Guide to validation of terminal sterilization process of drugs (GUI-0074): Overview 

Disclaimer: This document does not constitute legislation. If there is any inconsistency or conflict between the legislation and this document, the legislation takes precedence. This document is an administrative document intended to help by the regulated party comply with the legislation and the applicable administrative policies.

On this page

• Purpose
• Scope
• Introduction
• Note about guidance documents in general
• Principles
• Lifecycle approach

Purpose

This guide is for fabricators of sterile drugs. It provides guidance on how to establish the scientific effectiveness of terminal sterilization processes.

This guidance will help you understand and comply with Part C, Division 2 of the Food and Drug Regulations (regulations), which is about good manufacturing practices (GMP). This guide mainly refers to the requirements for:

• manufacturing control (sections C.02.011 to C.02.012)
• quality control department (sections C.02.013 to C.02.015)
• sterile products (section C.02.029)

This guide should be read along with the current editions of the following guidance documents:

• Good manufacturing practices guide for drug products (GUI-0001)
• Annex 1 to the Good manufacturing practices guide – Manufacture of sterile drugs (GUI-0119)
• Guide to validation – drugs and supporting activities (GUI-0029)

Scope

This guidance will help you validate the terminal sterilization of drugs, including pharmaceutical, radiopharmaceutical, biological and veterinary drugs. The terminal sterilization of drugs refers to sterilizing drugs that are in their final container.

The principles set out in this document can be extended to the sterilization of raw materials, bulk materials, in-process drugs and packaging materials.

For definitions of terms used in this guide, refer to the Glossary.

Introduction

These guidelines explain the requirements for validating the terminal sterilization of drugs. Health Canada developed the guidelines in consultation with stakeholders.

The guidelines are written to align with International Organization for Standardization (ISO) standards.

Note: This document replaces the following sterilization guides:

• Process validation: Gaseous sterilization for pharmaceuticals (GUI-0007)
• Process validation: Irradiation sterilization for pharmaceuticals (GUI-0009)
• Process validation: Moist heat sterilization for pharmaceuticals (GUI- 0010)

Consult the following documents for further information:

• Guide to validation - drugs and supporting activities (GUI-0029)
  • general guidance for qualifying and validating manufacturing processes, facilities, equipment, utilities and analytical methods within the drug lifecycle
• Guide to good manufacturing practice for medicinal products annexes, Annex 15: Qualification and validation (PE 009-17 (annexes)), by the Pharmaceutical Inspection Co-operation Scheme (PIC/S)
  • general qualification and validation guidance
• Annex 1 to the Good manufacturing practices guide – Manufacture of sterile drugs (GUI-0119)
  • guidance on manufacturing of sterile products and validating blow/fill/seal technology and aseptic processing
• Annex 11 to the Good manufacturing practices guide: Computerized systems (GUI-0050)
  • GMP requirements for computerized systems

Note about guidance documents in general

Guidance documents like this one help industry and health care professionals understand how to comply with regulations. They also provide guidance to Health Canada staff, so that the regulations are enforced fairly, consistently and effectively across Canada.

Health Canada inspects establishments to assess their compliance with the Food and Drugs Act (act) and associated regulations. Our inspectors will use this document as a guide to assess your compliance with GMP requirements for validating terminal sterilization processes.

These guidelines are not the only way to interpret GMP regulations and do not cover every possible case. Other ways of complying with GMP regulations will be considered with proper scientific justification. Also, as new technologies emerge, different approaches may be called for.

Guidance documents are administrative and do not have the force of law. Because of this, they allow for a flexible approach. Use this guide to help you develop specific approaches to meet your unique needs.

Principles

Note the following:

Sterilization:

• a suitably designed, validated and controlled process that inactivates or removes viable microorganisms in a product until sterility is obtained (European Medicines Agency)
• validated process used to render product free from viable microorganisms (ISO)

In a sterilization process, the nature of microbial inactivation is exponential and thus the survival of a microorganism on an individual item can be expressed in terms of probability. While this probability can be reduced to a very low number, it can never be reduced to zero.

Terminal sterilization:

• the application of a lethal sterilizing agent to finished product within a sealed container to achieve a predetermined sterility assurance level (SAL) of 10^-6 or better
  • in other words, the theoretical probability of there being a single viable microorganism present on or in a sterilized unit is equal to or less than 1 x 10^-6 (1 in a million) (PIC/S)
• process whereby product is sterilized within its sterile barrier system (ISO)

Terminal sterilization is the preferred method when fabricating sterile products. It provides better assurance of sterility than sterilization during product manufacturing.

For a given sterilization approach, the probability of microorganisms surviving is determined by the:

• number and resistance of microorganisms
• environment in which the organisms exist during treatment

It's important to monitor and assess the resistance as well as the number of organisms to assure that the terminal sterilization parameters continue to provide the required maximal sterility assurance level (SAL).

ISO/TS 19930 describes the elements of a quality management system. These elements are applied to enable the appropriate selection of a SAL for terminally sterilized, single-use health care product that is unable to withstand processing to achieve maximally a SAL of 10^-6.

This document assumes that the reader is familiar with the applications, limitations and effects of the following methods of terminal sterilization discussed in this guide:

• moist heat
• ionizing radiation
• ethylene oxide (EO) gaseous sterilization

Other technologies such as dry heat and alternative gaseous technologies are not in the scope of this guidance document

Lifecycle approach

The lifecycle approach applies to the validation of terminal sterilization processes. This approach is outlined in Guide to validation: Drugs and supporting activities (GUI-0029).

The validation lifecycle comprises the following 3 phases:

• phase 1, process design
• phase 2, process performance qualification
• phase 3, ongoing process verification

Validation is not a single study. It represents the cumulative knowledge gained during product development and manufacture. Process validation should incorporate a lifecycle approach, including:

• product and process development
• qualification of the commercial manufacturing process
• maintenance of the process in a state of control during routine commercial production