Simulation study stability OxytocicsMichiel de Goeje

- 2 -

Study design

Simulation study of several products of several brands at several storage conditions

Ergometrine injection

Methylergometrine injection

Oxytocine injection

- 3 -

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

- 4 -

Design

Influence of light

Manufacturing characteristics•pH, oxygen, antioxidants

Colour changes

- 5 -

Results and conclusion

Both Ergometrine as well as Methylergometrine are very sensitive to light.

- 6 -

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

- 7 -

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

- 8 -

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

- 9 -

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

- 10 -

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

- 11 -

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

- 12 -

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%

- 13 -

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%

- 14 -

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 !

- 15 -

•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

- 16 -

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

- 17 -

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.

- 18 -

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

- 19 -

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

- 20 -

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

- 21 -

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

- 22 -

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

- 23 -

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

- 24 -

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

- 25 -

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

- 26 -

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