1. Systems Strengthening & Market Development Approaches Working Groups Addis Ababa 21 June 2011 Peter Hall, Chief Executive Officer, Concept Foundation

2. Quality of reproductive health medicines WHO’s Prequalification programme RHSC Quality of reproductive health (QuRHM) programme Misoprostol

3. RH Medicines Eligible for PQ, May 2010 Hormonal contraceptives Combined oral contraceptives, progestogen-only pills and emergency contraceptive pills - ethinylestradiol + desogestrel, tablet 30 micrograms +150 micrograms - ethinylestradiol + levonorgestrel, tablet 30 micrograms + 150 micrograms - levonorgestrel, tablet 30 micrograms - levonorgestrel, tablet 750 micrograms (pack of two); 1.5 mg (pack of one) - norethisterone, tablet 350 micrograms - norgestrel, tablet 75 micrograms Progestogen-only and combined injectable contraceptives - medroxyprogesterone acetate, depot injection 150 mg/ml, in 1-ml vial - medroxyprogesterone acetate + estradiol cypionate, injection 25 mg + 5 mg - norethisterone enanthate, injection 200 mg - norethisterone enanthate + estradiol valerate, injection 50 mg + 5 mg Implantable contraceptives - two-rod levonorgestrel-releasing implant, each rod containing 75 mg of levonorgestrel (150 mg in total) - etonogestrel, implant, 68 mg of etonogestrel Other medicines for maternal health Oxytocics and anti-progestogens - oxytocin, injection 10 IU, 1-ml - mifepristone 200 mg tablet (only to be used in combination with misoprostol) - misoprostol 200 microgram tablet Prevention and treatment of eclampsia - magnesium sulphate, injection 500 mg/ml, in 2-ml and 10 ml ampoule or Uniject

4. Reproductive health products prequalified INN Formulation and strength CompanyManufacturing siteDate of PQ Ethinylestradiol+ Levonorgestrel Coated tablets 30µg+150µg Bayer Schering Pharma AG Weimar, Germany26 May 09 Ethinylestradiol+ Desogestrel Tablets 30µg+150µg NV OrganonOss, The Netherlands 29 Sep 10 EtonogestrelImplant 68mgNV Organon Oss, The Netherlands 02 Jun 10 Levonorgestrel Coated tablets 30µg Bayer Schering Pharma AG Weimar, Germany26 May 09 LevonorgestrelTablets 0.75mgGedeon Richter Budapest, Hungary 20 Aug 10 Levonorgestrel Implants 2 rods x 75mg Bayer Schering Pharma Turku, Finland23 Sep 09 LynestrenolTablets 500µgNV Organon Oss, The Netherlands 02 Jun 10 Medroxyprogest- erone acetate Suspension for injection 150mg/ml PfizerPuurs, Belgium20 Aug 10

5. Problems, perceptions and myths The study concluded: “Overall, the findings from this survey indicate that pharmaceutical manufacturers consider PQP to be a well-designed, well-executed programme. PQP assessors and inspectors are meeting or exceeding manufacturer expectations for service delivery in the process. However, pharmaceutical manufacturer applicants place a premium on feedback, communications and problem resolution during the prequalification process – with particular emphasis on the assessment of product dossiers – and these are potential improvement areas in the service design of PQP.”

6. Status of dossiers under assessment in progress additional data requireddossier acceptable Product (INNs)StrengthUnitDosage FormQuality Efficacy/ Safety levonorgestrel75mgimplant levonorgestrel/ethinylestradiol150/30µgtablet levonorgestrel/ethinylestradiol150/30µgtablet levonorgestrel/ethinylestradiol150/30µgtablet levonorgestrel/ethinylestradiol150/30µgtablet + placebo levonorgestrel/ethinylestradiol150/30µgtablet + placebo norethisterone enantate200mg/mldepot injection oxytocin10IU/mlsolution, injection oxytocin10IU/mlsolution, injection

7. Reproductive health product dossiers ProductSubmitted Not acceptedCancelledPendingApproved Levonorgestrel/ethinylestradiol, 150/30 µg tablets 165551 Desogestrel/ethinylestradiol, 150/30 µg tablets 1———1 Levonorgestrel, 750 µg tablets 52201 Levonorgestrel, 30 µg tablets 41201 Lynestrenol, 0.5 mg tablets 1———1 Levonorgestrel, 150 mg 2-rod implant 2——11 Etonogestrel, 68 mg implant 1———1 Depot medroxyprogesterone acetate, 150 mg injection 5—4 — 1 Norethisterone enantate, 200 mg injection 21—1— Norethisterone enantate/ estradiol valerate, 5/50 mg injection 22——— Oxytocin, 10 IU/ml 3—12— Total 42111498

8. Reasons for non-acceptance/cancellation Generic products Data provided do not demonstrate API or FPP quality Bioequivalence not demonstrated GMP standard not acceptable Innovator products Product not invited for prequalification Product not identical as approved by stringent authority Adequately documentation from stringent authority not provided

9. Problems, perceptions and myths The prequalification process is unnecessarily rigid and overly complex. It is slow and unresponsive. It favours western R&D-based pharmaceutical companies.

10. Problems, perceptions and myths The PQP applies internationally accepted criteria and uses the most qualified assessors and technical knowledge to assess the quality of products. It applies standards similar to those used by stringent regulatory agencies and which are beginning to be applied by other countries. It does not favour innovator companies and is keen to get generic reproductive health medicines prequalified. Most generic companies have been unable to respond adequately to the requirements.

11. Problems, perceptions and myths These perceptions have usually resulted from manufacturers not getting dossiers accepted or having them cancelled. This influences their attitudes to prequalification - something which is readily passed on to customers and surveys but not raised with PQP directly! Certainly, the programme started slowly and for some time there was a lack of information. WHO became aware of this and commissioned a study among manufacturers.

12. Addressing problems, dispelling myths WHO: Is giving RH medicines the highest priority. Will provide specific advice through at its assessment meetings in Copenhagen. Unlike other drug areas – no RH medicine manufacturer has taken advantage of this possibility. Is willing to provide an initial review of the quality part of the required dossier prior to formal submission of complete dossier. Has implemented improvements to PQP and has set specific time limits to inform and respond to manufacturers.

13. Addressing problems, dispelling myths The adoption of procurement policies (such as those approved by UNFPA’s Executive Board) that support prequalification or SRA approval is the greatest incentive for manufacturers to apply for prequalification.

14. RHSC QuRHM programme The Programme on Quality of Reproductive Health Medicines (QuRHM): funding under consideration by DfID; to be implemented by Concept, UNFPA and WHO; is a three year programme up to 31 July 2014; has four key outputs, relating to manufacturers, procurers, countries and RHSC stakeholders. Concept has developed an action plan for API and FPP manufacturers

15. API manufacturers CompanyLNGDESEEMPAECMSMFOXYMgS 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 No products PQd2/1/01/0/02/1/02/0/00/1/12/1/02/0/01/0/0-

16. FPP manufacturers CompanyCOC LNG/EE POP LNG ECP LNG POIComb. Inj. Implant LNG MisoMifeOxytocinMgS 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 No products PQd3/1/20/1/00/4/00/2/10/2/00/0/10/4/10/2/20/1/10/1/0

17. Activities 20 confidentiality/non-disclosure agreements in place between Concept and companies. APIs 9 priority companies, 14 others year 1, 6-12; year 2, 5-11, year 3, 0-6 PQd FPPs 18 priority companies, 7 others year 1, 3; year 2, 10-16; year 3, 10-16 PQd

18. SSWG/MDAWG Does the current list of products for prequalification represent all the products that you are purchasing? Can “The Interagency List of Essential Medicines for Reproductive Health” be revisited to update and prioritize? Can NDAs be established to ensure all current suppliers are approached for consideration in the QuRHM programme?

19. Misoprostol content by age

20. Misoprostol study - overall conclusions Significant problems with many misoprostol finished products relating to content and purity. Depending on the product, content can decrease rapidly between 3 months and one year. The key issues impacting on product quality are: - moisture at all stages, from API to storage of FPPs; - quality and stability of API; - manufacture of the FPPs; and - packaging of tablets.

21. 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.

22. Access for All - call to action More than twenty new reproductive health products prequalified by WHO in the next three years