Module 3 - Strategic case studies in practice

of the manufacturing site concluded that the proposed root cause was plausible. According to Kleemann, Engel (2019), two synthetic routes are usually applied to manufacture pioglitazone HCl on commercial scale. Pioglitazone HCl, contaminated with NDMA, was manufactured by a process similar to synthetic route I, making use of sodium nitrite for nitrosative diazotation of an aniline derivative. In contrast, synthetic route II enables manufacture of pioglitazone HCl without applying any nitrosating agent in the entire process. Due to the fact that the detected NDMA levels were found to be constantly kept below the limit of ≤ 1.935 ppm [NDMA ≤ 96.0 ng/day; MDD = 49.6 mg pioglitazone HCl] recalls of corresponding medicinal products were not initiated. Despite the additional possibility to avoid NDMA formation in the entire process e.g. by replacing the solvent DMF and herewith DMA as its nitrosatable impurity/degradation product, the API manufacturer has decided voluntarily to withdraw two CEPs on 30 July 2019. Following the above mentioned inspection, the manufacturing routes of all sources of pioglitazone HCl in the EU were assessed for the risk of N- nitrosamine formation. The MAHs using pioglitazone HCl from these manufacturers were subsequently requested to provide risk assessments for potential N- nitrosamine formation and batch analysis data on batches of their APIs. At this moment, seven CEPs for pioglitazone HCl remain valid according to the EDQM database, indicating with high probability a process specific route cause in this case. In summary, use of NaNO 2 and DMF in different but subsequent synthetic steps according to route I represents the critical compound combination responsible for N -nitrosamines generation and contamination in the entire pioglitazone HCl manufacturing process. Table 2.2.2.3-1 Critical Compound Combinations responsible for N -nitrosamine formation in pioglitazone HCl N- Nitrosamine NOX Source Amine Source Amine nitrosated by NOX Critical Compound Combination

O

O

N H DMA

reagent/solvent

N N

N

NaNO 2

NDMA

DMF

2.2.2.4. Root-causes identified in the ranitidine case

A review of ranitidine medicines (EMEA/H/A-31/1491) was initiated on 12 September 2019 at the request of the European Commission, under Article 31 of Directive 2001/83/EC 5 . This was in response to detection of NDMA in batches of active substance and finished product from a series of different manufacturers above the temporary limits defined in the sartans referral. After the finalisation of the review, final conclusions and any conditions and recommendations will be published on the EMA website. As a result of the discovery of NDMA in some ranitidine medicines, all CEPs for ranitidine HCl API were suspended by EDQM, indicating with high probability common process specific and/or common API specific root-cause(s) in these cases. In particular, NDMA formation from ranitidine over shelf life is being considered as a potential root cause 6 .

5 https://www.ema.europa.eu/en/medicines/human/referrals/ranitidine-containing-medicinal-products 6 https://www.ema.europa.eu/en/documents/referral/ranitidine-article-31-referral-chmp-list-questions_en.pdf

EMA/369136/2020

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