Ruffled feathers and interim measures: API rules applied 20 September 2013 Ian Schofield
It wasn't quite an international incident, but this year's introduction of new EU rules for certifying the quality of imported active pharmaceutical ingredients (APIs) certainly ruffled many feathers among regulators in the world's major API supply markets.
Called on to certify that their GMP systems were on a par with those of the EU, big exporting countries like India and China – which together supply some 60% of the EU's API needs – reacted angrily to the implication that their systems were somehow inferior to Europe's. Some let it be known that they did not plan to comply, raising fears of product shortages as a result.
After a last-minute scramble and some compromises, most countries had in one way or another managed to comply with the rules and the July 2013 deadline came and went with no major upsets. But it is possible that some product consignments could still fall through the regulatory net and hit problems at the EU's borders, and emergency procedures have been put in place for use where significant product shortages might occur.
The new requirements, part of the EU's falsified medicines Directive, are intended to guarantee the quality of imported raw materials, particularly from countries like China where memories of contaminated heparin are still fresh four years on but many unregulated firms still sell substandard APIs with no quality oversight.
The rules were introduced in two stages. As of 2 January 2013, all APIs imported into the European Economic Area from countries like China, India and Brazil must have been manufactured in accordance with good manufacturing practice (GMP) standards that are at least equivalent to those of the EU.
Then from 2 July 2013, compliance with this rule must be confirmed in writing by the relevant authorities in the exporting country for each manufacturing plant. This requirement is waived if the country is on a white list of "accredited" nations whose GMP framework is equivalent to that of the EU or, exceptionally, where an EU member state has inspected the manufacturing site in question and issued a GMP certificate.
If the country is not on the list, each batch of API sent from that plant must be accompanied by a copy of the "written confirmation" showing the plant to be in compliance with EU GMP-equivalent norms (or ICH Q7 standards), otherwise it will be refused entry into the EU. It is up to each exporting country to decide which body will issue the written confirmation; the manufacturer of the finished product concerned must check that each consignment imported has a written confirmation, and the relevant authorities will verify that these checks have been carried out.
But when the new requirements were announced, some countries resented what they saw as the unilateral imposition of onerous new requirements based on an EU standard, particularly as they already had their own inspection and quality control systems in place.
Indian firms, for example, claimed the rules constituted a non-tariff barrier that would hit Indian API supplies, create shortages and inflate drug prices across Europe. The additional inspections and certifications, they said, were superfluous in view of the existing system of repeated inspections of Indian plants by the EU and other regulatory authorities.
This led to concern among European companies and regulators that non-compliance could lead to many important APIs such as common antibiotics and paracetamol being in short supply. The
European Medicines Agency estimated that as many as 200 centrally authorized drugs were "clearly or potentially" at risk, while generics firms said the rules were being rushed through too quickly and without proper consultation with third countries.
Following much backroom discussion, a compromise was reached in February 2013 when the Commission made a small but crucial change, allowing facilities to be certified to the World Health Organization or ICH Q7 standards, as well as to EU GMP.
This made all the difference, but as the July deadline approached it was still far from clear whether enough of the major API suppliers would have either secured a place on the Commission's list or agreed to produce "written confirmations" for each of their manufacturing sites.
In the event, most countries managed one or the other, although interest in being on the white list appears to be limited and most seem to be opting for written confirmations. By the July deadline, only eight countries had applied for a listing, and only four of them – Switzerland, Australia, Japan and the US – had managed it.
As for the remainder, assessments of Brazil and New Zealand are still under way, as are contacts with Israel and Singapore, both of which in the meantime are issuing written confirmations. Most of the other countries, including India, China, South Korea, Canada, and Taiwan, have decided they will issue written confirmations.
India, which the Commission says has 496 API plants supplying the EU, has published a comprehensive list of all the sites for which written confirmations are being or have been issued by the Central Drugs Standards Control Organization (CDSCO). This regularly updated list is freely accessible on the internet, and includes copies of the certificates issued.
As an example of an Indian written confirmation, Lupin received a certificate on 5 July for a plant in Mandideep that produces APIs such as cefaclor, cefpodoxime proxetil, lisinopril and ramipril. It confirms that the plant meets EU-equivalent GMP standards and is subject to "regular, strict and transparent control," including unannounced inspections. The facility was last inspected in February 2012, and the written confirmation is valid until 2 July 2016.
China, with 438 sites, has said it will issue confirmations, but only for sites that are overseen by the State FDA. There are understood to be 30-40 sites that are not registered with the State FDA, and the European industry body EUCOPE has urged companies sourcing from those sites to encourage them to seek registration. The Chinese FDA said that it would set up a database on information collected on domestic manufacturing sites, to which the EU authorities would have access.
While much progress has been made in a relatively short time, the dust has not yet fully settled, and it is possible that, for an initial period of time of perhaps a few months, some batches of API will arrive at the EU's borders without the necessary documentation. Moreover, there are lingering concerns that the failure of some member states to implement the Directive into their national laws could cause legal difficulties.
These eventualities were foreseen, and earlier this year the EMA and Heads of Medicines Agencies issued guidance as to what to do in such circumstances, including quarantining of the product until the situation has been clarified and, in certain cases, a GMP inspection conducted. The UK MHRA published its own procedure for dealing with such products on a new website designed specifically to offer guidance to the new rules.
One possible hiccup, the MHRA noted, is that sometimes APIs move through other member states before arriving in the destination country, and an importer in the UK, for example, will need to comply with the requirements of the other member states. This applies in particular to the second waiver (i.e. where the API manufacturing site has been inspected by an EU member state and has received a certificate of compliance with EU GMP).
If an API is imported via Germany under this waiver, the import requirements are applied at the border, so the importer must apply to the relevant body in Germany for a special certificate justifying the lack of a written confirmation. UK importers will need to arrange such imports with a German importer, otherwise consignments could be held up in Germany.
Generally speaking, though, things seem to be going quite smoothly. At the end of August the European Commission told Scrip it had not been notified of any critical disruptions of API supplies of manufacture of finished products following implementation of the new rules, nor of any significant problems associated with the handling of API consignments without the required written confirmation.
As for concerns over member states not implementing the legislation, the Commission said that as of 27 August, seven member states had still not transposed the falsified medicines Directive into national law. However, this had not created any "critical problems" with the entry of APIs to the EU, it said, chiefly because most of those countries had implemented measures to ensure that only APIs complying with the new rules were allowed in. The seven countries that had not notified the Commission of transposition were the UK (which has since done so), Finland, Slovenia, Portugal, Poland, the Netherlands and Italy.
The Commission said it was closely monitoring the situation during the interim period, with the support of the EMA and via continuing contacts with industry, member states and exporting country authorities. In light of experience in the first eight weeks since the rules were applied, though, "we don't expect this teething period to be very long – a matter of a few months, possibly." It said it would "remain extremely vigilant to prevent problems linked to the poor implementation of the rules."
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