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

Systems Strengthening & Market Development Approaches Working Groups

Addis Ababa

21 June 2011

Peter Hall, Chief Executive Officer, Concept Foundation

Quality of reproductive health medicines

• WHO’s Prequalification programme• RHSC Quality of reproductive health (QuRHM) programme• Misoprostol

RH Medicines Eligible for PQ, May 2010Hormonal contraceptivesCombined 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

Reproductive health products prequalified

INNFormulation and

strengthCompany Manufacturing site Date of PQ

Ethinylestradiol+Levonorgestrel

Coated tablets 30µg+150µg

Bayer Schering Pharma AG

Weimar, Germany 26 May 09

Ethinylestradiol+ Desogestrel

Tablets 30µg+150µg

NV Organon Oss, The Netherlands

29 Sep 10

Etonogestrel Implant 68mg NV OrganonOss, The Netherlands

02 Jun 10

LevonorgestrelCoated tablets 30µg

Bayer Schering Pharma AG

Weimar, Germany 26 May 09

Levonorgestrel Tablets 0.75mg Gedeon RichterBudapest, Hungary

20 Aug 10

LevonorgestrelImplants 2 rods x 75mg

Bayer Schering Pharma

Turku, Finland 23 Sep 09

Lynestrenol Tablets 500µg NV OrganonOss, The Netherlands

02 Jun 10

Medroxyprogest-erone acetate

Suspension for injection 150mg/ml

Pfizer Puurs, Belgium 20 Aug 10

Problems, perceptions and mythsThe 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.” 

Status of dossiers under assessment

in progress additional data required dossier acceptable

Product (INNs) Strength Unit Dosage Form Quality Efficacy/Safety

levonorgestrel 75 mg implant  

levonorgestrel/ethinylestradiol 150/30 µg tablet  

levonorgestrel/ethinylestradiol 150/30 µg tablet  

levonorgestrel/ethinylestradiol 150/30 µg tablet  

levonorgestrel/ethinylestradiol 150/30 µg tablet + placebo  

levonorgestrel/ethinylestradiol 150/30 µg tablet + placebo

norethisterone enantate 200 mg/ml depot injection  

oxytocin 10 IU/ml solution, injection  

oxytocin 10 IU/ml solution, injection  

Reproductive health product dossiers

Product SubmittedNot

accepted Cancelled Pending ApprovedLevonorgestrel/ethinylestradiol, 150/30 µg tablets

16 5 5 5 1

Desogestrel/ethinylestradiol,150/30 µg tablets

1 — — — 1

Levonorgestrel, 750 µg tablets 5 2 2 0 1Levonorgestrel, 30 µg tablets 4 1 2 0 1Lynestrenol, 0.5 mg tablets 1 — — — 1Levonorgestrel, 150 mg 2-rod implant

2 — — 1 1

Etonogestrel, 68 mg implant 1 — — — 1Depot medroxyprogesterone acetate, 150 mg injection

5 — 4—

1

Norethisterone enantate, 200 mg injection

2 1 — 1 —

Norethisterone enantate/estradiol valerate, 5/50 mg injection

2 2 — — —

Oxytocin, 10 IU/ml 3 — 1 2 —Total 42 11 14 9 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

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.

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.

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.

Addressing problems, dispelling mythsWHO:

•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.

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.

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

API manufacturers Company LNG DES EE MPA EC MS MF OXY MgS

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

1617

18

19

20

21

22

23

No products PQd 2/1/0 1/0/0 2/1/0 2/0/0 0/1/1 2/1/0 2/0/0 1/0/0 -

FPP manufacturersCompany COC

LNG/EEPOP LNG

ECP LNG

POI Comb.Inj.

Implant LNG

Miso Mife Oxytocin MgS

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 PQd 3/1/2 0/1/0 0/4/0 0/2/1 0/2/0 0/0/1 0/4/1 0/2/2 0/1/1 0/1/0

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

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?

Misoprostol content by age

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

110%

120%

130%

0 200 400 600 800 1000 1200 1400 1600 1800 2000

Mis

op

rost

ol c

on

ten

t (%

LA

)

Time (days)

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.

Addressing these problemsConcept 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.

Access for All- call to action

More than twenty new reproductive health products prequalified by WHO in the next three years