Susanne Keitel on certification standards and sharing inspection information
Keitel is director of the European Directorate for the Quality of Medicines and Healthcare (EDQM) of the Council of Europe
in Strasbourg, France. EDQM is also responsible for the European Pharmacopoeia (PhEur).
Susanne Keitel, PhD
EDQM developed a program to certify suitability of the monographs of PhEur to adequately control the quality of a substance from a specific source (i.e., certification of suitability [CEP]), which
has been running since 1994. This procedure provides active substance manufacturers as well as brokers and distributors with
the option of filing their quality documentation for the active substance with EDQM for a centralized assessment, rather than
filing individual drug master files in different European Union member states or including the information in individual marketing
The focus of the procedure is to ensure that impurities are adequately controlled. Hence, a certificate will often include
additional tests and specifications to be conducted for a given active substance from a specific source in addition to the
mandatory pharmacopeial tests.
In 1997, it was decided that it would be prudent not only to rely on paper assessment, but also to include inspections of
manufacturing sites and processes. Based on a mandate from the European Commission, EDQM is now running GMP inspections for
APIs—these inspections also assess compliance with the dossier. Inspections are normally conducted by a team of inspectors
from EDQM and European national competent authorities. These inspections completely follow EU rules. This means that inspections
of API manufacturing sites are not done routinely, but following a risk-based selection of sites according to the triggers
identified at a European level and published... on the EMEA website.
Table I: Legislation and programs targeting the global pharmaceutical supply chain.
EDQM today faces a situation where the vast majority of inspections are conducted outside of Europe, predominantly in India
and China, reflecting the global shift in API production. The outcome of the inspections indicates the need for closer surveillance.
In 2008, EDQM conducted 28 on-site inspections, leading to 16 certificates (CEPs) being suspended. Between January 209 and
June 2009, EDQM performed 17 inspections, leading to 8 certificate suspensions. This means that 35% of the sites covered were
found to be non-GMP compliant. It is important to stress that this is not representative of the entire API market. In contrast,
it does indicate that the triggers used in the risk-based approach in the selection of inspection sites are the right ones.
In the case of a negative inspection outcome, European competent authorities and the local competent authority of the country
where the inspection took place are informed (local inspectorates are routinely invited to participate in any inspection performed
in their respective country). The competent authorities then take appropriate action.
As demonstrated by the number of suspended CEPs, there is a clear need for a broader coverage of inspection sites. EDQM therefore
welcomes EMEA's pilot project to exchange information on API inspections with the FDA and Australia's Therapeutic Goods Administration.
In fact, EDQM participates in this exercise on the European side.... Due to the absence of mutual recognition agreements,
it will not be possible to take action based on information received from the partners in this pilot project. However, the
information received from the partners will be very useful when applying risk-based selection of sites for inspection. For
example, why should a site already covered by a partner and found to be GMP-compliant be high on the priority list of another
Industry qualified importers proposal
Current EU pharmaceutical legislation requires the qualified person (QP) of the holder of the manufacturing authorization
certify that all API used in the product has been manufactured according to GMP.
This has to be certified in every single marketing authorization application or subsequent variation. Based on the outcome
of inspections carried out in the framework of EDQM's certification scheme, I have the impression that not all QPs really
take their responsibility serious enough to ensure an audit—else it would be difficult to explain why we still see so many
deficiencies. The planned revision of the pharmaceutical legislation, the EU Pharmaceutical Package, is [expected] to explicitly
require the performance of audits. The draft legislation requires that any contracted auditor be accredited by the national
competent authority of a member state. Hence, the draft legislation foresees more stringent requirements for the future. Based
on our experience in conducting inspections of API manufacturing site, we consider this a move into the right direction.