EMA's Inspectors Working Group will get together at the end of February. According to the "Concept Paper on the development of toxicological guidance for use in risk identification in the manufacture of different medicinal products in shared facilities" published in October 2011, the question of "Dedicated Facilities" and the determination of limits for cleaning validation will be addressed.
Yet, a first internal draft for a guideline has been announced which is elaborated together with a specialists' team of EMA's Safety Working Party (SWP). The key question which should be answered in this paper concerns the maximal acceptable carry over between products manufactured in the same facility or plant. Limits which have been frequently used until now for cleaning validation (namely the 1/1000 dose and the 10ppm criterion) are being questioned by the inspectorate expert group as they do not take into account the available pharmacological/ toxicological data. For instance, the so-called lead effect of a substance is not taken into consideration. This is the first effect which occurs when increasing doses of a medicinal product. This may be the pharmacologically desired therapy effect (actually the basis for calculating) or undesired adverse effects like, for example, teratogenicity in case of a drug for cancer. One of the possibilities to take into account these effects is to use the ADE (acceptable daily exposure) value. The calculation is based on the complete and actual toxicological and pharmacological properties of the substance. Basically, these include information about the lead effect of the substance, the NOEL (No Observed Effect Level) for the lead effect concerned, indications regarding bioavaibility of the substance and appropriate safety factors. The maximal values calculated on the ADE basis generally exceed the previous limits which are based on the 10ppm criterion or 1/1000 daily dose. Substances with a lead effect - which is not the same as the pharmacological therapy effect - may lead to a stricter value for the cleaning limit. Furthermore, the different dosage forms must be taken into account in the calculation. Indeed, when fixing the limit of a contaminating product A (for example to be taken orally), an important factor to consider is whether the subsequent product B is to be administered orally too or for parenteral use.
It is still unclear if and to what extent the requirement for dedicated facilities for certain products (like antibiotics, hormones, cytostatics) will become more detailed, i.e. as a detailed products list.
Still, the manufacture of highly active substances in multipurpose facilities is permitted as long as the manufacturer has performed a scientific risk assessment which exempts him from the obligation of producing in a mono plant. The new EMA Guideline should put an end to this grey area. It is expected that the guideline should contain certain cornerstones for the risk analyses concerned, i.e. indications for the calculation of acceptable residual contamination according to the respective ADEs. At the earliest, the draft should be published by June 2012. According to the current timetable, the guideline should become effective from March 2013 on with a 6-month implementation deadline.
Dr Robert Eicher
CONCEPT HEIDELBERG (a service provider entrusted by the ECA Foundation)