Module 3 - Strategic case studies in practice

the SWP response section. SWP derived a class specific TD 50 by using the TD 50 data of all nitrosamines listed in Lhasa carcinogenicity potency database (LCDB) and use of the lower 5th percentile. This TD 50 is then used to calculate the excess risk which would in theory not exceeded with 95% probability by any nitrosamine. The extrapolation to the excess risk level for cancer is then done by linear back extrapolation to the dose theoretically causing a 1:100,000 risk by dividing the TD 50 by 50.000 (50% or 0.5 x 100,000). This results in a class specific TTC of 18 ng/d ensuring with 95 % probability for any nitrosamine that a theoretical excess cancer risk of 1 in 100,000 will not be exceeded. The CHMP agreed that alternatively to the above TTC an SAR approach can be used as discussed in 2.5 above. Nitrosamines were first detected in sartans containing a tetrazole ring. The API manufacturing process was identified as the main source of those nitrosamine impurities and nitrosamine formation could be prevented by changes to the manufacturing processes. Therefore, the most stringent approach, an “avoidance” strategy, was chosen as outcome of the sartan referral. However, since the sartan referral, other medicinal products have been found to contain nitrosamine impurities originating from various root causes and, in some cases, still unknown root causes. The variety of the root causes and the possibility of multiple sources of contamination renders the outcome of the sartan referral not generalisable to all cases where nitrosamines are identified. In this context it should be mentioned that the nitrosamine impurities found in sartans, especially in valsartan from one API manufacturer, were considerably higher than those found in most other medicinal products later on. Subsequent to the sartan referral, low level presence of nitrosamines in some finished product batches from one MAH were attributed to the primary packaging. Setting limits in the API would not have addressed this particular root cause. The knowledge acquired since the sartan referrals confirmed that the root causes can be numerous, concomitant, at any stage of the production or storage of the medicinal product and cannot always be characterised. Therefore, a general “avoidance” strategy is not considered a realistic and feasible goal and would foreseeably lead to shortage problems of critical medicinal products. Therefore, CHMP was concerned with striking a viable balance in the best interest of patients, taking into account drug safety and ensuring availability of drugs that are important to human health. The as-low-as-reasonably-possible (ALARP) approach is applied in fields outside of medicinal products and is mainly understood as reaching the lowest possible level that is feasible in terms of manufacturing capability for the majority of the operators (e.g. in the rubber industry), and at the same time is safe enough for consumers. Whilst acknowledging the suitability of this approach in the fields where it is applied, the CHMP identified issues specific to medicinal products that do not render this approach suitable for the pharmaceuticals. There is no consistent and transparent way for regulators to determine when a pharmaceutical company has reduced the nitrosamine levels to an as far as reasonably possible level for a given medical product. It is also unclear how this can be handled in a regulatory manner so that MAHs and their medicinal products are treated in a consistent way, independent of the type of procedure (centralised, decentralised and national) and the relevant assessing competent authorities. It can be foreseen that the ALARP approach would result in inconsistent setting of specifications for the same products across the European Union due to subjectivity of the assessment related to this concept. The ALARP concept is based on the criterion of ‘reasonably practicable’ which is understood as the cost involved in reducing the risk further would be grossly disproportionate to the benefit gained. Whilst this approach is adapted to certain sectors, this is not advisable for the purpose of defining a limit for medicinal products, as establishing a ratio between industrial and public health factors for 2.5.3. Other risk management approaches

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