EU Raises API Standards: A Curse in Disguise?

Published on: 
BioPharm International, BioPharm International-09-01-2013, Volume 26, Issue 9
Pages: 40–45

The aim of the European Falsified Medicines Directive is to improve the quality of imported APIs, but does the pain now outweigh the gain?

The number of substandard pharmaceutical ingredients coming into the EU has increased in recent years; however, when the European Commission (EC) first revealed details of the implementation of new EU rules for GMP standards for imported APIs, both the pharmaceutical industry and regulators warned about the potential dangers of these restrictions in causing medicines shortages. The new regulation, part of the EU’s Falsified Medicines Directive (FMD), requires that imports of APIs into the EU must be accompanied with written confirmation by a national regulatory authority that the manufacturing plant complies with GMP standards. This requirement has raised concerns that the importation of a large proportion of APIs would be severely hampered as a result. And yet, six weeks after the new rules came into effect on July 2, 2013, there has been no evidence of any major upheaval in the supplies of APIs in the EU—approximately 70% of which are imported, with 60% of these imports coming from India and China.


“Currently, we have not been notified of any critical disruption of API supplies, or manufacture of medicinal products, linked to the enforcement of the new EU rules on the importation of active substances,” a spokesperson for the EC told BioPharm International. The European Federation of Pharmaceutical Industries and Associations (EFPIA), the main trade body for research-based pharmaceutical companies, also confirmed that it had not yet received any reports from its members about any immediate difficulties with imported API supplies after July 2. An EFPIA official, however, informed BioPharm International
that “it is too early to assess properly the impact of the new system.”

Exemption from written confirmation
To date, four countries (i.e., US, Japan, Australia, and Switzerland, which is a non-EU country), have been excluded from the requirement for written confirmation on grounds that their regulatory and monitoring standards on GMP are equivalent to those of the EU. Several other countries, including Brazil, Mexico, Singapore, and Israel, have applied to be exempted, or to have previous refusals of exemptions reviewed, according to the EC. The regulation also enables the authorities in the EU’s 28 member states to apply various waivers when implementing the written confirmation requirement. If, for example, an API plant has already been inspected and given a GMP certification by EU inspectors, written confirmation may be considered to be unnecessary.

Nonetheless, exactly how the new rules are being applied in individual EU countries has been unclear because of delays in including the FMD regulations in national statutes. By early August, eight of the 28 member states were yet to transpose the written confirmation obligation into their laws. In other countries, the implementation date has been held back. For example, in the UK, the requirement was not in full effect until August 20.

In most countries, the checking of whether an imported API is accompanied by a written confirmation is left to the individual pharmaceutical manufacturers. Without the confirmation, a medicine with the imported API cannot be marketed legally in the EU. “(We) will monitor compliance with the rules in relation to finished-product manufacturers as well as companies importing active substances,” explained the Danish Health and Medicines Authority in a statement on the new rules (1). “The Danish customs authorities will not check whether the import rules have been observed.” On the other hand, countries, such as Spain, are verifying compliance through import controls at their borders while Germany and the Netherlands are planning to do the same.

Alternative suppliers
Some manufacturers were quick to react to the possibility of new restrictions on imported APIs at the time when the FMD was being debated in the European Parliament and the European Council representing EU governments. They signed deals with alternative API suppliers with GMP certification, particularly those based in the EU. “In a recent survey of our members, we found that many of them had been asked by European pharmaceutical companies to become second-source suppliers of their active substances,” said Tony Scott, advisor to the European Fine Chemicals Group (EFCG), representing EU producers of APIs.

National licensing authorities have been working closely with their countries’ pharmaceutical manufacturers to pinpoint API sources that may have difficulties complying with the new EU restrictions. Risk assessments of potentially problematic active ingredients have been carried out. These assessments investigate reasons for the absence of written confirmations, levels of existing stocks of the APIs with the medicine manufacturers, and the availability of alternative products and treatments. “(We are) aware of 107 risk assessments being carried out by member states although it is highly likely that many more have been done,” says an official at the European Medicines Agency (EMA). EMA has been monitoring the implementation of the written confirmation requirement.

On the basis of the results of the risk assessments, national authorities have been helping pharmaceutical companies to take precautionary measures. “Some API sources for UK finished-product manufacturers were (shown to be) potentially at risk,” a spokesperson for the UK Medicines and Healthcare Products Regulatory Agency (MHRA) told BioPharm International. “However, further analysis by the manufacturers showed that such risks could be mitigated, for example, by stocks being held and the use of alternatives from approved API sources. The situation is being kept under review by MHRA at a UK level and by the weekly meetings at an EU level.”

Due to concerns about possible medicines shortages in the short to medium term, EU regulators have been prioritizing inspections of some non-approved plants outside Europe by EU GMP inspectors. “(We know) of 12 future planned inspections of sites for which no written confirmation is available although some of these inspections may ultimately not be necessary as more non-EU authorities start issuing written confirmations,” the EMA official told BioPharm International. “In addition, EMA is aware of three EU inspections that have been carried out although it is highly likely that there have been more.”

India and China step up GMP standards
In the longer term, EU regulators are hoping that India and China, which between them have more than 900 sites exporting APIs to Europe, will establish comprehensive and reliable GMP inspection systems that will eliminate the problem of certification of exported active substances. In India, the Central Drugs Standard Control Organization (CDSCO), part of the country’s Ministry of Health and Family Welfare, has been issuing written confirmations. Details of the confirmation with names of the APIs are available on the CDSCO website.

China only began issuing
written confirmations this spring through the Chinese Food and Drug Administration (CFDA), which supervises GMP inspections but only in pharmaceutical plants. It has no responsibility for GMP standards in chemical plants making and exporting APIs. “China is a very big country so there are difficulties with quality standards in APIs production while there is also a need for harmonization of GMP inspections,” commented Stefan Kettelhold, lead auditor at Germany’s blue inspection body GmbH, which does a lot of auditing work in China. “The Chinese government used to concentrate on raising production standards of companies supplying the domestic market. With the new legislation, it is also focusing on GMP of API suppliers for the international market. The Chinese authorities want to see a general upgrading of standards in pharmaceuticals.”

One likely result of tougher domestic and international regulations on production standards in India and China will be a consolidation among API manufacturers. There will be fewer of them, but they will be able to ensure that their active substances are of a more consistently acceptable quality than at present.

1. Danish Health and Medicines Authority, Requirements for Import of Active Substances (API)—Questions and Answers,, accessed Aug. 10, 2013.

About the Author
Sean Milmo is a freelance writer based in Essex, UK,