The European Agency for the Evaluation of Medicinal Products
Evaluation of Medicines for Human Use
London, 5 April 2000
CPMP/QWP/054/98 Corr
COMMITTEE FOR PROPRIETARY MEDICINAL PRODUCTS
(CPMP)
DECISION TREES FOR THE SELECTION OF
STERILISATION METHODS (CPMP/QWP/054/98)
ANNEX TO NOTE FOR GUIDANCE ON DEVELOPMENT
PHARMACEUTICS (CPMP/QWP/155/96)
DISCUSSION IN THE QUALITY WORKING PARTY October 1997
January 1998
TRANSMISSION TO THE CPMP January 1998
RELEASE FOR CONSULTATION January 1998
DEADLINE FOR COMMENTS July 1998
ADOPTION BY CPMP February 1999
DATE FOR COMING INTO OPERATION August 1999
Background:
These decision trees are intended to assist in the selection of the optimal sterilisation
method and are proposed for inclusion as an annex to the Note for Guidance on
Development Pharmaceutics. Reference is made to these Decision Trees in Section 5
(“Manufacturing Process”) of the Note for Guidance.
Minor modifications/corrections made in April 2000 to clarify titles of Decision trees and use
of term product / formulation as appropriate.
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ãEMEA 2000 Reproduction and/or distribution of this document is authorised for non commercial purposes only provided the EMEA is acknowledged
DECISION TREES FOR THE SELECTION OF
STERILISATION METHODS
(ANNEX TO NOTE FOR GUIDANCE ON DEVELOPMENT PHARMACEUTICS)
INTRODUCTION
Those products intended to be sterile should be terminally sterilised in their final container as
clearly stated in the European Pharmacopoeia, and in the CPMP Notes for Guidance. Where it
is not possible to carry out terminal sterilisation by heating due to formulation instability, a
decision should be taken to utilise an alternative method of terminal sterilisation, filtration
and/or aseptic processing. It is recognised that new terminal sterilisation processes other than
those described in the pharmacopoeia may be developed to provide sterility assurance levels
equivalent to present official methods, and such processes when properly validated may offer
alternative approaches.
When moving down the decision trees it is clear that these methods generally show decreasing
levels of sterility assurance, and it is therefore essential for product quality and safety to
ensure that the highest level of sterility assurance is achieved in conjunction with the lowest
level of pre-sterilisation bioburden appropriate. These decision trees are intended to assist in
the selection of the optimal sterilisation method taking into account the various complicating
factors. (A similar approach should be considered in the selection of sterilisation methods for
intermediates to be incorporated into the finished product using aseptic processing).
The use of an inappropriate heat-labile packaging material cannot in itself be the sole reason
for adoption of aseptic processing. Rather manufacturers should choose the best sterilisation
method achievable for a given formulation and select the packaging material accordingly.
However, it may be that the choice of a packaging material for a given product has to take into
account factors other than the method of sterilisation. In such cases these other factors need to
be clearly documented, explained and scientifically justified in the MA dossier.
Conventionally, it has been accepted that other factors such as the type of container, route of
administration and patient benefit have contributed to the choice of a particular container type,
which will not withstand terminal heat sterilisation (e.g. certain ophthalmic products) and
such products are therefore manufactured by validated aseptic processing. In such cases
manufacturers have a duty to continue the search for acceptable alternative containers which
would allow the move to the preferred terminal sterilisation in an acceptable timeframe.
Commercial considerations should not be used as justification for not using terminal
sterilisation with the highest possible level of sterility assurance.
CPMP/QWP/054/98 corr. 1/3
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DECISION TREE FOR STERILISATION CHOICES
FOR AQUEOUS PRODUCTS
Can the product be sterilised by
moist heat at 121°C for 15 minutes
NO YES
Can the product be sterilised by moist heat Use autoclaving at
with Fo ≥ 8 minutes achieving SAL of ≤10-6 121 °C for 15 minutes
YES
NO
Can the formulation be Use moist heat
filtered through a with Fo ≥ 8 minutes
microbial retentive filter
YES
NO
Use pre-sterilised individual Use a combination of
components and aseptic aseptic filtration and
compounding and filling. aseptic processing
CPMP/QWP/054/98 corr. 2/3
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DECISION TREE FOR STERILISATION CHOICES
FOR NON-AQUEOUS LIQUID, SEMI-SOLID OR DRY POWDER PRODUCTS
Can the product be sterilised by dry heat
at 160°C for 120 minutes?
NO YES
Can the product be sterilised by dry heat
with an alternative combination of time and Use sterilisation at
temperature to the standard cycle achieving 160 °C for 120 minutes
an SAL of ≤ 10-6?
YES
NO
Use dry heat with alternative
Can the product be sterilised by a method different from
combination of time and
dry heat e.g. ionising radiation with an absorbed
temperature to the standard cycle
minimum dose of ≥ 25 KGy?
achieving an SAL of ≤10-6
YES
NO
Can the product be sterilised using a validated Use sterilisation with an absorbed
lower irradiation dose (ref ISO 11137) minimum dose of
≥ 25 KGy
YES
NO
Can the formulation be filtered through Use sterilisation by
a microbial retentive filter validated irradiation dose.
YES
NO
Use pre-sterilised individual components Use filtration and
and aseptic compounding and filling aseptic processing
CPMP/QWP/054/98 corr. 3/3
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