Foreword
Introduction
1 Scope
2 Normative references
3 Terms and definitions
4 Requirements
4.1 General
4.2 Categorization of devices
4.3 Allowable limits
4.3.1 Permanent contact devices
4.3.2 Prolonged exposure devices
4.3.3 Limited exposure devices
4.3.4 Tolerable contact limits for EO for surface
contacting devices and implants
4.3.5 Special situations
4.4 Determination of EO and ECH residuals
4.4.1 General
4.4.2 Determination of residue
4.4.3 Product sampling and sample "blank"
4.4.4 Sample/fluid ratios
4.4.5 Extraction time and conditions
4.4.6 Product extraction
4.4.7 Data analysis and interpretation
5 Product release
5.1 Release of products without dissipation curve data
5.2 Procedure for product release using residue dissipation
curves
Annex A (normative) Evaluation of gas chromatograms
A.1 General
A.2 Background
A.3 Symbols and abbreviated terms
A.4 Minimum requirements
A.5 Chromatographic baseline
A.6 Resources
Annex B (informative) Gas chromatographic determination for
EO and ECH
B.1 Chromatographic procedures
B.1.1 Preparation of standards
B.1.2 General
B.2 Criteria for validating gas chromatographic methods
B.2.1 Accuracy
B.2.2 Precision
B.2.3 Linearity
B.2.4 Method detection limit (MDL)
B.2.5 Quantitation limit (QL)
Annex C (informative) Flowchart and guidance for the application
of this part of the ISO 10993-series of
standards to the determination of EO
residuals in medical devices
C.1 Background
C.2 Guidance
C.3 Simulated-use extraction procedure
C.3.1 Extraction fluid
C.3.2 Extraction temperature
C.3.3 Extraction time
C.3.4 Extraction of device
C.3.5 Grouping of devices
C.3.6 Device kits and trays
Annex D (informative) Factors influencing product residual
D.1 Sterilization process parameters
D.1.1 Material composition
D.1.2 Packaging
D.1.3 Ethylene oxide sterilization cycle
D.1.4 Aeration
D.1.5 Sample retrieval
D.2 Controlling variables
Annex E (informative) Extraction conditions for determination
of residual EO
Annex F (informative) Rationale for the provision of this
International Standard
F.1 General
F.2 Rationale for special situations
F.2.1 General
F.2.2 Intraocular lens limits
F.2.3 Blood cell separators used in donor or patient
blood collection
F.2.4 Blood oxygenators and blood separators
F.2.5 Devices used in cardiopulmonary bypass procedures
F.2.6 Extra corporeal blood purification devices
F.3 Rationale for 4,4 Determination of EO and ECH residuals
F.3.1 Product extraction
F.3.2 Analytical methods
F.3.3 Rationale for 4.4.1.7, Data analysis and
interpretation
Annex G (informative) Establishment of allowable limits for EO
G.1 General
G.2 Introduction
G.3 Methods
G.3.1 Route-to-route extrapolation of dose
G.3.2 Noncancer risk assessment approach
G.3.3 Cancer risk assessment approach
G.3.4 Effects not considered in deriving TI values
for EO
G.4 Noncancer-based TI values for EO
G.4.1 Selection of critical studies
G.4.2 Selection of uncertainty factors for noncancer
effects
G.4.3 Derivation of noncancer TI values for EO
G.5 Cancer-based TI values for EO
G.5.1 Approach 1: Linear extrapolation from human data
G.5.2 Approach 2: Linear extrapolation from animal data
G.5.3 Approach 3: Uncertainty factor approach
G.5.4 Approach 4: Linear dose-response modeling of human
data
G.5.5 Comparison of cancer-based TI value
G.5.6 Comparison of cancer-based TI values for EO
G.6 Calculation of Tolerable Exposure (TE) levels
G.6.1 Limited exposure TE
G.6.2 Prolonged exposure TE
G.6.3 Permanent exposure TE
G.6.4 Calculation of Tolerable Contact Level (TCL)
G.7 Calculation of allowable limits
G.8 Calculation of device limits
G.8.1 Limited contact devices
G.8.2 Prolonged contact devices
G.8.3 Permanent contact devices
G.8.4 Limit based on TCL value
Annex H (informative) Establishment of allowable limits
for ECH
H.1 General
H.2 Introduction
H.3 Methods
H.3.1 Route-to-route extrapolation of dose
H.3.2 Non-cancer risk assessment approach
H.3.3 Cancer risk assessment approach
H.3.4 Effects not considered in deriving TI valued for
ECH
H.4 Non-cancer based TI values for ECH
H.4.1 Selection of critical studies
H.4.2 Selection of uncertainty factors for noncancer
effects
H.5 Calculation of Tolerable Contact Level (TCL)
Annex I (informative) Establishments of Allowable Limits for
EG
I.1 Background
I.2 General considerations
I.2.1 Limited exposure
I.2.2 Prolonged exposure
I.2.3 Permanent exposure
I.2.4 Tolerable Contact Level (TCL)
Annex J (informative) Preparation of EO and ECH standards
J.1 Preparation of EO standards
J.1.1 EO standard dilutions for headspace methods
J.1.2 EO standard dilutions for solvent methods
J.2 Preparation of ECH standards
Annex K (informative) Ethylene oxide residue measuring methods
K.1 Results of interlaboratory evaluation of methods
K.1.1 EO methods
K.1.2 ECH methods
K.2 Apparatus and reagents
K.2.1 Apparatus
K.2.2 Reagents
K.3 Standard preparation
K.3.1 Preparation of ethylene oxide standards
K.3.2 Preparation of ethylene chlorohydrin standards
K.3.3 Preparation of propylene oxide (PO) standards
K.4 Product extraction
K.4.1 General
K.4.2 Extraction to simulate product use
K.4.3 Exhaustive procedure using thermal extraction
K.4.4 Exhaustive extraction with ethanol followed by
headspace gas analysis of the ethanol extract
K.4.5 Exhaustive extraction with solvent
K.4.6 Exhaustive extraction with ethanol followed
by preparation of the bromohydrin derivative
and chromatography using a gas chromatograph
equipped with an ECD
K.4.7 Simulated use extraction for ethylene chlorohydrin
using water
K.4.8 Exhaustive extraction for ethylene chlorohydrin
using water
K.5 Gas chromatography
K.5.1 General
K.5.2 Extraction to simulate product use for the
determination of EO or ECH
K.5.3 Exhaustive procedure using thermal extraction
K.5.4 Exhaustive extraction with ethanol followed by
headspace gas analysis of the ethanol extract
K.5.5 Exhaustive extraction with ethanol followed
by preparation of the bromohydrin derivative
and chromatography using a gas chromatograph
equipped with an ECD
Bibliography