Foreword
Introduction
1 Scope
2 Normative references
3 Abbreviations, terms and definitions
3.1 Abbreviations
3.2 Terms
4 Definition and maintenance of product families
for dose setting, dose substantiation and
sterilization dose auditing
4.1 General
4.2 Defining product families
4.3 Designation of product to represent a
product family for performance of a verification
dose experiment or sterilization dose audit
4.3.1 Product to represent a product family
4.3.2 Master product
4.3.3 Equivalent product
4.3.4 Simulated product
4.4 Maintaining product families
4.4.1 Periodic review
4.4.2 Modification to product and/or manufacturing
process
4.4.3 Records
4.5 Effect of failure of establishment of sterilization
dose or of a sterilization dose audit on product family
5 Selection and testing of product for establishing
the sterilization dose
5.1 Nature of product
5.2 Sample item portion (SIP)
5.3 Manner of sampling
5.4 Microbiological testing
5.5 Irradiation
6 Methods of dose establishment
7 Method 1: dose setting using bioburden information
7.1 Rationale
7.2 Procedure for Method 1 for product with an
average bioburden greater than or equal
to 1,0 for multiple production batches
7.2.1 General
7.2.2 Stage 1: Select SAL and obtain samples of
product
7.2.3 Stage 2: Determine average bioburden
7.2.4 Stage 3: Obtain verification dose
7.2.5 Stage 4: Perform verification dose experiment
7.2.6 Stage 5: Interpretation of results
7.2.7 Stage 6: Establish sterilization dose
7.3 Procedure for Method 1 for product with an average
bioburden greater than or equal to 1,0 for a single
production batch
7.3.1 Rationale
7.3.2 General
7.3.3 Stage 1: Select SAL and obtain samples of
product
7.3.4 Stage 2: Determine average bioburden
7.3.5 Stage 3: Obtain verification dose
7.3.6 Stage 4: Perform verification dose experiment
7.3.7 Stage 5: Interpretation of results
7.3.8 Stage 6: Establish sterilization dose
7.4 Procedure for Method 1 for product with an average
bioburden in the range 0,1 to 0,9 for multiple or
single production batches
8 Method 2: Dose setting using fraction positive information
from incremental dosing to determine an extrapolation factor
8.1 Rationale
8.2 Procedure for Method 2A
8.2.1 General
8.2.2 Stage 1: Select SAL and obtain samples of product
8.2.3 Stage 2: Perform incremental dose experiment
8.2.4 Stage 3: Perform verification dose experiment
8.2.5 Stage 4: Consideration of results
8.2.6 Stage 5: Establish sterilization dose
8.3 Procedure for Method 2B
8.3.1 General
8.3.2 Stage 1: Select SAL and obtain samples of product
8.3.3 Stage 2: Perform incremental dose experiment
8.3.4 Stage 3: Perform verification dose experiment
8.3.5 Stage 4: Consideration of results
8.3.6 Stage 5: Establish sterilization dose
9 Method VD[max] - Substantiation of 25 kGy or 15 kGy as
the sterilization dose
9.1 Rationale
9.2 Procedure for Method VD[max][25] for multiple production
batches
9.2.1 General
9.2.2 Stage 1: Obtain samples of product
9.2.3 Stage 2: Determine average bioburden
9.2.4 Stage 3: Obtain VD[max][25]
9.2.5 Stage 4: Perform verification dose experiment
9.2.6 Stage 5: Interpretation of results
9.2.7 Confirmatory verification dose experiment
9.3 Procedure for Method VD[max][25] for a single
production batch
9.3.1 Rationale
9.3.2 General
9.3.3 Stage 1: Obtain samples of product
9.3.4 Stage 2: Determine average bioburden
9.3.5 Stage 3: Obtain VD[max][25]
9.3.6 Stage 4: Perform verification dose experiment
9.3.7 Stage 5: Interpretation of results
9.3.8 Confirmatory verification dose experiment
9.4 Procedure for Method VD[max][15] for multiple
production batches
9.4.1 General
9.4.2 Stage 1: Obtain samples of product
9.4.3 Stage 2: Determine average bioburden
9.4.4 Stage 3: Obtain VD[max][15]
9.4.5 Stage 4: Perform verification dose experiment
9.4.6 Stage 5: Interpretation of results
9.4.7 Confirmatory verification dose experiment
9.5 Procedure for Method VD[max][15] for a single
production batch
9.5.1 Rationale
9.5.2 General
9.5.3 Stage 1: Obtain samples of product
9.5.4 Stage 2: Determine average bioburden
9.5.5 Stage 3: Obtain VD[max][15]
9.5.6 Stage 4: Perform verification dose experiment
9.5.7 Stage 5: Interpretation of results
9.5.8 Confirmatory verification dose experiment
10 Auditing sterilization dose
10.1 Purpose and frequency
10.2 Procedure for auditing a sterilization dose
established using Method 1 or Method 2
10.2.1 General
10.2.2 Stage 1: Obtain samples of product
10.2.3 Stage 2: Determine average bioburden
10.2.4 Stage 3: Perform verification dose experiment
10.2.5 Stage 4: Interpretation of results
10.2.6 Augmentation of a sterilization dose established
using Method 1, Method 2A or Method 2B
10.3 Procedure for auditing a sterilization dose
substantiated using Method VD[max][25] or VD[max][15]
10.3.1 General
10.3.2 Stage 1: Obtain samples of product
10.3.3 Stage 2: Determine average bioburden
10.3.4 Stage 3: Perform verification dose experiment
10.3.5 Stage 4: Interpretation of results
10.3.6 Confirmatory sterilization dose audit
10.3.7 Augmentation of a sterilization dose
substantiated using Method VD[max][25] or
VD[max][15]
10.4 Failure of the sterilization dose audit
11 Worked examples
11.1 Worked examples for Method 1
11.2 Worked examples for Method 2
11.2.1 General
11.2.2 Worked example for Method 2A (SIP equal
to 1,0)
11.2.3 Worked example for Method 2A (SIP less
than 1,0)
11.2.4 Worked example for Method 2B
11.3 Worked examples for Method VD[max]
11.4 Worked example of a sterilization dose audit for a
dose established using Method 1, the findings from
which necessitated augmentation of the sterilization
dose
11.5 Worked example of a sterilization dose audit for a dose
established using Method 2A, the findings from which
necessitated augmentation of the sterilization dose
11.6 Worked example of a sterilization dose audit for
a sterilization dose substantiated using Method
VD[max][25]
Annex ZA (informative) - Relationship between this International
Standard and the Essential Requirements of EU
Directive 93/42/EEC and 90/385/EEC
Bibliography