EDQM_top_ten_deficiencies_found_in_applications by rambabukomati


									Division Certification of Substances

(Level 1)

English only/Anglais seulement PA/PH/Exp. CEP/T (06) 35 Strasbourg, December 2006

Certification of suitability of Monographs of the European Pharmacopoeia

How can the content of the applications for a certificate of suitability for chemical purity be improved?

The TOP TEN deficiencies found in applications

Address: 226 Avenue de Colmar (entrance rue Schertz) B.P. 907 - F 67029 Strasbourg Cedex 1 Telephone: 33 (0) 3 88 41 30 30 - E-mail:cep@pheur.org - Fax: 33 (0) 3 88 41 27 71 Internet : http://www.pheur.org

Certification Unit

The TOP TEN deficiencies found in applications
How can the content of the applications for a certificate of suitability for chemical purity be improved?
This document presents a summary of the main deficiencies found in the dossiers for certificates of suitability (CEP) for chemical purity assessed from April to July 2006. It is based on the content of the deficiency letters sent to the applicants after the first evaluation of 87 applications. From the data obtained the average number of questions per application was 9 and the actual number ranged from 1 to 25. A previous analysis of the top ten deficiencies was presented in October 2005 during the Certification Conference in Istanbul and the recommendations made at that time have obviously been taken into account by applicants since improvement has been observed in the quality of the dossiers submitted since this conference. By including the recommendations described in this text together with the requirements described in the guideline in the submission (“Content of the dossier for chemical purity” (PA/PHCEP0413R) available on our website which replaces Annex I to Resolution AP-CSP (99) 4), the applicant for a CEP can improve the quality of their dossiers and therefore limit requests for additional information and the time taken to receive the CEP.

TOP  (3.2.S.2.3): Lack of information on the declared starting material(s). Lack of information on the description of its route of synthesis, absence or insufficience of its impurity profile (related substances, reagents, solvents, catalysts), and the carry-over of its impurities to the final substance (58.5% of dossiers). In the case of short synthesis, when the starting material is a complex product, the quality and impurity profile of the material is of key importance, and its route of synthesis should be shortly described. The absence of carry-over of its impurities (including related substances, solvents and catalyst) should be demonstrated. See also TOP  question below. TOP (3.2.S.3.2): Demonstration of the absence of particular reagents in the final substance (e.g. catalysts, alkylating agents,..) is insufficient (45% of dossiers). Demonstration should be given that the reagents used during the synthesis are not likely to be present in the final substance. This applies but is not limited to residues of catalysts or of alkylating agents. In some cases, toxic reagents can be used, and they should be properly removed from the final substance. The toxicity of these products should be taken into account when setting limits or when developing analytical methods to detect them. TOP (3.2.S.2.3): Specifications of starting materials do not include suitable limits for impurities (42% of dossiers). The key starting materials should have detailed specification, particularly with regards related substances and solvents, which may carry-over into the final substance. Appropriate limits should be set in the specifications of the starting material, in order to ensure appropriate purity of the final substance.
PA/PH/Exp. CEP/T (06) 35 2

TOP (3.2.S.3.2): Residual solvents: The demonstration that all solvents used during the synthesis are removed or suitably limited in the final substance is not complete. (42% of dossiers). The dossier should contain information showing that all solvents used during synthesis have been either properly removed or suitably limited in the specification of the final substance. The ICH and CHMP guidelines should be used as a basis for that. The methods used to demonstrate the absence of residual solvents should be properly described and validated, even if not routinely used. TOP (3.2.S.2.2):: Maximum/typical batch size and yields are not stated (34% of dossiers). This information should be included in the dossier, together with typical quantities of materials involved. TOP (3.2.S.4): Limits set for impurities are not in accordance with the specific European Pharmacopoeia monograph nor the general monograph 2034 Substances for pharmaceutical use (due to misunderstanding of the transparency list of the specific monograph) (33% of dossiers). The general chapter 5.10 of the European Pharmacopoeia “Control of impurities in Substances for Pharmaceutical use” and the revised general monograph 2034 Substances for pharmaceutical use introduce new requirements (as also described in the guideline CPMP/QWP/1529/04 Control of impurities of Pharmacopoeial substances) that should be consulted to understand how to read the limits of the monograph and how to apply the general monograph when setting specifications. It is to note that even for substances for which the provisions of the Related substances section of the general monograph Substances for pharmaceutical use (2034) do not apply, notably those concerning thresholds (excipients, biological and biotechnological products; peptides; oligonucleotides; radiopharmaceuticals; fermentation products and semisynthetic products derived therefrom; herbal products and crude products of animal and plant origin), the concepts of reporting, identification (wherever possible) and qualification of impurities are equally valid for these classes. This means that appropriate limits for known and unknown related substances should be set and suitably justified. Particular attention should be paid to monographs not yet revised which still include a nonspecific and non-quantitative TLC method, and which do not comply with the current regulatory requirements, as described in the above mentioned general chapter and revised general. In such cases, a suitably validated quantitative test method for related substances and suitable limits for these related substances in accordance with the general monograph should be proposed. The alternative method will be assessed and appended to the CEP when granted. The current policy requires that unknown impurities (those impurities not named or specified in the monograph) are limited to less than 0.10% (or 0.05% should the daily dose of the substance be higher than 2g/day). If such impurities are detected, a suitable limit should be introduced in the specifications of the final substance. TOP (3.2.S.2.3): Specifications for all reagents, solvents are not described or are not sufficient (32% of applications). Specifications of all materials used during the synthesis should be given, and suitable purity tests should be introduced. Particular attention should be paid to the quality of solvents used during the final purification steps (including water); these solvents should have adequate purity. If recovered materials are used their specifications should be given and justified.
PA/PH/Exp. CEP/T (06) 35 3

TOP (3.2.S.5): Characterisation of the reference standard (29% of the dossiers). Any working / in-house standards should be characterized versus the PhEur CRS.

TOP (3.2.S.3.2): Discussion on impurities (26% of the applications) is not satisfactory: All the potential impurities for the process with their origin (by-product or degradation) should be listed, correspondence with the transparency statement of the monograph should be established and individual impurity results (with 2 digits) should be provided. The suitability (or unsuitability) of the European Pharmacopoeia monograph to detect and limit the related substances of a particular synthetic process should be demonstrated, even if a suitable in-house method is used for the control of related substances. TOP  (3.2.S.2.4) Description of in-process controls (IPCs) is not sufficiently detailed (24% of the applications). Information on the tests performed and description of the analytical method used should be provided to guarantee the quality of the final substance and justify the specifications. TOP (3.2.S.4.4): Analytical results missing or incomplete (24% of the applications). Detailed results should be provided for 3 recent batches representative of the production (date of manufacture and batch size should be in accordance with the declared maximal batch size). Results should be presented as actual values instead of statement such as “complies”, “conforms”.

________ ______ __________________ ___ __

PA/PH/Exp. CEP/T (06) 35


To top