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30 June 2012 EMA/CHMP/CVMP/QWP/199250/2009 corr Committee for Medicinal Products for Human Use (CHMP)/ Committee for Medicinal Products for Veterinary Use (CVMP) Guideline on setting specifications for related impurities in antibiotics
Final Draft Agreed by Quality Working Party
May 2010 Adoption by CHMP for release for consultation
24 June 2010 Adoption by CVMP for release for consultation
15 July 2010 End of consultation (deadline for comments)
31 Jan 2011 Agreed by Quality Working Party
May 2012 Adoption by CHMP
14 May 2012 Adoption by CVMP
14 June 2012  Date for coming into effect
30 June 2013
Keywords
Antibiotics, specifications, related impurities
Guideline on setting specifications for related impurities in antibiotics
Table of contents
Executive summary (3)
1. Introduction (background) (3)
2. Scope (4)
3. Legal basis (4)
4. General requirements (5)
5. Impurity profiling and reporting, identification and qualification thresholds (6)
5.1. Active substances manufactured by semi-synthesis (6)
5.2. Active substances manufactured by fermentation, single compound (7)
5.3. Active substances manufactured by fermentation, family of compounds (7)
5.4. Peptides manufactured by fermentation/semi-synthesis (7)
5.5. Active substances for veterinary use (7)
5.6. Special cases for very complex impurity profiles (7)
6. New applications and variations (8)
6.1. New active substances (8)
6.2. Existing active substances, not subject to a Ph. Eur. monograph (8)
6.3. Active substances subject to a Ph. Eur. monograph (8)
6.3.1. Existing active substances subject to a Ph. Eur. monograph with transparency statement and availability of a CRS for peak identification or relative retention times for the related substances (8)
6.3.2. Existing active substances subject to Ph. Eur. monograph, with transparency statement, but no availability of a CRS for peak identification or relative retention times for the related substances (8)
6.3.3. Existing active substances subject to Ph. Eur. monograph, without transparency statement (9)
6.3.4. Revision of Ph. Eur. monographs (9)
7. Specifications for medicinal products (9)
8. Analytical procedures (10)
Definitions (10)
References (11)
Annex 1: Explanatory note regarding thresholds (12)
Annex 2: Thresholds (13)
Annex 3: Example of “fingerprint chromatogram” approach to control very complex impurity profiles (14)
Executive summary
Antibiotics active substances currently on the market are produced by fermentation, by fermentation followed by one or more synthetic steps (semi-synthetic substances) or by chemical synthesis. Fermentation processes are, in comparison to synthetic processes, more variable and less controllable, so the impurity profile of an active substance whose manufacturing process involves fermentation may be more complex and less predictable than that of a purely synthetic product. For this reason fermentation products and semi-synthetic substances are not included in the scope of the ICH Q3 and the VICH GL10/GL11 guidelines, which set thresholds for the identification, reporting and qualification of related impurities in active substances manufactured by chemical synthesis.
This guideline has been developed in order to provide guidance on how specifications for related impurities in antibiotics that are fermentation products or semi-synthetic substances derived from fermentation products, and are therefore not included in the scope of the (V)ICH guidelines mentioned above, should be set.
Thresholds are given in the guideline for reporting, identification and qualification of related impurities for antibiotics medicinal products whose active substance is produced by fermentation or semi-synthesis. In cases where the active substance consists of a mixture of closely related compounds, where it may be difficult to apply general thresholds, general guidance is given on how to set specific thresholds and specifications and on how to qualify impurity profiles. The relationships between the requirements in the guideline and the applicable Ph.Eur. chapters and monographs are also addressed.
1. Introduction (background)
Most of the antibiotics currently on the market are produced by fermentation or chemical synthesis. In certain cases the chemical structure of the antibiotics obtained by fermentation is further modified by some synthetic steps, before the substance is used as an active substance in the manufacture of medicinal products (semi-synthetic substances).
Fermentation processes involve biological systems which are less predictable, less controllable and more complex than straightforward chemical reactions. Because of this, the variability in products derived by fermentation is often greater than in products derived by chemical synthesis. Thus, the impurity profile of a fermentation product may be more complex and less predictable than that of a synthetic product.
For this reason, fermentation products and semi-synthetic substances derived from them are not included in the scope of the ICH Q3 and the VICH GL10/GL11 guidelines that set thresholds for the identification, reporting and qualification of related impurities in active substances manufactured by chemical synthesis. These thresholds are defined in the guidelines as limits above which an impurity has to be either identified, reported or qualified, and the same limits are applied in the Ph.Eur. general monograph ‘Substances for Pharmaceutical Use’. Fermentation products and their semi synthetic derivatives are also excluded from the scope of this general monograph.
In the absence of other guidance, related impurities in these products have been assessed on a case-by-case basis, which has resulted in the acceptance of different impurity thresholds for the same antibiotic and for different compounds within the same class (e.g. cephalosporins). There is also a need to ensure that the authorisation of new antibiotics is enabled by consistent approaches in setting
limits for their impurities.
active下载It is therefore necessary to provide guidance, based on current practice and experience, to formulate general recommendations for impurity thresholds in antibiotics produced by fermentation or semi-synthesis. These are presented in this guideline.
Even so, it is acknowledged that in some cases higher thresholds may be acceptable if necessary and justified taking account of use and exposure of the drug substance/product. This would also include analytical problems (see Annex 1: Explanatory note regarding thresholds).
2. Scope
This document provides guidance for marketing authorisation applications on setting specifications for related impurities in antibiotics (i.e. antibacterial substances) that are fermentation products or semi-synthetic substances derived from fermentation products. It is foreseen to widen the scope to other antibiotics (e.g. antifungal substances) at a later stage.
It provides guidance for the content and qualification of related impurities in both active substances and medicinal products. The guideline is not intended to apply to new active substances used in investigational medicinal products used in clinical trials.
In this guideline thresholds are given for reporting, identification and qualification of related impurities. For antibiotics where the active substance consists of a mixture of closely related compounds where it may be difficult to apply these general thresholds, general guidance is given on how to set thresholds and specifications and how to qualify impurity profiles. The thresholds given in this guideline would represent a general set of requirements, and this could be subject, for specific substances or products, to adaptation to the specific situation. Further requirements might be introduced when considered necessary, e.g. for safety reasons.
This guideline does not cover residues from the fermentation process, i.e. residues from the producer micro-organism, culture media, substrates and precursors; this is covered by the Ph.Eur. general monograph ‘Products of fermentation’. (This monograph applies to substances manufactured by fermentation only, and not to substances manufactured by semi-synthesis).
This guideline applies to new active substances and for new sources of existing active substances. It is the Applicant’s responsibility to demonstrate that the active substance has already been marketed in the EU when relevant.
The guideline should not be applied retrospectively, but it is intended that this guideline will act as a sti
mulus to establish best practice and to initiate the revision of relevant Ph.Eur. monographs (i.e. for registered products revised requirements according to the monograph will apply when the monograph is introduced/revised). For new sources of existing active substances this guideline should be read in conjunction with any existing Ph.Eur. monograph for the active substance. It should be noted that comparison with impurity levels/profiles of active substance sources or products approved in the EU is one of the options for qualifying impurities.
It is foreseen to re-evaluate the Scope when more experience has been obtained.
3. Legal basis
This guideline has to be read in conjunction with the introduction and general principles (4) and part 1 of the Annex Is to Directives 2001/82/EC and 2001/83/EC as amended.
4. General requirements
The impurity profile depends very much on the manufacturing process; even for the same strain of a micro-organism, impurity profiles may be different. In general, purification steps including column chromatography and ultra-filtration steps may be crucial to achieve a sufficiently pure active substance.
Semi-synthetic substances are not within the scope of the Ph.Eur. general monograph ‘Products of fermentation’. However, the specification of the fermented starting material should be justified with reference to current guidance, including general concepts described in this general monograph, if necessary. (The thresholds in this guideline are not intended to apply for fermented starting materials).
The shorter the synthetic route after the fermentation and the more complex the fermented starting material, the more relevance the general monograph has. Therefore, a detailed description of the fermentation steps as well as other aspects addressed in the general monograph, in particular purification steps, should be presented for semi-synthetic antibiotics, unless justified by the non-complexity of the fermented starting material and the number and/or nature of the synthetic steps following fermentation.
These synthetic steps should contribute to a relevant depletion and inactivation of fermentation by-products in the final active substance, so for example, esterification, etherification and salification of fermentation products (e.g., erythromycin derivatives like erythromycin ethylsuccinate or erythromycin lactobionate) are not considered as significant synthetic steps which would justify an omission of a detailed description of the fermentation process, in particular of the purification.
In cases where the fermented starting material is not complex and taking into consideration the number and nature of the synthetic steps after fermentation, it may be sufficient to have a suitable specification for the fermented starting material including assay, component distribution (if relevant) and related impurities (specified, unspecified, and total). This should be in any case justified. For active substances manufactured by semi-synthesis, the impurity profile of the fermented starting material should be critically evaluated for its contribution to the impurity profile of the final active substance. Related impurities observed after fermentation include by-products, intermediates and degradation products. For semi-synthesis the impurities also include the fermented starting material and related substances in this starting material, synthesis by-products (including those derived from impurities in the starting material), synthesis intermediates and degradation products.
Specifications should be given for any critical intermediates (this also includes intermediates between different purification steps). These specifications should include limits for specified and single unspecified impurities. Impurities that contribute to the impurity profile of the active substance should be specified. The applicant should provide a discussion on potential impurities, how they are removed and which impurities appear in the active substance.
Even if manufactured by fermentation or semi-synthesis, an antibiotic may be structurally well defined
as a mono component substance, and thus it may be efficiently purified. For each class of antibiotic, it is considered preferable to optimise purification steps as far as possible, in order to decrease the level of impurity to below the qualification threshold, than to provide (additional) safety data.
For antibiotics manufactured by fermentation, the active substance may consist of a mixture of closely related compounds that show the relevant biological activity. In such cases it may be difficult to decide whether a compound is part of the active substance or should be regarded as an impurity when setting specifications (e.g. gentamicin). The definition of which substances are components of the active
substance should be based on pre-clinical and clinical studies unless the active substance is described in a Ph. Eur. monograph where the active substance components are defined. Related compounds that are not defined to be components of the active substance are regarded as related impurities.
The thresholds given in the ICH Q3 and VICH GL10/GL11 guidelines and in the guideline ‘Chemistry of New Active Substances’ (CPMP/QWP/130/96 Rev 1, EMEA/CVMP/541/03) do not apply to fermentation products and semi-synthetic substances derived from fermentation products. For other aspects, where specific guidance is not given in the present guideline, reference is made to the principles described in these guidelines.
In qualifying an impurity or a given impurity profile at the level specified, several possibilities exist: appropriate battery of non-clinical tests, literature based data; comparison with impurity levels/profiles of active substance sources/products approved in the EU; or proving that the relevant impurity is a significant metabolite of the active substance.
5. Impurity profiling and reporting, identification and qualification thresholds
For antibiotic drug substances, the impurity profile should be characterised according to the guidance described in ICH Q3A (VICH GL10).
In accordance with that guidance, with respect to related substances, limits should be set for:
•Each specified identified impurity;
•Each specified unidentified impurity;
•Any unspecified impurity, with an acceptance criterion of not more than the identification threshold;
•Total impurities.
Exceptionally, if it is shown that it is not practically possible to identify an individual impurity, sufficient evidence of its structure should be provided (e.g. by HPLC/mass spectrometry to show that it may be satisfactorily classified as a related substance of the parent compound. In this case, it should be specified using an appropriate analytical HPLC Relative Retention Time (RRT), as a specified unidentified impurity. As a general principle, for impurities which are not structurally closely related (see section 5.3 below) to the parent compound, thresholds as given by ICH Q3A (VICH GL10) should be applied unless stated differently in the following sections.
For the reasons discussed in section 4 above, and taking into account that the duration of treatment with antibiotics is in most cases limited, for antibiotic related substances the thresholds to be applied may be higher than those stated in ICH Q3A/VICH GL10, and also different for each of the different classes of antibiotic. These thresholds are given below.
5.1. Active substances manufactured by semi-synthesis
Semi-synthetic substances are obtained from a fermented starting material by a process involving at least cleavage and formation of covalent bonds and including extraction/purification steps. Acceptance criteria for related impurities should be set in accordance with the thresholds given below.
The ICH Q3A thresholds for reporting, identification and qualification apply.
Reporting threshold: 0.05%/0.03%
Identification threshold: 0.10%/0.05%

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