Valsartan – Implications

Dr Andrew Teasdale – Chair AZ Impurities Advisory Group Pharmaceutical Industry and Regulators Symposium – May 2019

Valsartan recall

July 5th EMA made a press release relating to a product recall.

This relates to Valsartan manufactured by Zhjiang Huchai Pharma and

contamination with a known carcinogen

Dimethyl nitrosamine (DMNA) also referred to as N-Nitrosodimethylamine

(NDMA)

LEVELS NOT REPORTED INITIALLY

2

N

N

NH

N

N

CH3

CH3

O

CH3

O

OH

Valsartan recall

• Also mentioned in other press releases

• Multiple requests – globally 3

Media reaction

4

5

N-Nitrosodimethylamine (NDMA)

6

• Known animal

carcinogen

• Part of Cohort of

concern as

defined in ICH

M7

• TTC not

applicable

Valsartan Recall – Key Points

• Issue arose due to a change in the manufacturing process

• The exact change was not reported.

• However it is considered that the issue arose during the manufacture of the tetrazole ring

• Usually manufactured using an azide + nitrile

• e.g. tributyl tin azide + R-CN

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N

N

NH

N

N

CH3

CH3

O

CH3

O

OH

Valsartan Recall – Key

Points

• To generate NDMA requires the presence of Dimethylamine + Nitrite where do they come from?

• DMF from the azide step may contain dimethylamine which carries into the NaNO2 step.

• Disproportionation of DMF to dimethylamine and CO is known to be catalysed by acids and bases so the ZnCl2

may also lead to dimethylamine under the conditions over the 13hours at 80°C.

Valsartan Recall – Key Points

• To generate NDMA requires the presence of

Dimethylamine + Nitrite where do they come from?

• Zhjiang Patent – NaNO2 used in process

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Valsartan Recall – Key Points

• Why use NaNO2 ?

• Wikipedia reports the following

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Valsartan recall

11

Is this in fact correct?

NDEA – proposed mechanism

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Scope

• Concerns also relate to other drugs in the same

class

• Containing the tetrazole ring

13

Request from the French agency

No.3- Indicate in each case, in

collaboration with DS manufacturing sites,

if the DS manufacturing process include a

step which may lead to a potential

formation/development of N-nitrosamine

impurity especially in the last steps of DS

synthesis.

• Please take into account the impurities

or reagents in a solvent for

example dimethylamine in

dimethylformamide.

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Other N-Nitrosamines • Continued concerns expressed due to

the detection of other N-Nitrosamines.

– N-Nitrosodiisopropylamine (NDIPA

or DIPNA) and N-

Nitrosoisopropylethylamine (NIPEA

or EIPNA)

– NMBA (N-methyl-4-aminobutyric

acid), is generated from N-methyl-4-

aminobutyric acid.

• N-methyl-4-aminobutyric acid is

generated from the

decomposition of N-methyl-2-

pyrrolidone (NMP)

– Even of Valsartan itself

Not all risks are the same - Candesartan

• Although Candesartan contains the same tetrazole ring as Valsartan the synthesis is very different:

• DMF not used in tetrazole stage

• Tetrazole stage multiple stages from API

15

16

Pro

ce

ss

Co

ntr

ol Triethylamine

NPA

TCV-116

MET

(Tetrazole ring

formation step)

TCV-116(T) CV-11974

BEC

CV11974(T)

[ ]MBNBANMNA

DMF Sodium nitrite

TriethylamineDMF

Crude TCV-116

Starting

materialIntermediate

Drug

substance

Source of

nitrite

Source of

secondary

amine

High purge factor for dimethylamine

and other secondary amines

(8x1017

)

High purge factor for

sodium nitrite (1x106)

DMF

Potential source of

secondary amines

Purge of DMF, triethylamine and

any potential secondary amine

Purged

Purged

After formation of the tetrazole ring, the final 4

process steps provide multiple unit operations for

additional purging before drug substance

High purge factor

for DMF (7x109)

and NEt3 (8x108)

The magnitude of the calculated purge factors preclude the formation of nitrosamine

impurities during the tetrazole ring formation stage. In no instance are all of the

constituents for formation of N-nitrosamines present in the manufacturing process.

Purged

(if present) Purged

(if present)

Purged

(if present)

Purge of

sodium nitrite

In no instance are all the constituents for formation of N-nitrosamines present in the manufacturing process

Candesartan -Outcome of

testing

• > 100 batches of API tested –NDMA not detected Limit 150ppb

• NDEA also not detected

• DMA Not detected in Stage 5 (tetrazole) <100ppb

• Nitrite not detected in Stage 5

Article 31

• Pursuant to Article 31 of Directive 2001/83/EC, the European Commission initiated a procedure on 5 July 2018.

• The investigation has now been finalised and the report submitted to the European Commission

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Article 31 – Key points

The CHMP requires the following:

➢ Obligatory risk assessments to be performed for manufacturing processes of the drug substances in order to evaluate the theoretical risk of N-nitrosamine formation and contamination.

➢ Modifying manufacturing processes, where necessary, to minimise contamination as much as possible.

➢ Implement a control strategy to detect and control N-nitrosamine impurities in the API (or intermediate, if justified).

In terms of limits an interim position in place for 2 years has been established based on ICH M7.

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Article 31

• After the transition period, a limit for NDMA and NDEA of maximum 0.03 ppm should be implemented, which reflects the lowest quantifiable level based on capability of the available analytical methods.

• The underlying concept of the proposed approach is to keep the amount of N-nitrosamine impurities as low as possible, irrespective of the type of sartan or dose.

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Drug

substance

Max. daily

dose (mg)

NDEA

Limit in ppm in

API

NDMA

Limit in ppm in

API

Valsartan 320 0.082 0.300

Losartan 150 0.177 0.640

Olmesartan 40 0.663 2.400

Irbesartan 300 0.088 0.320

Candesartan 32 0.820 3.000

Implications / concerns

Divergence from ICH M7 in terms of:

➢ Limits

➢ Control strategy options – focus on Option 1

➢ Despite the fact that Official Medicines Control Laboratories

(OMCLs) have in the case of many Sartans failed to detect

any N-Nitrosamines.

➢ Analytical methodology

➢ Concerns have been expressed by EPFIA members of

member states challenging the use of alternative methods,

other than the OMCL methods.

➢ Also concerns over ‘false +ves’ 21

Impact on Global Supply • FDA announcement, applies

only to losartan and only to

the impurity N-Nitroso-N-

methyl-4-aminobutyric acid

(NMBA),

• “Distributing losartan

containing NMBA up to 9.82

ppm, will help maintain

adequate losartan supply

while companies obtain

approval for manufacturing

processes that produce

nitrosamine-free losartan for

patients,” the FDA said.22

Further Notification – FDA Nitrosamine advice letter

• Letter outlines a series of

proposals that relate to control.

• These relate to the process as

well as analysis of API / DP

• Makes clear that applicants / MAH

must report any detected levels of

N-Nitrosamines

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Further Notification – FDA Nitrosamine advice letter

Perhaps the most challenging is the following:

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Next Steps

• We need to understand the fundamentals of the

reaction / process

• Sulphonate esters !

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Sulphonate Esters - Analytical Procedure Based upon PFTP

Derivatization

1) Samples withdrawn overtime and treated with:

F

F

F

F

F

S- Na+

+ NaOH

2) Samples spikedwith small amount ofd5 EMS:

CH3S

O

O

OCD2CD3

3) samples heated for period oftime (15 min at 105 deg C inpublished method) to effectderivatization and insureequilibration within theHeadspace prior to assay

4) Levels of Et PFTB and d5Et PFTB(internal standard) analyzed by GC/MS:

F

F

F

F

F

SCH2CH3

F

F

F

F

F

SCD2CD3

Et PFTB d5Et PFTB

Concentration values vs

time based upon ratio of

Et PFTP to d5Et PFTP

area counts

K. Jacq, et al J.Pharm.

Biomed. Anal, 2008, 48(5), 1339

S

O

O

OR' R

SH

F

F

F

F

FS

F

F

F

F

F

R

S

O

O

OHR'+ +

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Instrument Design

Headspace syringe for injection(gas only)

Headspace incubator (105 °C)

GC

Liquid syringe (sample prep)

Heated tray(40 – 70 °C)

MS

Dual rail system

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• Reactions of (O18) labelled methanol with MSA were analysed by CG-MS.

• Reaction occurs through nucleophilic attack of

the sulfonate anion on the protonated alcohol

– O18 label appears in the WATER.

– Precludes mechanisms where the alcohol

is the nucleophile - O18 label would have

been found in the ester.

• NB Solvolysis is a significant additional

mechanism consuming ester to form the ether

and regenerate sulfonic acid

R2 S O-H

O

O

R1 O H R2 S

O

O

O R1 O H

H

R2 S O-R1

O

O

H O H

+18

+18

-+

+18

• This critical proton dependence underpins all the observed results

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EMS Formation – Presence of 2,6-Lutidine

N

• Excess lutidine (green trace): Ester

Undetectable over background…

• REMEMBER THE MECHANISM : No Proton

– No reaction

Effect of Added Base (70C)

0

0.1

0.2

0.3

0 2 4 6 8 10 12Time (hr)

% c

on

ve

rsio

n

1M MSA, 70degC

2% deficit lutidine

9% excess lutidine

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Implications for the future

• The reaction between 2° amines and nitrite is predictable and known.

• Overall - There are only a small finite number of side reactions that potentiallyform MIs.

• Even if formed, in any other step than the API stage, levels would be << levels of a reagent deliberately used in the synthesis

• Conclusion – there is no need to significantly revise the current assessment approach

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