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What do we know about the quality of misoprostol products? RHSC Membership Meeting Addis Ababa

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.

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What do we know about the quality of misoprostol products? RHSC Membership Meeting Addis Ababa

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  1. 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

  2. Misoprostol Misoprostol is closely related to the naturally- occurring prostaglandin E1 (15-deoxy-16-hydroxy- 16-methyl analogue of PGE1). Misoprostol acid is the active compound but misoprostol is manufactured as the methyl ester for issues of production and stability.

  3. Product availability - misoprostol • 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.

  4. 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.

  5. Misoprostol content by age

  6. Effects of packaging on misoprostolcontent by age

  7. Misoprostol impurities A+B+E by age

  8. Misoprostol content by age and manufacturer Package alu-alu alu-alu plastic-alu plastic-alu plastic-alu API A B B B/C ?/? Mfr 1 2 3 4 5/6

  9. 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.

  10. 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.

  11. 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 isas a 1% misoprostol dispersion in hydroxypropyl methylcellulose (HPMC). • In the 1980s, GD Searle almost abandoned development of misoprostol because of stability issues.

  12. 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.

  13. 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…..

  14. 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!

  15. 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.

  16. 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.

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