Simulation study stability Oxytocics

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• Simulation study stability Oxytocics
• Michiel 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
• 2-8C, RT(21), 25, 30, 40, 50C
• 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
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Influence of light
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Influence of light
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Influence Temperature
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Influence Temperature
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Influence Temperature
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Difference in products
Average decrease in content after 1 year
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
Oxytocin is the most stable product
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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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Design and manufacturing conditions

• The stability of ergometrine and
  methylergometrine is sensitive to changes in
  manufacturing proces
• Filling under nitrogen needed
• Oxytocin is more predictable in behaviour

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Stability current suppliers IDA
Average decrease in content after 1 year ()
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
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 2-8C (cool).
• The shelflife at this temperature is 3 years.
• Advice for shelflife IDA products at higher
  temperature
• at 25C the shelflife is reduced to 1 years.
• at 30C the shelflife is reduced to 6 months.
• at 40C transport maximum 1 week.

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Stability current suppliers IDA

• Methylergometrine
• Labeled storage temperature 2-8C 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 25C the shelflife is 2 years
• at 30C the shelflife is reduced to 1 year
• at 40C transport maximum 4 weeks

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Stability current suppliers IDA

• ergometrine
• Labeled storage temperature 2-8C The shelflife
  at this temperature is 2 years.
• Advice for shelflife IDA products at higher
  temperature
• at 25C the shelflife is reduced to 6 months
• at 40C transport maximum 2 weeks

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Pharmacopoeial requirements on sensitivity to
light
  BP2005 USP26
Ergometrine protect from light in a light resistant container
Methyl-ergmetrine Not included in a light resistant container
Oxytocin No require-ments No require- ments
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Pharmacopoeial requirements

• On storage temperature

  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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Recommendation on storage ergometrine

• Protect from light
• Store refridgerated.
• Manufacturer should be able to guarantee 2 years
  shelflife at refridgerated conditions.
• Storage outside refridgeration (up to 30C) may
  limit the shelflife to less then half year but is
  dependent on manufacturer.
• Do not use coloured products.

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Recommendation on storage methyl ergometrine

• Protect from light
• Store refridgerated, although some brand may
  guarantee it up to 25C
• 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.

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Recommendation on storage Oxytocin

• Recommended to store refridgerated.
• It is expected to remain of sufficient quality if
  stored below 21C up to 2 years.
• When stored up to 30C a loss of 15 in one year
  is expected. Thus shelflife is then limited to 6
  months only.

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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 Goeje Pharmacist IDA Foundation