Nitrosamines in sartans: A scandal or an unfortunate incident? - - PowerPoint PPT Presentation

Nitrosamines in sartans: A scandal or an unfortunate incident?

Thurloch O’Criodain QP Forum 23rd April 2020

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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.

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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

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Background - EMA

March 2020

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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.

What are Nitrosamines? The Most Common Types

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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). Structure Name Maximum Daily Intake

NDMA N-nitrosodimethylamine 96ng NDEA N-nitrosodiethylamine 26.5ng NDBA N-Nitrosodibutylamine 26.5ng

C H3 N CH3 N O CH3 N C H3 N O CH3 N C H3 N O

Other Nitrosamines

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Structure Name Maximum Daily Intake

NMBA 4-(methylnitrosamino)-butyric acid, also called BMSA 96ng NDIPA N-nitrosodiisopropylamine, also called DIPNA 26.5ng NEIPA N-nitrosoethylisopropylamine, also called EIPNA 26.5ng

N CH3 C H3 C H3 C H3 N O N CH3 C H3 C H3 N O

These 6 nitrosamines are sometimes referred to as “The Cohort of Concern”

N C H3 N O O OH

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.

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H N CH3 CH3

+ NO2

• N

N O CH3 CH3

How Nitrosamines are formed

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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.

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

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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.

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Timeline of events

EMA/EDQM FDA

Q1-18 Q2-18 Q3-18 Q4-18 Q1-19 Q2-19 Q3-19 Q4-19 Q1-20 Q2-20 Q3-20 Q1-18 Q4-20 EMA/EDQM Inspection September 5th-8th 2018 Taiwan FDA reported NDMA in Valsartan August 3rd. Deficiency list issued October 18th 2018 CAPA plan submitted November 15th 2018 Additional info request January 22nd 2019 Information sent February 21st 2019 Final report issued March 27th 2019

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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.

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Valsartan

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N CH3 O C H3 O CH3 O C H3 N N CH3 O C H3 O CH3 O C H3 N N N H N

NaN3, ZnCl2 Toluene, DMF Where are the amines? Where is the nitrite? The reaction is quenched with sodium nitrite to remove excess sodium azide

Losartan

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N N H O Cl C H3

+

N Br N N N C H3 OH Cl N N N C H3 OH Cl N H N N

TBAB, DMF toluene

TBAB is Tetrabutylammonium Bromide NMP is N-Methyl Pyrrolidone TEA is Triethylamine

NaN3, NaNO2 NMP , TEA-HCl

The role of DMF in Nitrosamine formation

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CH3 N H CH3

C H3 N CH3 N O

NDMA DMF Dimethylamine

DMF readily breaks down to diethylamine and formic acid The dimethylamine can then react with nitrite to form NDMA.

NO2

• Acid conditions

N CH3 C H3 O H

The role of NMP in Nitrosamine formation

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N CH3 O

C H3 NH O OH

C H3 N O OH N O

NMP NMBA/BMSA

NO2

NMP is a cyclic amide which readily opens to form a secondary amine. This can then react with nitrite ions to form BMSA (NMBA).

N-methyl-4-aminobutyric Acid

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.

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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.

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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.

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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

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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.

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Timeline of events

EMA/EDQM FDA

Q1-18 Q2-18 Q3-18 Q4-18 Q1-19 Q2-19 Q3-19 Q4-19 Q1-20 Q2-20 Q3-20 Q1-18 Q4-20 FDA Inspections At both sites April 2019 OAI letters issued July 2019 Losartan Deficiency Letter August 2019 Meeting with FDA October 2019 Additional questions received Request for meeting with FDA Information sent in advance Supplementary information to FDA Sent November 2019 EMA/EDQM Inspection September 5th-8th 2018 Taiwan FDA reported NDMA in Valsartan August 3rd. Deficiency list issued October 18th 2018 CAPA plan submitted November 15th 2018 Additional info request January 22nd 2019 Information sent February 21st 2019 Final report issued March 27th 2019

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EIR issued April 2020 Further comments from FDA Response issued

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

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FDA Observation: Lab equipment

Your firm’s performance qualification of «laboratory equipment» did not evaluate the system operating parameters for the range of conditions likely to be encountered in routine test methods. In addition the PQ did not establish calibration and maintenance intervals or define performance checks…….. The observation relates to USP «736» and mass accuracy/mass resolution Action: Complete requalification of the relevant equipment. The systems use a tuning fluid to check mass accuracy and mass resolution. The company implemented systems for regular checks using the tuning fluid and periodic replacement of the fluid.

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FDA Observation: Test methods

Your validation of test method…..used to detect NDEA and NDMA…..did not evaluate if there would be interference that could affect recovery…… Actions: Ongoing analytical method development and revalidation. The test method has been refined and requalified twice since April 2019. The method was improved to have a validated LOD of 5 ppb for NDMA in both Losartan and Valsartan.

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FDA Meeting, October 2019

One of the options FDA has with companies in OAI status is to call for a compliance review meeting. That is what happened in this case. 14 questions were received in advance of the meeting, with 12 days to prepare answers and submit to FDA. The questions related to such topics as:

• Risk assessment documents, and process validation reports.
• Destinations of batches shipped.
• Equipment qualification and compliance with USP «736»
• Qualification of test methods, sampling procedures, and test results.
• Controls on solvents, including tests on recovered solvents.
• Cleaning validation and cleaning procedures

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FDA Meeting Outcomes: More questions/instructions

• 1. Confirm all APIs to be tested for all six nitrosamines.
• 2. Provide more information on the test equipment used.
• 3. Review and verify the risks associated with triethylamine.
• 4. Test all recovered solvents for all nitrosamines and precursors.
• 5. Test fresh solvents for nitrosamines.
• 6. Provide analytical method validation reports.
• 7. Review the risk of N-nitroso derivatives of the API and implement associated

testing.

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DONE DONE DONE DONE DONE DONE IN PROGRESS

N-Nitroso derivatives of Sartans

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N CH3 O C H3 O CH3 O C H3 N NH N N

Valsartan

N N N C H3 OH Cl N H N N

Losartan The secondary amine in each could theoretically form a nitroso derivative. The toxicity of such a derivative is unknown. Preparation of standards and analytical method development are in progress

Current Status

• The company has identified the risks associated with nitrosamine formation in API

manufacture.

• The company has made significant improvements in process and material controls

to reduce and eliminate those risks.

• The company has implemented sophisticated analytical techniques that go

significantly beyond the levels associated with maximum daily intake.

• Current production is consistently below the LOD for nitrosamines:
• LOD for NDMA is currently at 2 ppb
• LOD for NDEA and NMBA is currently at 1 ppb
• The specification is “not detectable”.

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Timeline of events

EMA/EDQM FDA

Q1-18 Q2-18 Q3-18 Q4-18 Q1-19 Q2-19 Q3-19 Q4-19 Q1-20 Q2-20 Q3-20 Q1-18 Q4-20 FDA Inspections At both sites April 2019 OAI letters issued July 2019 Losartan Deficiency Letter August 2019 Meeting with FDA October 2019 Additional questions received Request for meeting with FDA Information sent in advance Supplementary information to FDA Sent November 2019 EMA/EDQM Inspection September 5th-8th 2018 Taiwan FDA reported NDMA in Valsartan August 3rd. Deficiency list issued October 18th 2018 CAPA plan submitted November 15th 2018 Additional info request January 22nd 2019 Information sent February 21st 2019 Final report issued March 27th 2019

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EIR issued April 2020 Further comments from FDA Response issued Inspection

Some developments

• The deadline for risk assessment completion has been extended by EMA until

March 2021.

• In June 2020, EMA issued a “Lessons Learned” document. It is recommended

reading.

• In July 2020, the EMA requirement to carry out a risk assessment was applied to

biological medicines, with a deadline of July 2021.

• In September 2020, FDA issued a guidance document: Control of Nitrosamine

Impurities in Human Drugs. That also requires risk analysis and corrective actions

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Was this a scandal or an unfortunate incident? The reality is probably somewhere in between the two. You can make up your own mind.

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Thank hank y you

• u

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THERE IS A LIGHT AT THE END OF EVERY TUNNEL. IF THERE ISN’T IT IS JUST A HOLE IN THE GROUND.

TOC Consulting Email: thurloch@live.com