What do we know about the
quality of misoprostol products?
RHSC Membership Meeting
Addis Ababa
24 June 2011
Peter Hall, Chief Executive Officer, Concept Foundation
Misoprostol
Misoprostol is closely related to the naturallyoccurring prostaglandin E1 (15-deoxy-16-hydroxy16-methyl analogue of PGE1). Misoprostol acid is
the active compound but misoprostol is
manufactured as the methyl ester for issues of
production and stability.
Product availability - misoprostol
• Searle (now part of Pfizer), registered misoprostol,
as Cytotec, worldwide (except for most subSaharan 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.
Study on content and purity of misoprostol
Misoprostol products were collected and assessed
for content and purity.
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).
Two were excluded which contained diclofenac;
74 analyzed for content; and 58 for impurities.
Misoprostol content by age
130%
120%
Misoprostol content (%LA)
110%
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
0
200
400
600
800
1000
1200
Time (days)
1400
1600
1800
2000
Effects of packaging on misoprostol
content by age
130.00%
120.00%
110.00%
100.00%
Misoprostol content (%LA)
90.00%
80.00%
70.00%
Plastic-Alu
Alu-Alu
60.00%
50.00%
40.00%
30.00%
20.00%
10.00%
0.00%
0
200
400
600
800
1000
Tim e (days)
1200
1400
1600
1800
2000
Misoprostol impurities A+B+E by age
Sum of Imp A,B and E (ratio)
9
7.5
6
4.5
3
1.5
0
0
500
1000
Time (days)
1500
2000
Misoprostol content by age and manufacturer
Package alu-alu
API
A
Mfr
1
alu-alu plastic-alu plastic-alu plastic-alu
B
B
B/C
?/?
2
3
4
5/6
140%
100%
80%
60%
40%
20%
Time (days)
499
476
277
223
50
1931
384
238
113
741
245
771
610
0%
472
Misoprostol Content (%LA)
120%
Results on content and purity
• 34 out of 74 samples tested have content less than
90% of labelled content; 8 have less than 20%.
• After one year, 19 out of 31 samples tested have
content less than 90% of labelled content; 7 have
less than 20%.
• The content of some products appear to decrease
between 3 months and one year.
• 31 out of 58 samples tested have impurities
> EP/USP limits, 18 > 2x EP/USP limits.
• Most products packed in a plastic-alu blister
appear to deteriorate rapidly with time, more so
than with alu-alu blisters packs.
Misoprostol study - overall conclusions
• Problems of content and purity with certain
misoprostol finished pharmaceutical products
(FPPs).
• The key issues affecting product quality are:
- impact of moisture at all stages, from the
active pharmaceutical ingredient (API) to
the storage of FPPs;
- manufacture and quality of APIs;
- manufacture and quality of the FPPs; and
- packaging of tablets.
Factors contributing to problems
Active Pharmaceutical Ingredient (API)
• Pure misoprostol is an oil which must be stored
below -20°C. It is extremely sensitive to
humidity. For stability purposes the API
supplied for finished products is as a 1%
misoprostol dispersion in hydroxypropyl
methylcellulose (HPMC).
• In the 1980s, GD Searle almost abandoned
development of misoprostol because of
stability issues.
Factors contributing to problems
Manufacture of finished product
• There are between 30 and 40 manufacturers of
FPP worldwide. Several companies in India
use contract manufacturers.
• There are demonstrable differences in content
and purity between products from different
manufacturers. This may be due to: the quality
of the API purchased; inability to meet (or be
required to meet) current Good Manufacturing
Practice (CGMP); packaging; or a combination
of any of these.
Factors contributing to problems
Heat and humidity
• Many formulations are not stable above 25°C
if exposed to moisture. Humidity can have an
impact at all stages: manufacture of API;
manufacture of FPP; storage of inappropriately
packaged product.
Packaging
• Packaging is critical – this definitely relates to
humidity. There are less problems with
products using alu-alu packaging rather than
plastic-alu blister packs – but…..
Factors contributing to problems
Transport and storage
• Temperature and humidity have a significant
impact during the transport and storage of the
API and the FPP; the manufacturing process of
the FPP and the packaging of the product.
• Product shipped by sea and sitting on the shelf
of a drug seller’s store or even a hospital
pharmacy at >25°C and high humidity is at risk
of being physiologically ineffective!
Addressing these problems
Concept is:
• Developing analytical specifications and impurity
limits for 1% misoprostol in HPMC and
misoprostol FPP.
• Developing FPP manufacturing specifications.
• Planning technical assistance to selected
manufacturers for submission to WHO’s PQP of:
- documentation on two APIs; and
- the quality documentation and the design and
implementation of bioequivalence studies for up
to six FPPs.
Thanks are due to:
Ms Navaporn Tagontong and her staff at Health
Concepts International, Bangkok for the
analytical work.
Gynuity Health Projects for funding the study.
Friends and collaborators who collected the
samples.