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

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

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

Page 2 of 4
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.