1. Simulation study stability Oxytocics Michiel de Goeje

2. - 2 - Study design Simulation study of several products of several brands at several storage conditions  Ergometrine injection  Methylergometrine injection  Oxytocine injection

3. - 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. - 4 - Design Influence of light Manufacturing characteristics pH, oxygen, antioxidants Colour changes

5. - 5 - Results and conclusion Both Ergometrine as well as Methylergometrine are very sensitive to light.

6. - 6 - Influence of light

7. - 7 - Influence of light

8. - 8 - Influence of light

9. - 9 - Influence Temperature

10. - 10 - Influence Temperature

11. - 11 - Influence Temperature

12. - 12 - Difference in products Average decrease in content after 1 year Oxytocin is the most stable product D4-8D21LrmD25D30 Ergometrine 5,1%21%91%27%31% Methyl- ergometrine 3,7%14%91%15%18% Oxytocin 0,0%4,1%7% 14%

13. - 13 - Variability in stability of the different products Relative Standard deviation in content after one year D4-8D21LrmD30 Ergometrine6%27%87%24% Methylergmetrine5%15%NA18% Oxytocin1.1%1.5%2.5%3.8%

14. - 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. - 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. - 16 - Stability current suppliers IDA Simulation studyD4-8D21LrmD25D30 Ergometrine5%21%91%27%31% Methylergometrine4%14%91%15%18% Oxytocin1.4%5%7% 15% Average decrease in content after 1 year (%) Current suppliersD4-8D21D25 Ergometrine2 % 19 % Methylergometrine 5 %*2,4 % Oxytocin2 %4 % * Stability from a different brand

17. - 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. - 18 - Stability current suppliers IDA Methylergometrine Labeled storage temperature 2-8°C or 25° depending on manufacturer The 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. - 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. - 20 - Pharmacopoeial requirements on sensitivity to light BP2005USP26 Ergometrine protect from light in a light resistant container Methyl- ergmetrine Not included in a light resistant container Oxytocin No require- ments

21. - 21 - On storage temperature Pharmacopoeial requirements BP2005USP26 Ergometrine2° to 8 °C8-15 ºC Methyl- ergometrineNot includedNo requirements OxytocinNo requirements2° to 8 °C

22. - 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. - 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. - 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. - 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. - 26 - Simulation study stability Oxytocics Stability data simulation study are based on study performed in collaboration with WHO WHO/DAP/93.6 Michiel de Goeje Pharmacist IDA Foundation