Sterility, Sterilisation and Sterility Assurance for Pharmaceuticals

Technology, Validation and Current Regulations

Tim Sandle

• Publisher: Woodhead Publishing
• Year: 2013
• eBook ISBN: 9781908818638
• Topic: Medicine
• Subtopic: Pharmacology

Failure to adequately control any microbial challenge associated within process or product by robust sterilisation will result in a contaminated marketed product, with potential harm to the patient. Sterilisation is therefore of great importance to healthcare and the manufacturers of medical devices and pharmaceuticals. Sterility, sterilisation and sterility assurance for pharmaceuticals examines different means of rendering a product sterile by providing an overview of sterilisation methods including heat, radiation and filtration. The book outlines and discusses sterilisation technology and the biopharmaceutical manufacturing process, including aseptic filling, as well as aspects of the design of containers and packaging, as well as addressing the cleanroom environments in which products are prepared. Consisting of 18 chapters, the book comprehensively covers sterility, sterilisation and microorganisms; pyrogenicity and bacterial endotoxins; regulatory requirements and good manufacturing practices; and gamma radiation. Later chapters discuss e-beam; dry heat sterilisation; steam sterilisation; sterilisation by gas; vapour sterilisation; and sterile filtration, before final chapters analyse depyrogenation; cleanrooms; aseptic processing; media simulation; biological indicators; sterility testing; auditing; and new sterilisation techniques.- Covers the main sterilisation methods of physical removal, physical alteration and inactivation- Includes discussion of medical devices, aseptically filled products and terminally sterilised products- Describes bacterial, pyrogenic, and endotoxin risks to devices and products

1

Sterility, sterilisation and microorganisms

Abstract:

This chapter provides an introduction to the main themes of this book. It examines the theory of sterility and how it is a concept of probability. Microorganisms and viability in relation to sterility and sterilisation are considered. The discussion of microorganisms highlights the limitations both with environmental assessments (due to the presence of so-called viable but non-culturable microorganisms) and with the Sterility Test (limited by the sample size and growth based factors). With sterilisation, and returning to the theme of sterility as a probabilistic idea, this chapter examines the Sterility Assurance Level (SAL) in relation to terminal sterilisation and contrasts this quantitative assessment with aseptic processing, which is reliant upon environmental controls.

Key words

sterility

sterilisation

Sterility Assurance Level

terminal sterilisation

aseptic processing

viability

viable but non-culturable

Sterility Test

pharmaceutical science

dosage forms

good manufacturing practice

sterile bulk manufacturing

quality assurance

1.1 Introduction

Injections, infusions and pharmaceutical forms for application to eyes and mucous membranes must meet the requirement to be sterile. This is because certain medicines, such as peptides, proteins and many chemotherapeutic agents, would be inactivated in the gastrointestinal tract if they were given by mouth. Thus, most types of sterile products are administered by injection [1].

The development and production of such sterile medicinal products, from large-scale pharmaceutical processing to small-scale biotechnology, with medicines made on a named patient basis prepared within a hospital pharmacy to the processing of sterilised components, is arguably the most difficult and important facet of the preparation of pharmaceutical medicines. This is not necessarily due to the formulation of the products but because the medicines, due to their route of administration, are required to be sterile at the point where they are administered to the patient. If medicines are not sterile, this could lead to patient harm or even death. It is not possible to determine to what extent a non-sterile product would affect an individual patient. This is because people are unique in relation to form and physiology, and also because the context of administration and treatment will vary widely between individuals. Nonetheless, a contaminated product, especially one administered intravenously (via a vein) or intrathecally (via the brain or the spinal cord), is likely to cause harm.

The most effective means of reducing the risk of infection is the provision of a sterile product together with the complete prevention of microbial ingress up to and including the time of administration to the patient. This includes using sterile items to administer the drug (i.e. a sterile syringe and needle) and to administer the drug under clean conditions, using trained medical or nursing practitioners.

In addition to the medicinal product, the various components required for the production and development of sterile products are equally as important. These too need to be sterile, whether they are large stainless vessels subjected to steam sterilisation using an autoclave, or packaging or ready-assembled sterile disposable kits, which have been sterilised using radiation or gas.

A further area in which sterilisation applies is to medical devices, which cover a large spectrum of items including instruments, apparatus, implants, in vitro reagents and any articles that are used to diagnose, prevent or treat disease or other conditions. Medical devices do not achieve these purposes through chemical action within or on the body, unlike medicines [2].

Each of these various elements, which combine to create a sterile product or item, relate to the industrial process of sterile manufacturing. Sterile manufacturing itself is a continuum that stretches from development to manufacturing, to finished product, to marketing and distribution, and to utilisation of drugs and biologics in hospitals, as well as in patients’ homes. Although the terms ‘sterile manufacture’ or ‘aseptic manufacturing’ are widespread, there is no generic approach to the manufacturing of sterile products. Each plant or process will differ in relation to the technologies, products and processing steps. The common point is that a product is produced which is sterile and where there is no risk of contamination until the contents of the outer packaging are breached (i.e. through the injection of a needle through a bung of a product vial).

Sterility and production of sterile products are relatively new concepts in the history of human development. Unhealthy practices were part and parcel of the medical profession until the late 1800s, when the germ theory of disease gained credibility by explaining the increased cases of illnesses within hospital settings (notably the work of Lord Joseph Lister and aseptic methods in surgery, including the use of carbolic acid from 1867) [3]. Throughout the 1880s and 1890s, antiseptic surgical dressings and other forms of sterilisation such as dry-heat and steam pressure, were introduced to the medical field. For example, Ernst von Bergmann introduced the autoclave in the 1870s, a device used to sterilise surgical instruments [4] and in the 1920s the wide-scale production of sterile syringes and needles began [5]. Since these early beginnings, hygienic practices and sterilisation methods have been used and developed to decrease the spread of disease and infections [6]. For example, increased development in technology led to the first use of ethylene oxide gas as a hospital sterilant in 1940, radiation sterilisation in 1956 and gamma radiation sterilisation in 1964.

As a way of introducing the reader to many of the concepts, terms and ideas outlined in this book, this chapter explores the theory of sterility, the objectives of sterilisation and microbiological concepts such as viability. Presenting such material without veering too much to the abstract or leaning too heavily upon the theoretical is not possible. However, if the reader gains familiarity with these terms (or, depending upon their experience, using this chapter as an aide-mémoire), this will help them to understand and contextualise many of the more practical based chapters that are to follow.

1.2 Sterility

1.2.1 Defining sterility

Sterility can be defined as ‘the absence of all viable microorganisms’. Therefore, something would be deemed sterile only when there is complete absence of viable microorganisms within it. Sterility is an absolute term. Either something is sterile or it is not. There is no such thing as ‘slightly sterile’ or ‘almost sterile’.

Microorganism refers to a living entity, only visible through a microscope, which comprises a single cell (unicellular), cell clusters or multicellular relatively complex organisms. Microorganisms includes bacteria (prokaryotes), fungi (eukaryotes) and viruses in various states (notably, not all microbiologists consider viruses to be living) [7]. The prokaryotes, bacteria and archaea are the most diverse and abundant group of organisms on Earth [8]. They are found in sea water, soil, air, animals’ gastrointestinal tracts, hot springs and even in rocks deep within the Earth’s crust. Fungi too are found in a diverse range of habitats. As eukaryotic organisms, fungi are more complex organisms than bacteria. Many types of bacteria and fungi are found within the environments where medicinal products are processed, being carried into the areas through air-streams, via equ...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyrights
• Dedication
• List of figures and tables
• Preface
• About the author
• Introduction
• Chapter 1: Sterility, sterilisation and microorganisms
• Chapter 2: Pyrogenicity bacterial endotoxin
• Chapter 3: Regulatory requirements and Good Manufacturing Practices (GMP)
• Chapter 4: Gamma radiation
• Chapter 5: Electron beam processing
• Chapter 6: Dry heat sterilisation
• Chapter 7: Steam sterilisation
• Chapter 8: Gaseous sterilisation
• Chapter 9: Hydrogen peroxide vapour sterilisation
• Chapter 10: Sterilisation by filtration
• Chapter 11: Other methods of sterilisation
• Chapter 12: Depyrogenation and endotoxin
• Chapter 13: Cleanrooms, isolators and cleanroom technology
• Chapter 14: Aseptic processing filling
• Chapter 15: Media simulation trials
• Chapter 16: Cleaning disinfection of sterile processing facilities
• Chapter 17: Biological indicators
• Chapter 18: The Sterility Test
• Chapter 19: Investigating sterility test failures
• Chapter 20: Auditing sterilisation processes facilities
• Conclusion
• Index