Does quality matter?

1. Does quality matter? Peter Hall Chief Executive Officer Concept Foundation Bangkok, Thailand and Geneva, Switzerland

2. Does quality matter -to the people that use the products? Poor quality product can: • Contain extraneous impurities or increased levels of known degradation products from the API, improper manufacture or inappropriate storage - can lead to increase in known side-effects; other adverse events; and in extreme circumstances, serious adverse events, such as anaphylactic shock or death. • Have poor content uniformity - leading to overdosing or failure of treatment.

3. Does quality matter -to the people that use the products? This means poor quality hormonal contraceptives can: • Give rise to adverse events BUT are adverse events recorded? Adverse events are recorded in clinical trials but recording is virtually impossible in routine use in many countries. Even if we could – we counsel women to put up with side-effects! • Lead to failure BUT we accept there is lower efficacy in routine use rather than “ideal” use – we blame it on the woman! The impact of poor quality hormonal contraceptives is hard to measure BUT we know that by ensuring availability of quality products the risk is minimized.

4. Does quality matter -to the people that buy the products? Poor quality product leads to: • Additional testing and rejection of batches • Loss of time • Waste of product and money • Legal fees • Stock outs

5. Does quality matter -to the people that buy the products? • The extent of the problem of contraceptive need and the way we address it means that the buying community is concerned with getting the greatest amount of product for the lowest price. • Many manufacturers are willing to compete at low cost and bear any resulting risks/costs. • BUT this is false economics – designing and assuring quality products may mean higher production costs but lower overall costs!

6. Why quality matters –the people that buy the products • Purchasing a product that has been approved by a stringent drug regulatory agency or prequalified by the WHO programme means that all aspects of quality and safety and efficacy of the product have been assessed. • This can never be a 100% guarantee but it is an enormous step forward to eliminate poor quality products.

7. Nearly twenty years ago • “Numerous examples of problems relating to the quality of hormonal contraceptive formulations from various developing country manufacturer have been reported following observation and analysis of products obtained from pharmacies or other service delivery points (P.E. Hall, S. Matlin and M. Morrow, personal communication). Examples have included: • Oral contraceptives • tablets with highly variable active ingredient content. In one example, these ranged from 14% (4.2μg) to 141% (42μg) of labelled content. In another, tablets contained up to 1,000μg instead of 50μg of ethinyl estradiol; • tablets that crumbled in the packaging; • discoloured tablets; • tablets with active ingredients misplaced in the • placebo tablet row; • faulty packaging. • Injectable contraceptives • active ingredients that were clumped, preventing them • from being resuspended in the vehicle.”

8. Four years ago – company review • A review of 47 companies showed that most companies manufacture products according to outdated requirements that do not conform to CGMP, or even outside GMP. Many have inadequate understanding and ability to implement and invest in quality assurance. Some should be closed! • Most are not in a position to supply products into international markets, not having considered regulatory approval for their products outside their home markets. (Hall et al, Contraception, 2007:75,311-317)

9. Four years ago – prequalification of essential RH medicines • In January 2006, the MDAWG held a meeting of a Subgroup on generic manufacturers • Its findings and recommendations were resulted in commitment to prequalification at the RHSC meeting in Bonn in October 2006. • The first Expression of Interest for products for reproductive health was issued by WHO’s Prequalification Programme in October 2006.

10. So what is the situation today? • There has been significant work undertaken to improve quality. In particular, the PQ programme has received some 37 product applications. Three contraceptive products have been prequalified and a further 11 are under review (+ 1 oxytocin). • There has been an increasing awareness on the part of both procurers and suppliers that quality matters. Moreover, as we will hear from the Global Fund, WHO prequalification of products yields results. • So what are the challenges that remain and why are we not further forward?

11. So what is the situation today? • Many generic manufacturers have not: • appreciated that national GMP approval, is not always • CGMP • understood the process of prequalification • been able to compile appropriate dossiers or have • inadequate data to do so • have not been willing or able to undertake • bioequivalence studies • had the incentive to invest in upgrading their facilities • or processes or have still been getting orders for • existing product. • We are on the cusp of change – it has taken time but the ability to purchase quality assured products will happen!

12. What are the issues? Hormonal contraceptives • contain highly potent drugs • require separate manufacturing facility with own HVAC, water • require worker protection • oral contraceptives contain tiny amounts of API • injectables must be sterile • content uniformity can be a problem for both tablets and injectables

13. Amount of API in a tablet

14. Amount of API in a COC tablet

15. Current Good Manufacturing Practice(WHO TRS 908, 2003 – Annex 4) Good Mfg Practices QA GP in quality control Sanitation & hygiene GP in production Qualification & Validation Documentation Complaints Materials Equipment Product recalls Premises Contract production & analysis Personal hygiene Self-inspection & Quality audits Training Personnel

16. Challenges to procuring quality products • Since there are no generic products yet PQ’d, procurers are still having to undertake their own risk management. • This is not a uniform process nor do different procurers have a common definition of risk.

17. Challenges to procuring quality products • Were there ordering time constraints to be met? • Were there agreed criteria for the audit? • What is the background of the auditor? Have they had any production experience? • Was the production facility functioning and, if so, was the product being manufactured? • Can a single auditor on a short trip address all “17 GMP issues” in depth? • How was the report written – were there conditions to be met before purchase could be considered?

18. Can all 17 issues be addressed in depth? Good Mfg Practices QA GP in quality control Sanitation & hygiene GP in production Qualification & Validation Documentation Complaints Materials Equipment Product recalls Premises Contract production & analysis Personal hygiene Self-inspection & Quality audits Training Personnel

19. Addressing these challenges • Prequalification helps minimize risk and allows procurers greater confidence in their risk management strategies. • Meantime, it would help procurers both in terms of risk management and avoiding duplication of effort to work towards a harmonized procurement and quality assurance strategy, in particular, the development of a common set of approaches to assessing manufacturers and their products.

20. To obtain products of assured quality Quality cannot be assessed, tested or inspected in Quality has to bebuilt in!

21. Does quality matter? Yes!