Medical Device Link.

REGULATION AND STANDARDS

Reason for the revision

The first European standards for sterilisation were published in 1994 and the first international standards in 1994 and 1995 (Table I). These European standards are harmonised and give a presumption of conformity with the European medical device Directives. The international standards have been adopted as a United States (US) standard and recognised by the Food and Drug Administration. The 1994 and 1995 European and international standards are technically equivalent and entirely compatible, but they are editorially different. This has meant added complexity for manufacturers and sterilisation contractors who need to meet US and European requirements to market medical devices in both jurisdictions.

Table I: Comparison of previous European and international standards for the principal methods of sterilisation. (click image to enlarge)

Under the normal practice of standards organisations, standards are reviewed after five years. It was agreed in 1999 that a joint revision should be prepared under the leadership of the International Organisation for Standardisation (ISO). This process is coming to an end and revised standards are now being published.

The revised standards will simplify the compliance requirements for manufacturers supplying multiple geographical markets. The radiation and moist heat standards are published; the ethylene oxide (EtO) standard is expected be published in the second quarter of 2007. They are available as national adoptions of the European standards from national standards bodies in all the European countries. For the moist heat standards it has been agreed to have an extended withdrawal period, thus both the new and older standards will remain in force for three years.

Numbering

Because the lead for the revision process was taken by ISO Technical Committee (TC) 198, the ISO numbering system was applied; the standards will ultimately be dual numbered as European standards with an EN ISO prefix. The standards for EtO and radiation sterilisation retain the original ISO numbers of 11135 and 11137, respectively. The new standard for moist heat sterilisation is applicable to industry and health care and has a new number: ISO 17665.

Structure of the revised standards

The review and revision of the sterilisation standards were undertaken in parallel. It was decided at the beginning of the revision process that the structure of the standards for the three methods of sterilisation should be the same. It was also agreed that the same definitions should apply where the same term is used in the three process standards.

Based on these early decisions, the title of the documents giving requirements and guidance was agreed to be: Sterilisation of Health Care Products, Ethylene Oxide/Radiation/Moist Heat, Part 1: Requirements for the Development, Validation and Routine Control of a Sterilisation Process for Medical Devices. The main clauses of the standards are set out in Table II. The changes in each of the revised sterilisation standards are outlined below.

Table II: The Clauses of the revised international sterilisation standards and the aspects they cover. (click image to enlarge)

ISO 11135-1.2, Sterilisation of Health Care Products, Ethylene Oxide

This standard has been published as a Final Draft International Standard (FDIS) for comment and voting by ISO member bodies. FDIS status means that no further technical changes are expected to be made to this document. So that ISO TC 198 Working Group (WG) 1 would meet ISO publishing deadlines, it was decided to limit the informative guidance contained in the standard to only that which is necessary to clarify a normative requirement. In addition, a Technical Specification (TS) is being produced, which will provide comprehensive guidance on the application of the standard and general guidance on EtO sterilisation of medical devices. It is intended to provide guidance for users in industry and health-care facilities. The TS has been issued as preliminary draft (PD) ISO PDTS 11135, Part 2, with the aim of publication as soon as possible after ISO11135-1 is published, which is expected during the third quarter of 2007.

Important changes

There are many new or changing requirements and guidance in the revised the standard. Some of these new requirements reflect what is common practice in the industry today.

Environmental consideration. There are new requirements to assess the impact of the sterilisation process on the environment. Protective measures must be identified to ensure that emissions of toxic EtO are treated in an appropriate way to meet local and national regulations.

Microbiological quality. It is now a requirement to define systems to ensure the microbiological quality and cleanliness of the products presented for sterilisation and to estimate bioburden at defined intervals, in accordance with ISO11737-1, Sterilisation of Medical Devices, Microbiological Methods, Part 1, Determination of the Population of Microorganisms on Products.

Use of A research steriliser. Process definition activities can be performed in a research steriliser or the production steriliser. However, if process definition is performed in a research steriliser, at least three microbiological performance qualification cycles must be performed in the production steriliser to confirm the data from the developmental chamber.

The biological indicator. It is a requirement to demonstrate that the biological indicator (BI) is at least as resistant as the bioburden of the product to be sterilised to ensure the BI provides a valid challenge to the process. If tests of sterility for product are used to demonstrate compliance with this requirement, the performance of the test must comply with ISO11737-2, Sterilisation of Medical Devices, Microbiological Methods, Tests of Sterility Performed in the Validation of a Sterilisation Process.

Microbiological performance qualification. It is recognised that reduced microbiological performance qualification (MPQ) may be permitted for equivalent sterilisers. If this approach is implemented, a rationale must be documented.

Physical performance qualification. It is a new requirement to perform three consecutive physical performance qualification (PPQ) runs. However, some of these may be performed in parallel with MPQ, providing at least one PPQ run is performed at the full routine process specification. In addition, the recommended number of temperature and relative humidity sensors have been revised to take account of the use of both small- and large-scale sterilisers.

Validation parametric release. Parametric release may now be validated using the half cycle approach without the need for survivor curve (Method A) or Fraction Negative (Method B) as required in the 1994 version of the standard.

Routine monitoring. There is no requirement to measure load temper-ature in routine sterilisation using parametric release.

Product release. If saleable product is to be used in validation activities, the requirements for its release for distribution must be defined before the validation activities commence.

Requalification. There are new requirements to requalify periodically to verify the appropriateness of the BI and the loading patterns of the product for sterilisation.

Determining process lethality. Two approaches are defined in the standard:

• I Bioburden/BI approach. This is based on understanding the relative rates of deactivation for the BI and the bioburden and requires one of three methods to be used for process definition:
  
• Ia – Direct enumeration (existing Method A): minimum five exposures, that is, one with no treatment, one with treatment to reduce initial BI population to less than 0.01% of original population and three exposures during those treatment times.


• Ib – Fraction negative using Holcomb- Spearman Karber procedure (existing Method B): minimum seven expo-sures, that is, one all BIs positive, four where fraction BIs show growth, two all BIs negative.


• Ic – Fraction negative using Stumbo Murphy Cochran procedure: Minimum four exposures, all where fraction of BIs show growth.

• II Conservative (overkill approach). This method often delivers a process that significantly exceeds the treatment necessary to achieve the required product sterility assurance level. Process Definition can be performed as follows:
  
  • IIa – Half cycle approach: minimum four exposures, that is, three with all BIs negative, one with reduced treatment time to show BI growth,
  
  
  • IIb – Using any of the methods in Ia, Ib or Ic.
    

ISO 11137, Sterilisation of Health Care Products, Radiation

This standard is divided into three parts:

• Part 1: Requirements for development, validation and routine control of a sterilisation process for medical devices. This part is normative and contains an annex, which is informative and provides guidance on the application of each clause in Part 1, where guidance is available.


• Part 2: Establishing the sterilisation dose. If a decision is made to follow the methods detailed in Part 2, then the methods must be followed in their entirety.


• Part 3: Guidance on dosimetric aspects. This part is informative and contains guidance on the application of dosimetry to the validation and routine control of sterilisation of health-care products using radiation.

The new standard was published in April 2006. However, Part 2 had to be republished to correct errors introduced by the ISO editors. It has been published as a European standard.

Important changes

The main changes are to the requirements detailed in Part 1.

Environmental considerations.This is a new requirement to assess the potential effect on the environment of the operation of the radiation sterilisation process and measures to protect the environment must be identified.

Maximum dose. There is more emphasis on the establishment of the maximum acceptable dose. When treated with the maximum dose, product must meet its specified functional requirements throughout its defined lifetime. It is suggested a test programme be designed to assess variations in raw materials, manufacturing processes, radiation dose, type of radiation and storage conditions after irradiation. The programme should include assessment of functionality and safety, including biological safety using appropriate tests with specific acceptance criteria.

Transfer of dose. There is more emphasis and greater clarity on the transference of maximum acceptable verification or sterilisation dose between radiation sources. The transfer of maximum acceptable dose is permitted if an assessment is performed to demonstrate that the differences in irradiation conditions of the two radiation sources do not affect the validity of the dose. This assessment must be documented and the outcome recorded. The transfer of verification or sterilisation dose is permitted if data are available to demonstrate that differences in operating conditions of the two radiation sources have no effect on microbial effectiveness. If data are not available then a distinction is made between product containing water in the liquid state and products that do not. Transfer of verification and sterilisation dose for product that does not contain water is permitted between:

• one gamma irradiator and another gamma irradiator


• one electron beam generator and another electron beam generator


• one X-ray generator and another X-ray generator.

• one gamma irradiator and another gamma irradiator


• two electron sources operating under identical operating conditions


• two X-ray radiation sources operating under identical operating conditions.

Product definition. There is more emphasis on product definition. Products to be sterilised, including packaging, must be specified. A system must be implemented to ensure the product presented for sterilisation, including its bioburden, is controlled so that the effectiveness of the sterilisation process is not compromised. Products can be divided into families for establishing the dose and categories for the purpose of routine processing. These categories must be subject to periodic review and the review recorded.

Validation. The validation process is now divided into three stages: Installation qualification (IQ), Operational qualification (OQ) and Performance qualification (PQ).

Maintenance of process effectiveness. This is a new clause that includes bioburden determination and sterilisation dose audits. There is a need to demonstrate the continued effectiveness of the sterilisation process. This can be achieved by

a) Determinations of bioburden to monitor the number of microorganisms present on product against an established specification
b) Sterilisation dose audits to monitor radiation resistance of the bioburden on product.

The interval of time between bioburden determination is generally a maximum of three months. However, if the average bioburden is < 1.5 microorganisms per product unit and the sterilisation dose has been set using Method 1 or a sterilisation of 15 kGy is selected, then the maximum interval must be one month. If the interval of time between manufacture of each batch is greater than the maximum permissible interval then determination of bioburden on each production batch must be performed. One of two approaches may be taken to determine the interval of time between the performance of dose audits.

a) Select an interval of three months between dose audits.
b) Prepare and document a rationale for the selection of the intervals of time.

An increase in the time interval between dose audits can only be permitted if

• at least four consecutive dose audits are successful
• data are available to demonstrate the stability of bioburden within the bioburden specification over the same period of time
• the manufacture of the product in relation to bioburden is controlled and effectiveness is demonstrated by the implementation of ISO 13485:2003 Medical devices, Quality Management Systems.

The maximum intervals of time between determinations of bioburden shall be three months and performance of sterilisation dose audits shall be 12 months.

This clause of the new standard also covers recalibration, maintenance of equipment, re-qualification of equipment and assessment of change.

Changes to Part 2

The main methods set out in Part 2, Establishing the Sterilisation Dose for Radiation Sterilisation, have remained unchanged. However, the table associated with Method 1 is different. It now starts at 0.1 average bioburden per product unit. The values of bioburden have been rounded to give whole numbers. This has resulted in a small change in dose values for sterility assurance level (SAL) 10^-2 and SAL 10^-6.

The main change in Part 2 is the addition of VD_max for the substantiation of 15 kGy and 25 kGy. The maximum average bioburden permissible for the application of VD_max is as follows:

• VD_max 15 5 1.5 microorganisms per unit product
• VD_max 25 5 1000 microorganisms per unit product.

Both VD_max methods substantiate at a SAL of 10^-6 and the verification dose is set at SAL 10^-1.

The method of dose augmentation if a dose audit fails has changed. It is now an extrapolation method, which is linked to the number of audit failures and is applicable to Method 1, Method 2A and 2B.

Changes to Part 3

Part 3, Guidance on Dosimetric Aspects, contains useful information on the dosimetric aspects of IQ, OQ and PQ. It also covers the selection and calibration of dosimetry systems and the role of dosimeters in routine monitoring and control. There is an annex to Part 3 that provides an introduction to the application of modelling to design and operation of irradiators, utilising point kernel and Monte Carlo methodology.

ISO 17665, Sterilisation of Health Care Products, Moist Heat

This standard is divided into two parts:

• Part 1 covers requirements with minimal guidance only.
• Part 2 provides extensive guidance on how to implement each section in the individual fields of application with suggested limiting values and tolerances for process variables.

These two documents form a framework onto which each region or country can, if needed, formulate more detailed guidance for specific areas of application. The publication of ISO 17665 consolidates the basic principles outlined in the previous moist heat standards. The new standard covers requirements for the development, validation and routine control of moist heat sterilisation processes for medical devices, including saturated steam venting systems, saturated steam active air removal systems, air steam mixtures, and water spray and water immersion systems used by industry and in health care.

ISO 17665-1 is already published. ISO 17665-2 is currently being processed by ISO. Because this document is a technical specification rather than a standard, the number of public comment stages is reduced and publication could occur without the FDIS stage.

Important changes

Limiting values and tolerances.

The new standard rarely specifies limiting values or tolerances for the process variables. This is because of the regional differences in practice and in regulatory requirements. Guidance on limiting values and tolerances is given in Part 2, but more specific detail may need to be developed on a country or regional level.

Sterilising agent characterisation. Many comments on the draft standard requested deletion of this section arguing that it was redundant for moist heat. However, to maintain a common format it was retained, but states that only if unusual process parameters are employed, is it necessary to conduct microbicidal effectiveness studies.

Physical and biological monitoring approach. The new standard recognises that some areas of application commonly employ biological indicators as an integral part of process evaluation. Therefore, it discusses their use in various sections, including process equipment and characterisation, process definition, validation and routine monitoring and control, together with annexes detailing specifics. When biological indicators are used they should conform to ISO 11138, Sterilisation of Health Care Products, Biological Indicators, Parts 1 and 3.

Use of product families. The new standard recognises that in some application areas, it is common to use inhomogeneous load configurations. To reduce the amount of PQ testing, the concept of product families is referenced. As new devices requiring sterilisation are introduced, an assessment is made of their sterilisability. Having identified essential characteristics, the user is required to fit the new device into a similar family of devices, whose characteristics are well understood and for which processes are defined.

Retained tests. The new standard retains the need for air removal and steam penetration tests when required, that is, in saturated steam processes where air removal is essential before steam penetration can take place. Steam quality is discussed, but limiting values and test methods are covered in Part 2.

Process challenge devices. The concept of process challenge devices (PCD) is introduced. These are devices that are used to challenge a specific element of the sterilisation process and represent a worst case. If used, the design of the PCD must reflect the design attributes of the product and its use validated.

Overall conclusion

After a revision process that has taken seven years, revised standards for the validation and routine control of sterilisation by the principal sterilisation methods are being published. These revised standards represent a significant step forward in consolidating previously separate international and European standards into single, globally applicable documents. This will benefit manufacturers of medical devices, particularly those that supply products internationally.

The intention was not to raise the regulatory bar during the revision process and there are some changes in the standards that offer opportunities for manufacturers. There is a recognition of advances in validation and routine control since the original standards were published in 1994. In particular, the increased recognition of parametric release in EtO sterilisation and the expansion of methods of establishing the sterilisation dose in radiation sterilisation represent improvements over the previous editions.

Eamonn Hoxey is Executive Director EMEA at Johnson & Johnson Quality & Compliance Worldwide, Atrium Court, The Ring, Bracknell RG12 1BW, UK , e-mail: ehoxey@medgb.jnj.com, www.jnj.com

Peter Strain is Vice President Technology, Sterigenics UK Ltd, Cotes Park Estate, Somercotes, DE55 4NJ, UK, tel. +44 1773 543 200, e-mail: pstrain@eu.sterigenics.com, www.sterigenics.com

John Harries is Corporate Quality Manager at Isotron plc, Group Head Office, Ground Floor Stella, Windmill Business Park, Swindon SN5 6NX, UK, tel. +44 1793 891 891, e-mail john.harries@isotron.com, www.isotron.com

Dr Brian Kirk is Senior Technical Services Specialist (Sterilisation), 3M Health Care, 1 Morley Street, Loughborough LE11 1EP, UK, www.3mhealthcare.co.uk