Simulation study stability Oxytocics Michiel de Goeje
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Transcript of Simulation study stability Oxytocics Michiel de Goeje
Simulation study stability OxytocicsMichiel de Goeje
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Study design
Simulation study of several products of several brands at several storage conditions
Ergometrine injection
Methylergometrine injection
Oxytocine injection
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Study design
Different brands•3 or 4 brands for each product
•2 batches of each brand
Different temperatures•2-8°C, RT(21°), 25°, 30°, 40°, 50°C
Different times•0; 0.5; 1; 2; 3; 6; 12; 24 months
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Design
Influence of light
Manufacturing characteristics•pH, oxygen, antioxidants
Colour changes
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Results and conclusion
Both Ergometrine as well as Methylergometrine are very sensitive to light.
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Influence of light
Ergometrine
0
20
40
60
80
100
120
0 0.5 1 2 3 6 12 24
time (months)
acti
ve in
gre
die
nt
%
Lrm
Drm
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Influence of light
Methylergometrine
0
20
40
60
80
100
120
0 0.5 1 2 3 6 12 24
time (months)
act
ive
ing
red
ien
t %
Lrm
Drm
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Influence of light oxytocin
84
86
88
90
92
94
96
98
100
102
0 0.5 2 6 12 24
time (months)
act
ive in
gre
die
nt
(%)
D21
Lrm
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Influence Temperature
Ergometrine
0
20
40
60
80
100
120
0 0.5 1 2 3 6 12 24
time (months)
acti
ve in
gre
die
nt
%D4-8
D21
Lrm
Drm
D25
D30
D40
D50
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Influence Temperature
Methylergometrine
0
20
40
60
80
100
120
0 0,5 1 2 3 6 12 24
time (months)
acti
ve i
ng
red
ien
t %
D4-8
D21
Lrm
Drm
D25
D30
D40
D50
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Influence Temperature oxytocin
0
20
40
60
80
100
120
0 0,5 2 6 12 24
time (months)
acti
ve i
ng
red
ien
t (%
) D4-8
D21
Lrm
D30
D40
D50
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Difference in products
Average decrease in content after 1 year
Oxytocin is the most stable product
D4-8 D21 Lrm D25 D30
Ergometrine 5,1% 21% 91% 27% 31%
Methyl-ergometrine 3,7% 14% 91% 15% 18%
Oxytocin 0,0% 4,1% 7% 14%
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Variability in stability of the different products
Relative Standard deviation in content after one year
D4-8 D21 Lrm D30
Ergometrine 6% 27% 87% 24%
Methylergmetrine 5% 15% NA 18%
Oxytocin 1.1% 1.5% 2.5% 3.8%
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Colour changes
Both Ergometrine and Methylergometrine show discolouration if degradation is more then 10%.
Slight colour changes are not easy detectable in the field
Coloured injection should not be used !
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•The stability of ergometrine and methylergometrine is sensitive to changes in manufacturing proces
•Filling under nitrogen needed
•Oxytocin is more predictable in behaviour
Design and manufacturing conditions
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Stability current suppliers IDA
Simulation study D4-8 D21 Lrm D25 D30
Ergometrine 5% 21% 91% 27% 31%
Methylergometrine 4% 14% 91% 15% 18%
Oxytocin 1.4% 5% 7% 15%
Average decrease in content after 1 year (%)
Current suppliers D4-8 D21 D25
Ergometrine 2 % 19 %
Methylergometrine 5 %* 2,4 %
Oxytocin 2 % 4 % 4 %
* Stability from a different brand
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Stability current suppliers IDA
Oxytocin Labeled storage temperature 2-8°C (cool).The shelflife at this temperature is 3 years.
Advice for shelflife IDA products at higher temperature
• at 25°C the shelflife is reduced to 1 years.• at 30°C the shelflife is reduced to 6 months.• at 40°C transport maximum 1 week.
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Stability current suppliers IDA
Methylergometrine Labeled storage temperature 2-8°C or 25° depending on manufacturerThe shelflife at this temperature is 2 years.
Advice for shelflife IDA products at higher temperature (only for manufacturer Gland)
• at 25°C the shelflife is 2 years• at 30°C the shelflife is reduced to 1 year• at 40°C transport maximum 4 weeks
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Stability current suppliers IDA
ergometrine Labeled storage temperature 2-8°C The shelflife at this temperature is 2 years.
Advice for shelflife IDA products at higher temperature
• at 25°C the shelflife is reduced to 6 months• at 40°C transport maximum 2 weeks
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Pharmacopoeial requirements on sensitivity to light
BP2005 USP26
Ergometrineprotect from light
in a light resistant container
Methyl-ergmetrine
Not included
in a light resistant container
OxytocinNo require-ments
No require- ments
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On storage temperature
Pharmacopoeial requirements
BP2005 USP26
Ergometrine 2° to 8 °C 8-15 ºC
Methyl-ergometrine Not included No requirements
Oxytocin No requirements 2° to 8 °C
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Quality assurance
Product should be procured through a reliable source.
BP assay is not specific for degradation products and therefore release and stability studies should be based on analysis by validated HPLC methods
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Protect from light
Store refridgerated.
Manufacturer should be able to guarantee 2 years shelflife at refridgerated conditions.
Storage outside refridgeration (up to 30°C) may limit the shelflife to less then half year but is dependent on manufacturer.
Do not use coloured products.
Recommendation on storage ergometrine
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Protect from light
Store refridgerated, although some brand may guarantee it up to 25°C
Manufacturer should be able to guarantee 2-3 years shelflife at refridgerated conditions.
Storage outside refridgeration may limit the shelflife to a year but is dependent on manufacturer.
Do not use coloured products.
Recommendation on storage methyl ergometrine
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Recommended to store refridgerated.
It is expected to remain of sufficient quality if stored below 21°C up to 2 years.
When stored up to 30°C a loss of 15% in one year is expected. Thus shelflife is then limited to 6 months only.
Recommendation on storage Oxytocin
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Simulation study stability Oxytocics
Stability data simulation study are based on study performed in collaboration with WHO WHO/DAP/93.6
Michiel de GoejePharmacist IDA Foundation