Below
is a list of monographs and general chapters that are new, or that have been
revised, corrected or deleted for the 9th Edition (supplement 9.2). The implementation
date is 1st July 2017.
Revised
texts
2.2.1 Clarity and degree of opalescence of liquids
General
revision to restructure the text and eliminate unnecessary repetition. The requirements
for accuracy and repeatability of the instrument have been changed.
2.6.30 Monocyte-activation test
As
a result of a survey distributed by the EDQM in 2013 to users of the Ph.Eur.,
the following improvements have been made:
Introduction:
the wording ‘very steep dose-response curves’ has been changed to ‘very steep
or non-linear dose-response curves’ as the latter better characterises the
responses when non-endotoxin contaminants are present.
Definitions:
clarification added that calculation of the maximum valid dilution (MVD) is
based on the endotoxin reference standard; the possibility of using an
estimated limit of detection (LOD) based on historical data when calculating
MVD has been introduced.
Cell
sources and qualification - Additional cross-references to sections relating to
the qualification of cells according to their origin, preparation and/or
intended use (i.e. for the detection of endotoxin and/or nonendotoxin
contaminants) have been included in sections 5-1, 5-2, 5-4, 5-5 and 5-6.
Section
5-4. Qualification of cells pooled from a number of donors: a caution statement
has been added regarding the need to consider the averaging effect when cells
are pooled.
Section
5-5. Qualification of cryo-preserved cells: the repetitive description
regarding the preparation of cell pools has been deleted.
Section
5-6. Monocytic continuous cell lines: a statement regarding the limited use of
monocytic cell lines for the detection of non-endotoxin pyrogens has been
introduced. Preparatory testing
Section
6-1. Assurance criteria for the endotoxin standard curve: numerical example
provided to illustrate the term ‘as low as possible’, which defines the blank.
Section
6-2. Test for interfering factors: text revised so that the concentration of
added endotoxin in the preparation or the diluent is to be justified and can be
estimated before starting the test. In Method C, it is stated that the type of
analysis used to compare the test and reference lots must be justified and
validated for each preparation, that assay validity criteria are to be included
and that the dilutions tested depend on the type of analysis used. In addition,
more information is given on how to test preparations with an inherently high
pyrogen content.
Section
6-3. Method validation for non-endotoxin monocyte-activating contaminants: text
revised to note that during preparatory testing, at least 2 non-endotoxin
ligands for toll-like receptors must be used to validate the test system, 1 of
which is also used to spike the test preparation, and that the choice of
non-endotoxin pyrogens used should reflect the most likely contaminant(s) of
the test preparation. In addition, more information is given regarding the
available ligands that can be used.
Methods:
Section 7-1-1. Method A, Test procedure: regarding the qualification procedure
applied to monocytes of different origin, the term ‘qualified cells’ has now
been introduced throughout the text. Changes to Table 2.6.30.-1 have been made
so that all 3 test solutions (A, B and C) are to be spiked and not just the
highest concentration. Solution D has therefore been deleted and replaced by
solutions AS, BS and CS (i.e. spiked solutions A, B and C).
Section
7-1-2. Calculation and interpretation: text reworded to reflect the changes in
Table 2.6.30.-1. In addition, the text now states that dilutions with an
invalid spike recovery are deleted from further analyses and that at least 1
valid dilution is required for a valid test.
Section
7-1-3. Pass/fail criteria of the preparation: conditions for the use of
monocytic cell lines have been deleted.
Section
7-2-1/2. Method B, Table 2.6.30.-2: text updated accordingly, as above for
Method A.
Section
7-3. Method C. Reference lot comparison test: although there is flexibility on
the type of analysis used, the analysis must be justified and validated for
each product and is to include assay validity criteria; the text has been
changed to reflect this. A statement has also been included to emphasise that
the description of the test method includes just an example of a type of
analysis which could be used.
Section
7-3-2. Calculation and interpretation: numerical example provided to show a
possible acceptance value.
Guidance notes
Section
2-1. Information regarding the choice of methods: further clarification is
given on the inappropriateness of Method A if the dose-response curve for the
preparation to be examined is not parallel to that of the standard endotoxin
curve. In addition, a notice has been added regarding the product specific
validation and capacity of the chosen method to identify
non-responders
along with low and high responders to a particular product/contaminant(s)
combination(s).
Section
2-5. Cross-validation has been added. Regarding the presence of non-endotoxin
pyrogens in the product, a recommendation to perform cross-validation of the
monocyteactivation test together with the bacterial endotoxins test has been
introduced. In the context of the 3Rs, the rabbit pyrogen test can be performed
for cross-validation purposes where the monocyte-activation test cannot be
validated.
A
new entry has been included in Table 2.6.30.-4 for ‘Parenteral formulations
administered per square metre of body surface’, in accordance with the recently
revised general chapter 5.1.10. Guidelines for using the test for bacterial
endotoxins.
It
is now specified that MAT is considered as a replacement for the rabbit pyrogen
test
5.1.1. Methods
of preparation of sterile products
This
text has undergone a general revision and has been completely rewritten. The
sections on the different sterilisation processes, where appropriate, now have
the same format: principle, equipment, sterilisation cycle, cycle effectiveness
and routine control; where required, specific information has been added.
Sterility
assurance level: the reference to exponential inactivation has been removed as
membrane filtration is not a first-order process.
Steam
sterilisation: modern concepts for validation have been added.
Dry
heat sterilisation: a wider description of the suitable equipment has been
provided.
Ionising
radiation sterilisation: the reference to European Notes for Guidance has been
removed.
Gas
sterilisation: 2 types of agents are defined: alkylating agents and oxidising
agents; the establishment of the cycle effectiveness has been described in more
detail.
Membrane
filtration: the description of the microbial challenge test has been moved to
general chapter.
5.1.2.
Biological indicators and related microbial preparations used in the
manufacture of sterile products (previously Biological indicators
of sterilization)
Aseptic
assembly: freeze-drying under aseptic conditions is added.
The
general chapter has undergone significant revision as listed below.
Title:
it has been adapted to take into account microbial preparations used for
sterilization grade filtration.
Introduction:
describes when biological indicators (BIs) are intended to be used and what is
outside the scope of the general chapter, including that BIs are in most cases
only to be used for development of the sterilisation process and are not to be
employed for routine monitoring unless otherwise stated in this general
chapter. A definition of BIs is given and the processes in which they can be
used are described. Importantly, the Introduction section introduces the
concept of the use of reduced sterilisation process conditions in order to
ensure the validity of the sterilisation process. It is also made clear that
there should be no surviving microorganisms when the biological indicator is
subject to a full sterilisation process.
BIs
for sterilisation processes: this section gives guidance on how BIs are
selected and how they are used to characterise sterilisation processes.
A
description is provided of 4 types of BIs for sterilisation processes:
inoculated carriers, self-contained BIs, characterised spore suspensions and
custom-made BIs.
Information
regarding the quality requirements for BIs and user requirement specifications
have been introduced.
BIs
for heat sterilisation: the parameters of BIs for heat sterilisation are
described and how a validation cycle is established. Further information on
biological validation with reduced sterilisation cycles has been included.
BIs
for moist heat sterilisation: it is recognised that Geobacillus
stearothermophilus may not be suitable for sterilisation processes delivering
an F0 between 8 and 15, therefore a different test micro-organism may be used.
BIs
for dry heat sterilisation: description of the reference conditions and an
example of how survivor rates of typical BIs are affected by temperature
variations are given.
BIs
for gas sterilisation: this section sets out that the use of gas sterilisation
for disinfection is outside the scope of the general chapter. There are a
number of different types of gas sterilisation processes and no reference
cycles, therefore no criteria to which the BIs shall comply have been defined.
Suitable micro-organisms for ethylene oxide sterilisation are given. It is,
however, the responsibility of the user to define the cycle and the suitability
of any BI used.
BIs
for ionising radiation sterilisation: it is recognised that BIs are not
considered to be necessary for defining the suitability of the radiation
sterilising dose, but their use may be required for the development and
validation of ionising radiation sterilisation in specific cases. Information
on test micro-organisms is given.
Microbial
preparations for sterilisation grade filtration: information on test microorganisms
is now given for the validation of retention of micro-organisms using a
membrane.
Posted by Dr. Tim Sandle
