ISO 11138 is a crucial standard in the field of sterilization, specifically focusing on the validation of sterilization processes for healthcare products. Developed by the International Organization for Standardization (ISO), this standard provides guidelines for assessing the efficacy of sterilization methods such as steam, ethylene oxide, and dry heat. It outlines procedures for validating these methods to ensure they consistently achieve the required level of sterility, essential for maintaining the safety and efficacy of medical devices and pharmaceutical products. Compliance with ISO 11138 is paramount for manufacturers, healthcare facilities, and regulatory bodies to guarantee that sterilization processes effectively eliminate harmful microorganisms while preserving product integrity.
The requirements outlined within ISO 11138 provide criteria for the management of production, labeling, testing methodologies, and performance attributes of biological indicators, including both carriers and suspensions, along with their constituent components. These indicators are employed in the validation and regular monitoring of sterilization procedures. This article is part of the discussions related to the sterilization process which we have already started with 4EasyReg, dealing with topics such as gamma sterilization process, ethylene oxide sterilization, packaging requirements for sterile products, process validation and much more.
There are different ISO 11138 standards, the first one highlighting the general requirements for biological indictors while the others are focused on each specific sterilization process.
Before providing an overview of the main requirements associated to biological indicators, let’s start with some definitions that will be very important to adequately understand the upcoming sections of this article:
biological indicator: test system containing viable microorganisms providing a defined resistance to a specified sterilization process;
nominal population: manufacturer’s stated number of viable microorganisms;
inoculated carrier: supporting material on or in which a defined number of viable test organisms have been deposited;
self-contained biological indicator: biological indicator presented in such a way that the primary package, intended for incubation, contains the incubation medium required for recovery of the test organism
survivor curve: graphical representation of the inactivation of a population of microorganisms with increasing exposure to a microbicidal agent under stated conditions; viable count: actual number of recoverable colony-forming units or other appropriate units.
General Requirements for the manufacturing of Biological Indicators
In this section we can provide a broad overview of the main requirements applicable to the manufacturing of biological indicators.
Quality Management System
First, it is necessary that the manufacturers have a compliant quality management system in place, aligned with ISO 13485 or GMP or other national applicable regulations.
Finished Product Requirements
There are specific requirements which are applicable to the finished product:
- Labelling;
- Manufacturing;
- Resistance characteristics;
- Storage and Transport;
- Incubation.
Before analyzing the requirements associated to the elements mentioned before, let’s discuss the requirements associated to test organisms. The test organisms must originate from a specified strain, obtainable from an acknowledged culture repository, and must undergo identification using suitable testing procedures. Upon request, a declaration of traceability must be furnished to the buyer. It is important that when transporting and storing according to label instructions, the test organism must maintain its resistance characteristics throughout the specified shelf-life duration. It should be a strain suitable for handling without necessitating special containment facilities, eliminating the need for specific handling procedures or transportation requirements (e.g., WHO 2004 Risk Group 1).
Labelling Requirements
Each unit of suspension, packaging for inoculated carriers, and biological indicator must bear the following details on its label:
- A distinctive code enabling the tracking of manufacturing history.
- The name of the test organism.
- Specification of the applicable sterilization process.
- Expiry date formatted in accordance with ISO 8601 (e.g., YYYY-MM-DD).
- Manufacturer’s identification, including name, trademark, address, or equivalent means.
- Appropriate internationally recognized symbols may also be employed.
Furthermore, information included within table 1 of ISO 11138-1 shall also be included on or within the secondary packaging of each batch of product.
Overview of the Manufacturing Requirements
The carrier, the primary packaging, and the specified storage conditions shall be designed so that the performance characteristics of the biological indicator meet the requirements of ISO 11138-1 throughout the stated shelf life of the product. It is also important that the materials of the carrier and the primary and secondary packaging shall not contain any contamination (physical, chemical, or microbial) that would adversely affect the performance of the biological indicator.
It is necessary that the purchaser shall be provided with a statement of the maximum and minimum values of each dimension of the carrier on request. During and after the sterilization process, the carrier and the primary packaging shall not retain or release any substance to such an extent that, on transfer to the incubation medium, under the culture conditions, the growth of low numbers of surviving test organisms will be inhibited.
Resistance Characteristics
The determination of resistance characteristics involves a combination of methods which are defined within the Annexes C, D and E of ISO 11138-1. Specifically:
a) The D value is determined by constructing a survivor curve (see Annex C of ISO 11138-1).
b) The D value is determined through a fraction negative method (see Annex D of ISO 11138-1).
c) Verification of the survival/kill response characteristics is conducted (see Annex E of ISO 11138-1).
Values obtained from these methods must fall within the specified ranges outlined in relevant sections of ISO 11138. At least two of these values must be included in the labeling of biological indicators, as specified within Table 1 of section 4.3.2 of ISO 11138-1. The D value, when determined by the manufacturer during the stated shelf life using the specified method, should be within ±20% of the manufacturer’s stated value.
Storage and Transport
The requirements for storage and transportation conditions are defined within section 4.4 of Iso 11138-1. In case inoculated carriers are prepared for storage or transportation, their packaging should be arranged in a manner that does not negatively impact their nominal population or individual performance. Likewise, conditions for storing and transporting inoculated carriers must be upheld to guarantee adherence to the requirements outlined in ISO 11138.
Biological indicators that are individually packaged should be placed within a secondary packaging for both transportation and storage. The packaging utilized for transportation and storage must be designed to maintain compliance with the standards set forth within ISO 11138 family of standards.
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