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 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.
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

130%
120% 110%

Misoprostol content (%LA)

100% 90% 80% 70% 60%

50%
40% 30%

20%
10% 0%

200

400

600

800

1000

1200

1400

1600

1800

2000

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

Manufacturer 1 API A Package alu-alu

140%

2 B alu-alu

3 B alu-alu

4 B/C plastic-alu

5/6 ?/? plastic-alu

120%

Misoprostol Content (%LA)

100%

80%

60%

40%

20%

0%
472 610 771 245 741 113 238 384 50 223 277 476 1931 499

Time (days)

130.00% 120.00% 110.00% 100.00% 90.00%

Misoprostol content (%LA)

80.00% 70.00%

B
60.00% 50.00% 40.00% 30.00%

Plastic-Alu Alu-Alu

C
20.00% 10.00% 0.00% 0 200 400 600 800 1000 Time (days) 1200 1400 1600 1800 2000

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

Concept has visited 14 companies and concluded:
Possible PQ by end of 2013 5 Potential for PQ by 2015 2-3 Not very interested 3 Unlikely to achieve PQ 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 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 WHOs 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