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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

Quality of misoprostol products Asia Regional Meeting on Interventions for Impact in Essential Obstetric and Newborn

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

• Study on quality of misoprostol products • Factors influencing quality • What is being done

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 • Searle (now part of Pfizer), registered misoprostol, as Cytotec, worldwide (except for most

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

Product availability • In 2009, Ipas estimated are some 50 manufacturers of misoprostol worldwide. • In

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

Study on misoprostol content and purity Samples collected - 76 samples collected from Argentina, Bangladesh, Cambodia,

Misoprostol content by age

1200 20% 10% 0% 40% Time (days) Misoprostol content (%LA) 2000 1800 1600 1400 200 1000
1200
20%
10%
0%
40%
Time (days)
Misoprostol content (%LA)
2000
1800
1600
1400
200
1000
800
600
400
30%
0
130%
120%
110%
100%
90%
80%
70%
60%
50%

Prevention and Management of Postpartum Hemorrhage and Pre-eclampsia/Eclampsia. Dhaka, Bangladesh, 4-6 May 2012

Misoprostol content by age 1200 20% 10% 0% 40% Time (days) Misoprostol content (%LA) 2000 1800

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

Results on content and purity • 34 out of 74 samples tested had content less than
499 1 ?/? B/C B A Manufacturer 4 3 2 API Misoprostol Content (%LA) Time (days)
499
1
?/?
B/C
B
A
Manufacturer
4
3
2
API
Misoprostol Content (%LA)
Time (days)
5/6
476
223
277
100%
50
1931
384
238
113
741
245
771
610
472
140%
120%
80%
60%
40%
20%
0%
B
plastic-alu
plastic-alu
alu-alu
alu-alu
alu-alu
Package
130.00% 120.00% 110.00% 100.00% A 90.00% 80.00% 70.00% B Plastic-Alu Alu-Alu 60.00% 50.00% 40.00% 30.00% C
130.00%
120.00%
110.00%
100.00%
A
90.00%
80.00%
70.00%
B
Plastic-Alu
Alu-Alu
60.00%
50.00%
40.00%
30.00%
C
20.00%
10.00%
0.00%
0
200
400
600
800
1000
1200
1400
1600
1800
2000
Time (days)
Misoprostol content (%LA)
130.00% 120.00% 110.00% 100.00% A 90.00% 80.00% 70.00% B Plastic-Alu Alu-Alu 60.00% 50.00% 40.00% 30.00% C

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

Misoprostol study - overall conclusions • Results show significant problems with certain misoprostol finished products when

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

Factors influencing quality The quality of a misoprostol FPP is impacted by: • the API -

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 Results discussed with several of the principal manufacturers of misoprostol FPPs Evidence that

Addressing these issues

Concept has visited 14 companies and concluded:

Possible

Potential

Not very

Unlikely to

PQ by end

for PQ by

interested

achieve

of 2013

2015

PQ

5

2-3

3

3

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.

Prevention and Management of Postpartum Hemorrhage and

Pre-eclampsia/Eclampsia. Dhaka, Bangladesh, 4-6 May 2012

Addressing these issues Concept has visited 14 companies and concluded: Possible Potential Not very Unlikely to

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

Addressing these issues Concept is: • Working with VSI on a manual on best practices and

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 • To obtain products of assured quality, it must be understood that quality

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

Implications for procurement Preshipment testing may be of little value for inappropriately manufactured and packaged product.