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Peter Hall (Concept Foundation)
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Quality of misoprostol products
Asia Regional Meeting on Interventions for Impact
in Essential Obstetric and Newborn Care:
Prevention and Management of
Postpartum Hemorrhage and Pre-eclampsia/Eclampsia
and Special Care for Newborns
Dhaka, Bangladesh, 4-6 May 2012
Peter Hall, Chief Executive Officer,
Concept Foundation, Bangkok and Geneva
• Study on quality of misoprostol products
• Factors influencing quality
• What is being done to address issues
• Implications for procurement
Prevention and Management of Postpartum Hemorrhage and
Pre-eclampsia/Eclampsia. Dhaka, Bangladesh, 4-6 May 2012
Product availability
• Searle (now part of Pfizer), registered misoprostol,
as Cytotec, worldwide (except for most sub-
Saharan African countries) for the prevention
of gastric ulcers associated with NSAIDs.
• Misoprostol is widely available as generic
formulations and, in many countries, cheaply.
• Has begun to be registered for obstetric
indications in various countries.
• Included on WHO Model List of Essential Medicines
for induction of labour; incomplete abortion; with
mifepristone for early abortion; and for prevention of PPH.
Prevention and Management of Postpartum Hemorrhage and
Pre-eclampsia/Eclampsia. Dhaka, Bangladesh, 4-6 May 2012
Product availability
• In 2009, Ipas estimated are some 50
manufacturers of misoprostol worldwide.
• In India are some 30 brands of misoprostol and 10
brands of combination packs of mifepristone and
misoprostol; are several contract manufacturers
giving at least 16 FPP manufacturers;
• Are at least 20 brands in other lower and middle
income countries, excluding China and S Korea.
Because of proliferation of products, Gynuity Health
Projects funded Concept Foundation to undertake a
study on quality of misoprostol FPPs.
Prevention and Management of Postpartum Hemorrhage and
Pre-eclampsia/Eclampsia. Dhaka, Bangladesh, 4-6 May 2012
Study on misoprostol content and purity
Samples collected
- 76 samples collected from Argentina,
Bangladesh, Cambodia, Egypt, Kenya, India,
Mexico, Nigeria, Pakistan, Peru and Viet Nam.
(30 from India, 23 from other Asian countries,
14 from Africa and 9 from Latin America).
Samples analyzed
- 2 excluded which included diclofenac;
- 74 analyzed for content, 58 for impurities.
Prevention and Management of Postpartum Hemorrhage and
Pre-eclampsia/Eclampsia. Dhaka, Bangladesh, 4-6 May 2012
Misoprostol content by age
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
110%
120%
130%
0 200 400 600 800 1000 1200 1400 1600 1800 2000
Mis
op
rosto
l co
nte
nt
(%L
A)
Time (days)
Prevention and Management of Postpartum Hemorrhage and
Pre-eclampsia/Eclampsia. Dhaka, Bangladesh, 4-6 May 2012
Results on content and purity
• 34 out of 74 samples tested had content less than 90% of labelled content; 8 had less than 20%.
• One year from manufacture, 19 out of 31 samples tested had content less than 90% of labelled content; 7 had less than 20%.
• The content of some products appear to decrease between 3 months and one year.
• 31 out of 58 samples tested had impurities > EP/USP limits, 18 > 2x EP/USP limits.
Prevention and Management of Postpartum Hemorrhage and
Pre-eclampsia/Eclampsia. Dhaka, Bangladesh, 4-6 May 2012
0%
20%
40%
60%
80%
100%
120%
140%
472
610
771
245
741
113
238
384
1931
50
223
277
476
499
Time (days)
Mis
op
ros
tol C
on
ten
t (%
LA
)API
2 3 4 Manufacturer
A B B B/C ?/?
1 5/6
Package alu-alu alu-alu alu-alu plastic-alu plastic-alu
0.00%
10.00%
20.00%
30.00%
40.00%
50.00%
60.00%
70.00%
80.00%
90.00%
100.00%
110.00%
120.00%
130.00%
0 200 400 600 800 1000 1200 1400 1600 1800 2000
Time (days)
Mis
op
ro
sto
l co
nten
t (
%L
A)
Plastic-Alu
Alu-Alu
C
A
B
Misoprostol study - overall conclusions
• Results show significant problems with certain
misoprostol finished products when analyzed
for content and purity.
• With a few products, misoprostol appears to
degrade rapidly between 3 months and one
year (these would not have been detected by
preshipment QC!).
But there are quality products that do not
deteriorate with time.
Prevention and Management of Postpartum Hemorrhage and
Pre-eclampsia/Eclampsia. Dhaka, Bangladesh, 4-6 May 2012
Factors influencing quality
The quality of a misoprostol FPP is impacted by:
• the API - how it was manufactured: whether
manufacture meets current Good Manufacturing
Practices (CGMP); and how it is stored;
• the manufacturing process of the finished
product - whether it meets CGMP; whether
adequate environmental controls instituted
during manufacturing process; and conditions
under which the finished product is stored;
• the type of packaging used.
Prevention and Management of Postpartum Hemorrhage and
Pre-eclampsia/Eclampsia. Dhaka, Bangladesh, 4-6 May 2012
Addressing these issues
Results discussed with several of the principal
manufacturers of misoprostol FPPs
Evidence that appropriate environmental control
at all stages of manufacturing process and use of
a double aluminium blister pack will prevent
degradation of the finished product.
With API is of proven quality and appropriate
quality assurance procedures established,
manufacturers can make quality FPPs.
Prevention and Management of Postpartum Hemorrhage and
Pre-eclampsia/Eclampsia. Dhaka, Bangladesh, 4-6 May 2012
Addressing these issues
Possible
PQ by end
of 2013
Potential
for PQ by
2015
Not very
interested
Unlikely to
achieve
PQ
5 2-3 3 3
Concept has visited 14 companies and concluded:
Prevention and Management of Postpartum Hemorrhage and
Pre-eclampsia/Eclampsia. Dhaka, Bangladesh, 4-6 May 2012
In the absence of prequalified products, UNFPA has
instituted an interim process for product review by a
new Expert Review Panel for RH Medicines to be
undertaken by WHO. Manufacturers must demonstrate
adequate compliance with GMP and a commitment to
continue to prequalification. Up to 5 products could
complete this process in 2-6 months.
Addressing these issues
Concept is:
• Working with VSI on a manual on best practices
and technical information for finished product
manufacturers. Draft about to be made available.
• Working with two API manufacturers to get
misoprostol dispersion prequalified by WHO.
• Providing technical assistance to selected
manufacturers for to meet CGMP and submit
appropriate documentation first to the new
ERP/RHM and then to WHO’s PQ Programme
Prevention and Management of Postpartum Hemorrhage and
Pre-eclampsia/Eclampsia. Dhaka, Bangladesh, 4-6 May 2012
Implications for procurement
• To obtain products of assured quality, it must be
understood that quality cannot be assessed, tested or
inspected in finished products - quality must be built in!
• WHO prequalification helps minimize risk and allows
procurers greater confidence in their risk management
strategies. Concept is aiming for 4 FPPs prequalified
by end of 2013.
• Meantime, in order to reduce risk and avoid duplication
of effort, procurers should work towards a harmonized
procurement and quality assurance strategy that
acknowledges the following issues.
Prevention and Management of Postpartum Hemorrhage and
Pre-eclampsia/Eclampsia. Dhaka, Bangladesh, 4-6 May 2012
Implications for procurement
Preshipment testing may be of little value for
inappropriately manufactured and packaged
product.
Procurers must ensure that misoprostol FPPs are
sourced from a manufacturer that can demonstrate:
• API and excipients are of proven quality,
supported by a DMF
• FPP is manufactured under CGMP and
appropriate environmental controls
• FPP is packed in a double aluminium blister pack
Prevention and Management of Postpartum Hemorrhage and
Pre-eclampsia/Eclampsia. Dhaka, Bangladesh, 4-6 May 2012