Address: 7 allée Kastner CS 30026 - F 67081 Strasbourg Telephone: 33 (0) 3 88 41 30 30 - E-mail:cep@edqm.eu - Fax: 33 (0) 3 88 41 27 71

Internet : http://www.edqm.eu

PPR/CB Working document, with no legally binding Status, intended exclusively for the addressees and their associates, under the responsibility of the addresses (listed opposite). Level 4 English only/Anglais seulement PA/PH/CEP ( 08) 11 rev 00

Strasbourg, September 2008

Certification of suitability to Monographs of the European Pharmacopoeia

TOP DEFICIENCIES FOUND DURING FIRST ASSESSEMENT OF NEW

APPLICATIONS FROM OCTOBER 2007 TO DECEMBER 2007

EDQM PA/PH/CEP ( 08) 11 rev 00 Certification of Substances Division

Page 2 of 4

TOP DEFICIENCIES FOUND DURING FIRST ASSESSEMENT OF NEW

APPLICATIONS FROM OCTOBER 2007 TO DECEMBER 2007

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 October to December 2007. It is based on the content of the deficiency letters sent to the applicants after the first evaluation of 84 applications. From the data obtained the average number of questions per application was 9 and the actual number ranged from 0 to 23. A previous analysis of the top deficiencies was published on the web in December 2006 and applicants have obviously taken the recommendations made at that time into account since improvement has been observed in the quality of the dossiers submitted since that time. Therefore it was found valuable to update this list with the current situation. 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/PHCEP04 1 4R) 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 the time taken to receive the CEP. TOP 1 (3.2.S.3.2): Absence of any discussion on Genotoxic Impurities. Discussion based on the requirements of the CHMP Guideline on the Limits of Genotoxic Impurities (EMEA/CHMP/QWP/251344/2006), is applicable to new applications for active substances obtained by a manufacturing process not yet approved by European Authorities. A specific discussion as part of the overall discussion on impurities should be provided with regard to impurities with potential genotoxicity. This item is new in the top deficiencies. TOP 2 (3.2.S.2.3): Absence of any discussion on the carry-over of impurities/by-products from starting materials. In the case of few steps 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 impurities (related substances, solvents and catalyst) from the starting materials into the API should be demonstrated. This item corresponds partially to the previous top 1. TOP 3 (3.2.S.2.3): Absence of any discussion on benzene as a contaminant in identified solvents based on the Note for Guidance on Specifications for Class 1 and Class 2 residual solvents in active substances, annex to the CPMP/ICH/283/95 Impurities: Guideline for Residual Solvents & CVMP/VICH/502/99 Guideline on Impurities: Residual Solvents: Either a limit is set for the contaminant in the solvent or where a Class 1 solvent might be present in another solvent (Acetone, Toluene, Ethanol, Methanol, Isopropanol, Xylene, Hexane and Petroleum ether) a routine test for this Class 1 solvent, on a suitable intermediate or on the final active substance, is not required when: The limit applied to the originator solvent is such that the Class 1 solvent will be present in the active substance at levels below the limits set out in the guideline, taking into account the maximum likely level of contamination of the Class 1 solvent. OR

It is demonstrated with a validated method that the Class 1 solvent is not more than 30% of the specified limit, in a suitable intermediate or in the final active substance. Supporting data should be presented on 6 consecutive pilot scale batches or 3 consecutive industrial scale batches. OR The specification for the originator solvent used includes a routinely performed test and limit for the Class 1 solvent. TOP 4 (3.2.S.2.3): Absence of any information on the specifications of the declared starting materials: individual specified impurities/total impurities/solvents/catalysts. Lack of information on the description of its route of synthesis, absence or insufficiency of its impurity profile (related substances, reagents, solvents, catalysts); See also TOP 2 (question above). TOP 5 (3.2.S.2.3): Absence of any discussion for starting materials from different suppliers: Where more than one supplier of the starting materials(s) is used, batch analysis results from the substance manufactured from the different suppliers should be given to confirm that specification of the active pharmaceutical ingredient remains unchanged whichever the supplier used. In addition to this top 5, attention should be paid to the following points, which are frequently not appropriately documented: (3.2.S.2.3): Purity test for solvents/reagents: 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 materials should have adequate purity. (3.2.S.3.2) Limits set for impurities should be in accordance with the specific European Pharmacopoeia monograph and the general monograph 2034 Substances for pharmaceutical use. 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 semi-synthetic 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. 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. (3.2.S.4.2) Particular attention should be paid to monographs not yet revised which still include a non-specific 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 monograph. 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. (3.2.S.4.3): Absence of any validation of the in-house methods used for the control of related substances: Where additional or alternative methods are used in quality control of the final substance they should be adequately validated and/or cross validated with reference to the monograph's method(s) using Ph. Eur. CRS where prescribed (typical chromatograms should be provided).

(3.2.S.3.2): 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.