act23
created three classifications of medical devices based on the level of risk:
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