20/21 April 2021
In July 2012 the EU Commission published a new requirement for APIs manufactured outside of the EU. Since January 2013 all imported APIs need to be accompanied by a so called "Written Confirmation" (except a few countries with equivalent GMP standards like the US and Switzerland) which should confirm that the manufacturing site is working under GMP (ICH Q7). The idea behind the approach of the EU Commission was to put pressure on regulators outside of the EU to supervise the GMP compliance of the manufacturing sites located in their home country. In fact, about 80% of the APIs used to manufacture medicinal products for patients in Europe come from countries outside of the EU, many of them from Asia (especially from India and China). The EU Commission came to the conclusion that inspections prior to the first import into the EU and regular GMP compliance inspections e.g. every three years would not be possible because of the high number of manufacturing sites located outside of the EU. For medicinal products, these initial inspections and compliance inspections are mandatory.
A number of associations and reports have questioned the idea to rely on foreign authorities to issue the "Written Confirmation". Some groups had concerns because if the EU does not have an MRA agreement in place with a certain country (which would require an evaluation of similar standards for inspections) why should the EU then rely on a certificate which confirms that inspections by the local authority would be able to confirm compliance with GMP for APIs (ICHQ7)? Moreover, many countries do not inspect on the basis of ICH Q7. They have their own regulations (such as China and India) which require less than ICH Q7. So from a pure practical point of view, compliance with ICH Q7 can not be confirmed by those countries.
However, the system has been in place since 2013, and after a few months with more or less issues, the written confirmation procedure has now been established. Companies receive the certificate required for the import. So everything is fine - or not?
A country of major concern was India. There have been reports that even medicinal product manufacturers are not controlled by the authority. What about API manufacturing sites then? Over the last years EU and FDA inspectors have found more and more problems in Indian manufacturing sites. It was kind of a surprise that only a few months after the EU requirements on written confirmations have come into force a huge list of Written Confirmations was published. Many of them expired in 2016 because each Written Confirmation has to contain a validity date and as they were issued in 2013, a 3-year validity period was considered reasonable (this is normally the time period after which a re-inspection should be performed but the validity period is not defined in the requirements for Written Confirmations).
This is why the CENTRAL DRUGS STANDARD CONTROL ORGANIZATION (CDSCO) has issued a list of renewed Written Confirmations now. Currently, this Written Confirmation list contains 230 manufacturers which comply to ICH Q7. A detailed look at the confirmation reveals that the overall system might need some further investigation and maybe also a better control. Some examples:
- Some Written Confirmations have been issued for a much longer period than 3 years. For example Mac-Chem Products in India (Boisar, Dist.-Thane-401 506, Maharashtra) obtained a Written Confirmation in May 2014 valid until April 2017. So, everything is fine? Maybe not, because the inspection used as a basis for the Written Confirmation had already been performed on 11 January 2012. This extends the validity to 5 years and 3 months. It is also very unlikely that a one-day inspection is able to identify major GMP problems. In Europe a one-day inspection would only work for a small site with only a few employees, but not for a chemical plant.
- The Written Confirmation of Vitalife Laboratories (a division of Pharmalabs Limited) Village-Pathreri, Bilaspur Tauru Road, Distr. Gurgaon (Haryana) 122 412 has also been issued following a one-day inspection. However, the certificate states that the inspection was performed on 28 September 201x. The last digit is missing!
- Some Written Confirmations have been issued on the basis of FDA and EU inspections. But this was never the intention. The local authorities should have the oversight of the GMP status. Moreover, the Indian authorities might not have the full details of the inspection reports. Europe does not publish them and FDA only releases part of the information. This makes a compliance decision by a foreign authority impossible.
- Some Written Confirmations have been issued although FDA and/or EU authorities found the manufacturing site out of compliance. This means, the Indian Authority has confirmed the GMP compliance although products are legally no longer allowed to enter ICH markets such as Europe or USA. On the list of the renewed Written Confirmations one can find:
The random samples reveal that the current procedure in India (and maybe in other countries as well) need to be evaluated in more detail. Either a stronger control of the procedure regarding Written Confirmations in foreign countries by EU Commission or own inspections (e.g. in cooperation with FDA) should be considered. In the past, it has been feared that the number of manufacturing sites outside of the EU would be too high to be inspected. Indeed, India as one of the most important countries counts 230 sites. All EU Members States together in cooperation with US FDA should have enough resources to inspect those sites every three years (would result in approx. 75 inspections per year).