Guideline On Stability Testing For Applications For Variations To A Marketing Authorisation
Guideline On Stability Testing For Applications For Variations To A Marketing Authorisation
Guideline On Stability Testing For Applications For Variations To A Marketing Authorisation
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13 July 2011
EMA/CHMP/CVMP/QWP/441071/2011
Committee for Medicinal Products for Human Use (CHMP)/ Committee for Medicinal Products for Veterinary
Use (CVMP)
Draft
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Draft Agreed by Quality Working Party
June 2011
June 2011
July 2011
31 January 2012
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This guideline replaces Guideline on Stability Testing for Applications for Variations to a Marketing
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Comments should be provided using this template. The completed comments form should be sent to
[email protected]
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Keywords
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European Medicines Agency, 2011. Reproduction is authorised provided the source is acknowledged.
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Table of contents
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1. Introduction (background)...................................................................... 3
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2. Scope....................................................................................................... 3
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7. Commitment batches............................................................................... 7
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References .................................................................................................. 7
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Annex I ....................................................................................................... 8
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Annex II ...................................................................................................... 8
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Executive summary
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The following guideline provides guidance on the stability data which have to be generated in order to
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support a variation to a Marketing Authorisation. The guideline provides general guidance on stability
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testing in case of type I (A and B) variations and addresses the data requirements for widely
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1. Introduction (background)
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The following guideline sets out the stability testing requirements for variations to a Marketing
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Authorisation after approval. This guideline is an extension of the CHMP and CVMP Guidelines on
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Stability Testing of Existing Active Substances and Related Finished Products and the respective
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ICH/VICH Guidelines for New Active Substances and Drug Products. It is intended to be applied in the
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European Union.
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The guideline seeks to exemplify the stability data required for variations to active substances and/or
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finished products. It is not always necessary to follow this when there are scientifically justifiable
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The guideline provides a general indication on the requirement for stability testing, but leaves sufficient
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flexibility to encompass the variety of different practical situations required for specific scientific
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2. Scope
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The purpose of this guideline is to outline the stability data which have to be generated in case of
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variations. It is applicable to chemical active substances and related finished products, herbal drugs,
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herbal drug preparations and related herbal medicinal products, however not to radiopharmaceuticals,
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Variations for active substances and finished products encompass a wide range of situations. The
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Guideline provides general guidance on stability testing in case of type I (A and B) variations,
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furthermore, it addresses the information required for active substances and/or finished products in
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3. Legal basis
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This guideline has to be read in conjunction with Regulation No 1234/2008 and the introduction and
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general principles (4) and annex I to Directives 2001/82 and 2001/83 as amended.
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4. General requirements
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In cases of variations which require generation of stability data on the finished product, the stability
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studies required, including commitment batches, should always be continued up to the approved shelf-
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life and the authorities should be informed immediately if any problems with the stability appear during
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The scope and design of the stability studies for variations and changes are based on the knowledge
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and experience acquired on the active substances and finished products. The available information
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In all cases of variations, the applicant has to investigate whether the intended change will have an
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impact or not on the quality characteristics of active substances and/or finished products and
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When stability data are required, the choice of test conditions defined in this guideline refers to the
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CHMP/ICH Guideline on Stability Testing of New Drug Substances and Products, the CHMP/QWP
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Guideline on Stability Testing of Existing Active Substances and Related Finished Products, the
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CVMP/VICH Guideline on Stability Testing of New Veterinary Drug Substances and Medicinal Products,
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and the CVMP/QWP Note for Guidance on Stability Testing of Existing Active Substances and Related
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Finished Products, respectively. Where appropriate, the concept of bracketing and matrixing as
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described in the CHMP/ICH and the CVMP/VICH Note for Guidance on Bracketing and Matrixing Designs
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for Stability Testing of Drug Substances and Drug Products may be applied across related products.
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Where extrapolation of data are applicable, see Annex II for further information.
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5. Type I variations
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1234/2008 for Type IA variations, and if stability data are required, the minimum set of data to be
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submitted with the variation is defined in the Guideline on the details of the various categories of
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variations to the terms of marketing authorisations for medicinal products for human use and
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veterinary medicinal products. The results of these studies, covering the requested time period as
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defined in above guideline, using accelerated and long-term testing conditions, should be compared to
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the results of studies performed on the unchanged active substance/finished product in order to ensure
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that the change does not negatively impact the stability profile, i.e. that the specification limits of the
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active substance/finished product will still be met at the end of the proposed retest period/shelf-life.
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The comparison data for the unchanged product may come from earlier studies, and need not
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Type IB is the new default category under the new variations Regulation. As far as the associated
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classification guideline is concerned, some examples of different types of Type IB changes have been
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included in the guideline, along with recommended documentation. Where a change may impact on
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stability, the required satisfactory stability data requirements at the time of submission are specified in
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the guideline. In case of other Type IB by default changes, which are not specifically described in the
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classification guideline, the required stability data has to be decided on a case by case basis. However,
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consideration should be given to specified requirements for any other similar changes which have
actually been included as examples in the guideline.
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6. Type II variations
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European Commission Regulations EC 1234/2008 define Type II variation as major variations which
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have the highest potential impact on the quality, safety or efficacy of medicinal products. Type II
Guideline on stability testing for applications for variations to a marketing authorisation
EMA/CHMP/CVMP/QWP/441071/2011
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variations are defined in the Guideline on the details of the various categories of variations to the
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terms of marketing authorisations for medicinal products for human use and veterinary medicinal
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products. However data to be submitted with these variations are not defined in the majority of cases.
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In case of an introduction of a new manufacturer of the active substance that is supported by an ASMF
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stability data should be part of the applicants part of the ASMF. In cases where no retest period is fixed
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(according to the relevant guidelines) the active substance has to be tested immediately prior use.
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If the quality characteristics/impurity profile of the active substance are changed in such a way that it
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may impact the stability of the finished product, additional stability data on the finished product, in
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accelerated and long term conditions, six months on two batches on at least pilot scale, may be
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required.
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If the quality characteristics (e.g. physical characteristics, impurity profile) of the active substance are
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changed in such a way that stability may be compromised, comparative stability data are required in
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accelerated and long term testing conditions, on the active substance before and after the change:
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- for active substances known to be stable: three months on one batch of at least pilot scale (see
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- for active substances known to be unstable: six months on three batches of at least pilot scale.
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If the quality characteristics of the active substance are changed in such a way that it may impact the
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stability of the finished product, additional stability data on the finished product, in accelerated and
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long term testing conditions, six months on two batches on at least pilot scale, may be required.
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In case of variations to the manufacturing process of the active substance, the following approaches
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If the quality characteristics (e.g. physical characteristics, impurity profile) of the active substance are
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changed in such a way that stability may be compromised, comparative stability data are required in
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accelerated and long term testing conditions, on the active substance before and after the change:
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- for active substances known to be stable: three months on one batch of at least pilot scale (see
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- for active substances known to be unstable: six months on three batches of at least pilot scale.
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If the quality characteristics of the active substance are changed in such a way that it may impact the
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stability of the finished product, additional stability data on the finished product, in accelerated and
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long term testing conditions, six months on two batches on at least pilot scale, may be required
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In case of a change to the immediate packaging of a sterile active substance the following approach
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Comparative stability data are required using accelerated and long term testing conditions of six
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In case of a change in the composition of the finished product, the following approaches may be
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considered as acceptable:
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For conventional dosage forms (e.g. conventional release solid dosage form, solutions) and when the
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active substance is known to be stable, comparative stability data, 6 months duration, long term and
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For critical dosage forms (e.g. prolonged release form) or when the active substance is known to be
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unstable, comparative stability data, 6 months duration long term and accelerated stability testing
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In case of a change in the coating weight of oral dosage forms, the following approaches may be
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considered as acceptable:
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For critical dosage forms (e.g. prolonged release form) or when the active substance is known to be
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unstable, comparative stability data, 6 months duration long term and accelerated stability testing
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In case of variations to the manufacturing process of the drug product, the following approaches may
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be considered as acceptable:
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If the quality characteristics (e.g. physical characteristics, impurity profile) of the active substance or
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an excipient are changed in such a way that stability may be compromised, comparative stability data
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are required in accelerated and long term testing conditions, on the drug product before and after the
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change:
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For conventional dosage forms (e.g. conventional release solid dosage form, solutions) and when the
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active substance is known to be stable, comparative stability data, 6 months duration, long term and
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For critical dosage forms (e.g. prolonged release form) or when the active substance is known to be
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unstable, comparative stability data, 6 months duration long term and accelerated stability testing
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In case of variations to the batch size of the drug product, the following approaches may be considered
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as acceptable:
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If the quality characteristics (e.g. physical characteristics, impurity profile) of the active substance or
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an excipient are changed in such a way that stability may be compromised, comparative stability data
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are required in accelerated and long term testing conditions, on the drug product before and after the
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change:
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For conventional dosage forms (e.g. conventional release solid dosage form, solutions) and when the
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active substance is known to be stable, comparative stability data, 6 months duration, long term and
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For critical dosage forms (e.g. prolonged release form) or when the active substance is known to be
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unstable, comparative stability data, 6 months duration long term and accelerated stability testing
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In case of a change to the immediate packaging of the finished product the following approach may be
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considered as acceptable:
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In the case of less protective packaging or when a risk of interaction occurs, mainly for semi-solid or
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liquid dosage forms, comparative stability data are required using accelerated and long term testing
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conditions of six months duration on three pilot batches of the finished product.
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7. Commitment batches
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For all Type IA and IB variations that require the generation of stability data on the finished product,
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For all Type II variations that require the generation of stability data on the finished product, at least
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the first production scale batch manufactured according to the approved variation should be placed on
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long term stability testing using the same stability testing protocol as described in the original
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application unless it has already been submitted as part of the variation application. Stability studies
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need to be continued to cover the entire shelf-life. The results of these stability studies should be made
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available on request and the authorities should be informed if any problems appear with the stability
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studies.
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References
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Guideline on the details of the various categories of variations to the terms of marketing authorisations
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for medicinal products for human use and veterinary medicinal products (OJ L 334, 12.12.2008, p. 7)
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Guideline on Stability Testing of New Drug Substances and Products (CPMP/ICH/2736/99-ICH Q1A)
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Guideline on Stability Testing of New Veterinary Drug Substances and Medicinal Products
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Guideline on Stability Testing of Existing Active Substances and Related Finished Products
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Note for Guidance on Stability Testing of Existing Active Substances and Related Finished Products
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(EMEA/CVMP/QWP/846/99-Rev.1)
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Note for Guidance on Bracketing and Matrixing Designs for Stability Testing of Drug Substances and
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Bracketing and matrixing designs for stability testing of new veterinary drug substances and medicinal
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Annex I
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An active substance is considered as stable if it is within the initial specifications when stored at 25C/
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Annex II
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Where the data submitted, long term 25C/60% RH or 30C/65% RH, respectively, and accelerated
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40C/75% RH or, in case of aqueous products in semi-permeable containers, the respective storage
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conditions defined in the CHMP and CVMP Guidelines on Stability Testing of Active Substances and
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Related Finished Products, show that there is no adverse effect on the stability of the active
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substance/finished product, the retest period/shelf life originally granted can normally be retained,
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based on comparison with the original data submitted. However, where the data demonstrate an
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adverse change in product stability, a new shelf life must be assigned. Based on a case-by-case
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If real time data are supported by results from studies conducted under accelerated or intermediate
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storage conditions, the retest period/shelf-life may be extended beyond the end of real time studies.
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Normally, extrapolation to twice the length of the real time studies can be accepted. However, the
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maximum shelf-life justified by extrapolation should not exceed 3 years. The degree up to which
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extrapolation will be acceptable following to a change to the active substance or finished product that
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shows an adverse effect to the stability will largely depend on the change over time, variability of data
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observed, proposed storage conditions and extent of statistical analyses performed. It will always have
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to be a case-by-case decision. For more detailed information on statistical evaluation of stability data
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please refer to the CHMP/ICH Note for Guidance on Evaluation of Stability Data; similar principles are
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