• A number of dosage forms, medical products and devices need to be free of microorganisms.

• Failure to achieve sterility and the lack of validation or documentation of a sterilization process has led to patient deaths.

• Pharmacopoeias usually recommend five processes for the sterilization of sterile dosage forms: steam (under pressure), dry heat, gaseous (ethylene oxide) ionizing radiation and filtration.

• The use of sterilization parameters allows the calculation of the efficacy of a given sterilization regimen for a given load/products and enables comparison of efficacy between processes.

• High-level disinfection is used for the ‘sterilization’ of certain medical devices.

• A number of new technologies, notably high-pressure and gas plasma sterilization might offer appropriate alternatives to common sterilization processes.

Introduction

Previous chapters in this Part of the book have described the types and properties of microorganisms (Chapter 13) and the action of heat and chemical agents upon them (Chapter 15). This chapter will build on those fundamentals and describe the principles underlying the different methodologies available to achieve sterility. These will be described both for pharmaceutical preparations and also for medical products and devices. This chapter will also describe the criteria used to measure sterility. The practicalities associated with the processes of sterilization are described in Chapter 17.

By definition, a sterile preparation is described as the absolute absence of viable microbial contaminants. In practice, this definition is not achievable as a preparation cannot be guaranteed to be sterile. This remark is discussed further in Chapter 17.

Certain pharmaceutical preparations, medical devices and items for which usage involves contact with broken skin, mucosal surfaces or internal organs, injection to the blood stream and other sterile parts of the body, are required to be sterile. These are frequently referred to in pharmacopoeias as sterile products or sterile dosage forms. Microbiological materials, such as soiled dressings and other contaminated items, also need to be sterilized before disposal or reuse.

Sterilization is the process by which a product is rendered sterile, i.e. the destruction or removal of microorganisms. The majority of the processes recommended by pharmacopoeias (i.e. steam under pressure, dry heat, gaseous and ionizing radiation) are terminal sterilization processes for which the preparation is sterilized in its final container or packaging. For other multiple component preparations that cannot be sterilized with such methodologies, filtration sterilization can be used. Finally, high-level disinfection is used for the ‘sterilization’ of medical devices.

Need for sterility

As mentioned in the introduction, certain pharmaceutical preparations, medical products and devices are required to be sterile (further information is given in Chapter 17, Table 17.1). Briefly, these include:

Failure to achieve sterility can result in serious consequences. In the best case scenario, surviving microorganisms induce spoilage of the product (i.e. chemical and physical degradation) that might be identified before the preparation is used. The product (or batch of product) is then removed from use and destroyed. In the worst case scenario, where microbial survival cannot be identified through deleterious effects to the product, infection (sometimes fatal) might result from the use of the contaminated preparation. There have been many reports in the literature of such incidents over the years. For example, in the Devonport incident (in 1971–1972) the death of five patients (from acute endotoxic shock) was traced to dextrose 5% infusion bottles sterilized with a faulty autoclave. In 1996, in Romaira (Brazil), 35 newborn infants died of sepsis attributed to locally produced intravenous solutions (Editorial 1998). In 2005, a contaminated heparin intravenous flush was responsible for infecting several patients in different states in the USA (Editorial 2005). In these cases, inappropriate quality control procedures were implicated. These incidents emphasize that not only must an appropriate sterilization regimen be used but appropriate monitoring and control must be performed. This requires an understanding of the principles of sterilizing processes and their control and validation.

Sterilization parameters

The inactivation kinetics of a pure culture of microorganisms exposed to a physical or chemical sterilization process is generally described by an exponential relationship between the number of organisms surviving and the extent of treatment (ISO 2000), although variations from this are likely (Chapter 15 gives more details). Survivor curves have been used to generate inactivation data for specific sterilization processes using specific biological indicators (see Chapter 17). These data are important for calculating a number of sterilization parameters which help to establish a sterilizing regimen adapted to a specific preparation or product.

Principles of sterilization processes

Five main types of sterilization processes are usually recommended for pharmaceutical products (British Pharmacopoeia 2012). Among these, steam sterilization (sometimes referred to as steam under pressure sterilization or high-temperature steam sterilization) still represents the gold standard. Novel sterilization processes are being developed and have already been applied in the food industry. These are mentioned in the ‘New Technologies’ section later in this chapter.