Denmark report on APIs finds supplier audits 'inadequate'

The Danish Medicines Agency recently published a review of its oversight of active pharmaceutical ingredient suppliers, concluding that on the whole they were meeting Good Manufacturing Practice (GMP) standards.

However, the report also exposes limitations in the way pharmaceutical manufacturers carry out audits of API suppliers - as well as how they make use of information obtained in the audits - and the agency says it now intends to draw up guidelines for drugmakers on this issue.

"The purpose of the project was to improve the basis for pharmaceutical companies’ control of API manufacturers and traders," says the report, noting that it was set up in answer to concerns about the safety of the API supply chain in light of events such as the contaminated heparin scandal in 2008 and the general globalisation of API supply to the drug industry.

Overall "the existing legislation effectively ensures that finished product manufacturers use APIs of a high quality," it concludes.

That said, the quality of audits and audit reports should be improved for audits of both API manufacturers and traders, and more attention should be paid to analytical control of APIs.

Among the findings was that, at least within the confines of this project, "audit reports requested from Danish finished product manufacturers were inadequate," according to the agency.

The reports sometimes did not provide enough detail on the actual processes that were scrutinised, and there was sometimes inadequate follow-up where deficiencies were discovered, missing documentation on auditor qualifications and independence, and reports which had not been signed off by the drugmaker's Qualified Person. Some did not tally with the findings of regulatory inspections.

Overall, there tended to be a lower frequency of audits of API manufacturers than recommended (every three years is the minimum, even when an EU medicines agency has carried out an inspection in the interim).

"Of the medicinal products requested by the agency’s laboratory, 11 per cent contained APIs from API manufacturers that had not been audited on behalf of the finished product manufacturer within the past three years," says the report.

 A low audit frequency increases the risk of GMP non-compliance by API manufacturers, it notes.

The sample revealed one instance in which a marketing authorisation holder failed to discontinue use of an API even though its certificate of suitability (CEP) had been withdrawn by the EU authorities.

"Withdrawal of CEPs should always result in a risk assessment by both the finished product manufacturer and the MAH," notes the report.

There were also several occasions where the MAH had transferred a supplier's certificate of analysis for an API to the CoA for its finished product without adhering to the re-testing commitments laid out in the marketing authorisation.

The project looked at 12 manufacturers supplying 20 selected APIs to the Danish market, including domestic producers as well as organisations in India, China, Mexico, Israel, Japan and the USA. It also looked at the auditing processes of 12 Danish finished product manufacturers.

Laboratory testing by the Danish Medicines Agency also uncovered some differences in analysis results compared to the specifications laid out in monographs and it has requested chromatographic raw data from both the API manufacturer and the finished product manufacturer to investigate these deviations further.

The complete report is available to download here.