Nitrosamines in sartans: A scandal or an unfortunate incident? Thurloch O’Criodain QP Forum 23 rd April 2020 TOC Consulting 23/04/2020 1
Disclaimer • The issues and actions presented here are specific to the company and manufacturing sites in question. • I make no claim that they are appropriate or even applicable to any other company, manufacturing site or product. • They are presented here solely to outline the experience of one organisation, and if that experience is of benefit to others in evaluating risks and deciding on actions, then that is enough. TOC Consulting 2 23/04/2020
Agenda 1. What are Nitrosamines, and the types of most concern? 2. How are nitrosamines formed? 3. Case history: inspections, actions and results. 4. Current status TOC Consulting 3 23/04/2020
Background - EMA June 2018 – Notification to FDA of discovery of nitrosamines in Sartans at the Zheijiang Huahai Pharmaceutical Co. Rest of 2018 and 2019 – Other manufacturers of Sartans also found to be at risk. February 2019 – EMA assessment report EMA/217823/2019 January to April 2019 – Publication of test methods for nitrosamines from FDA, LOD as low as 5 ppb. September 2019 – Reports of nitrosamines in Ranitidine (trade name Zantac) products. September 2019 – EMA instruction to MAHs to evaluate all medicines, with target date of March 2020. Due to Covid-19, this was rescheduled to October. TOC Consulting March 2020 4
What are Nitrosamines? The Most Common Types Structure Name Maximum Daily Intake N O NDMA N-nitrosodimethylamine 96ng H 3 C N CH 3 H 3 C N O NDEA N-nitrosodiethylamine 26.5ng N CH 3 H 3 C N O NDBA N-Nitrosodibutylamine 26.5ng N CH 3 All are considered genotoxic and carcinogenic agents in animals and are classified as probably carcinogenic to humans (Class 2A carcinogen) by the International Agency for Research on Cancer (IARC, WHO). TOC Consulting 23/04/2020 5
Other Nitrosamines Structure Name Maximum Daily Intake N O NMBA 4-(methylnitrosamino)-butyric acid, H 3 C N 96ng OH also called BMSA O H 3 C N O NDIPA N-nitrosodiisopropylamine, N 26.5ng H 3 C CH 3 also called DIPNA H 3 C NEIPA N-nitrosoethylisopropylamine, H 3 C N O 26.5ng N also called EIPNA CH 3 H 3 C These 6 nitrosamines are sometimes referred to as “The Cohort of Concern” TOC Consulting 23/04/2020 6
How are Nitrosamines formed • In general, nitrosamines are formed in a reaction between secondary amines and nitrite ions under acid conditions. For example NDMA is formed from dimethylamine. O CH 3 CH 3 N N + NO 2 - H N CH 3 CH 3 TOC Consulting 7 23/04/2020
How Nitrosamines are formed EMA has said in document EMA/217823/2019 that it is possible to form NDEA from Triethylamine as shown here. In my experience this is a very low risk during sartan manufacture. TOC Consulting 23/04/2020 8
Case History • Company Profile: • Located in China • Two sites manufacturing sartans • Site 1 making Losartan, Irbesartan and Telmisartan • Site 2 making Valsartan, Olmesartan, Candesartan • Annual output >5000 tonnes/year TOC Consulting 9 23/04/2020
Sartans • Sartans belong to a class of medicines called Angiotensin Receptor Blockers (ARBs). • They are an effective medication against hypertension. • Generally well tolerated in the body, with relatively few adverse effects. • All are characterised by the presence of a tetrazole ring. TOC Consulting 10 23/04/2020
Timeline of events EMA/EDQM Inspection Deficiency list issued September 5 th -8 th 2018 October 18 th 2018 EMA/EDQM CAPA plan submitted Additional info request Information sent November 15 th 2018 January 22 nd 2019 February 21 st 2019 Taiwan FDA reported NDMA Final report issued in Valsartan March 27 th 2019 August 3 rd . Q1-18 Q1-18 Q1-19 Q2-18 Q3-18 Q4-18 Q2-19 Q3-19 Q4-19 Q1-20 Q2-20 Q3-20 Q4-20 FDA TOC Consulting 23/04/2020 11
Observation (The Company’s) knowledge of the process was considered as insufficient to detect and address risks associated with the use of reagents and solvents such as sodium nitrite, DMF, potable water, impurity profiles (e.g. secondary amines), etc. Actions: • Complete process review of steps that might give rise to nitrosamines and steps that would remove or reduce the risk of nitrosamines. • Revision of the manufacturing process with re-engineering of the process to avoid and to remove impurities. • Implementation of a robust process development process. TOC Consulting 12 23/04/2020
Valsartan Where are the amines? N Where is the nitrite? H N N N N NaN 3 , ZnCl 2 O O N N Toluene, DMF H 3 C H 3 C H 3 C O CH 3 H 3 C O CH 3 O CH 3 O CH 3 The reaction is quenched with sodium nitrite to remove excess sodium azide TOC Consulting 23/04/2020 13
Losartan Cl N Cl Br OH H 3 C N TBAB, DMF N N + O N N toluene H H 3 C Cl N OH NaN 3 , NaNO 2 N H 3 C N N H N N NMP , TEA-HCl TBAB is Tetrabutylammonium Bromide NMP is N-Methyl Pyrrolidone TEA is Triethylamine TOC Consulting 23/04/2020 14
The role of DMF in Nitrosamine formation O H 3 C CH 3 CH 3 N N - NO 2 Acid conditions H N N CH 3 H 3 C CH 3 O H DMF NDMA Dimethylamine DMF readily breaks down to diethylamine and formic acid The dimethylamine can then react with nitrite to form NDMA. TOC Consulting 23/04/2020 15
The role of NMP in Nitrosamine formation O CH 3 N OH OH NO 2 N O N NH H 3 C O H 3 C O N-methyl-4-aminobutyric Acid NMBA/BMSA NMP NMP is a cyclic amide which readily opens to form a secondary amine. This can then react with nitrite ions to form BMSA (NMBA). TOC Consulting 23/04/2020 16
Observations Other potential root causes were not considered, such as impurity re-introduction from recovered solvents. Actions: • Restrict use of recovered solvents to the step where they were originally used. • Testing of recovered solvents for NDMA, NDEA and NMBA • Only released for use after completion of testing. TOC Consulting 17 23/04/2020
Observations N-Nitrosodimethylamine can occur in drinking water through the degradation of dimethylhydrazine, as well as from several other industrial processes. Potable water is used throughout the manufacturing process of Losartan and Valsartan. The Company failed to include this potential source of nitrosamine contamination in their risk assessment. Actions: • Implementation of a testing program for incoming water to detect nitrosamines. • Spiking experiments at lab scale: Water spiked to 100 ppb with NDMA (reference WHO guidelines for potable water of 2017) showed no nitrosamine contamination in drug substance when other factors were controlled. TOC Consulting 18 23/04/2020
Observation The Company’s NDMA risk assessment for Valsartan and Losartan was considered as incomplete with regard to DMF used in the step before the tetrazole ring formation. For Valsartan, the company failed to address the risk of downstream carryover and potential reaction with HCl resulting in the by-product diethylamine. Action: Implemented revised procedures to reduce/eliminate risk of DMF carryover. TOC Consulting 19 23/04/2020
Observation The inspection team observed a phase separation after the quenching of azide with sodium nitrite. There was no permanent light installed behind the sight glass, making it difficult to assess the exact termination point. Actions: • Equipment upgrades to make the phase separation easier to see. • Retraining of operators to use the upgraded equipment TOC Consulting 20 23/04/2020
Observation The working standard for NMBA was insufficiently qualified. Furthermore, the specification for the standard (≥ 90.0% purity) was insufficient. Actions: Reference standards for NMBA are not readily available. A new standard was synthesised and confirmed at > 97% purity. Records of the analytical standard qualification were reviewed and approved. TOC Consulting 21 23/04/2020
Timeline of events EMA/EDQM Inspection Deficiency list issued EMA/EDQM September 5 th -8 th 2018 October 18 th 2018 CAPA plan submitted Additional info request Information sent November 15 th 2018 January 22 nd 2019 February 21 st 2019 Taiwan FDA reported NDMA Final report issued in Valsartan March 27 th 2019 August 3 rd . Q1-18 Q1-18 Q1-19 Q2-18 Q3-18 Q4-18 Q2-19 Q3-19 Q4-19 Q1-20 Q2-20 Q3-20 Q4-20 FDA Inspections At both sites April 2019 EIR issued April 2020 Further comments from FDA FDA OAI letters issued Response issued July 2019 Supplementary information to FDA Sent November 2019 Losartan Deficiency Letter August 2019 Meeting with FDA Request for meeting with FDA October 2019 Information sent in advance Additional questions received TOC Consulting 23/04/2020 22
FDA Observation: Complaints Process Written records are not always made of investigations into the failure of a batch or any of its components to meet specifications. The specifics relate to reports of nitrosamines in API which did not go through the standard complaint investigation process. Actions: • Revised procedures regarding Quality Incidents. • Review and revision of roles and responsibilities. • Review and revision of complaint workflows and communication processes TOC Consulting 23 23/04/2020
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