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
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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
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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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