Access to quality-assured medicines for maternal and child health: focus on uterotonics

Joint UNICEF-UNFPA-WHO Meeting with Manufacturers and SuppliersLester Chinery

Copenhagen, Denmark – 24 September 2018

Introduction

• WHO recommends that, all women giving birth should be offered uterotonics during the third stage of labour for the prevention of PPH; oxytocin (IM/IV, 10 IU) is recommended as the uterotonic drug of choice. Other injectable uterotonics and misoprostol are recommended as alternatives for the prevention of PPH in settings where oxytocin is unavailable.

• Numerous studies in recent years have demonstrated that the quality of 2 key uterotonics (oxytocin and misoprostol) – used in the prevention and treatment of PPH and other maternal health indications at point of use in many LMICs are sub-standard

• Procurement of uterotonics and other maternal health medicines is highly fragmented and predominantly procured by governments direct from manufacturers or other wholesalers for LMI Countries – purchasing by international agencies/wholesalers very limited

• Unlike family planning commodities and medicines for the major communicable diseases (ie: HIV/AIDS, tuberculosis and malaria), maternal health medicines (uterotonics) are not primarily supported or procured by international donors and agencies

Why does uterotonic quality matter?

• 27.1% of all maternal mortality deaths are caused by hemorrhage, and of these 19.7% are due to PPH

• In 2015, it was estimated 303,000 women died during childbirth, with two countries accounting for over one third of the global figures.

• Globally, every 6 minutes, a new mother dies from bleeding complications

Many of these deaths are preventable with the use of a high quality, effective uterotonic

Download at:

https://www.conceptfoundation.org/wp-content/uploads/2018/03/Oxytocin-Quality-Evidence-for-Action.pdf

Oxytocin Quality –Evidence for Action

• A publication detailing the collectionof all published (and someunpublished) studies relating to thequality of oxytocin

• An advocacy tool targeted toward governments of LMICs

The impact of poor quality

Quality Problem Effect

Contains too much active ingredient needed to achieve the expected result

Too much oxytocin can cause additional side effects and/or contractions that are too strong

Contains too little active ingredient need to achieve the expected result

Failure of the uterus to contract, continued bleeding, hemorrhage, additional surgical interventions, use of additional drugs, potential death

Contains anything else Medicines containing anything other than they are supposed to can cause serious and sometimes fatal consequences

In the case of injectables, is not sterile Unsterile injectable medicines can cause serious infections and sometimes death

Poor quality is a waste of life and resources

The Evidence – Poor quality products are in country markets

Nigeria 201812 74.2% of oxytocin samples failed

India 201713 41.3% of oxytocin samples were out of specification

WHO Systematic Review of Literature 201614

45.6% of oxytocin samples failed quality tests (median prevalence of failed samples)

WHO Quality of Misoprostol 201615 45% of misoprostol samples tested were out of specification

UNCOLSC 201516 64% of oxytocin injection samples non-compliant

India 201417 Oxytocin ampoules outside manufacturer specification:

36.4% in Karnataka State

50% in Uttar Pradesh State

Methylergometrine ampoules outside manufacturer specification:

97.8% in Karnataka State

49% in Uttar Pradesh State

Ghana 201318 and 201419 55.62% of the 169 oxytocin samples failed assay (2013), 62% failed (2014)

74% of ergometrine amps, 100% of ergometrine tabs failed assay (2013), 73.5% failed (2014)

97.5% of oxytocin samples failed API sterility, assay, or both (2013)

Oxytocin injection is not heat stable

• 8 significant studies• Laboratory stability testing of oxytocin formulations, or• “real life” stability testing where samples are followed through the supply chain and

tested at different points for reaction to temperature.

• Oxytocin degrades when stored outside refrigeration

• Product labelled for storage at 20 degrees – no different to product labelled store 2-8 degrees (UNFPA Monash study)

• Heat stability is a problem because:• Low income countries lack access to reliable, effective cold chains for medicines• The temperatures in many LMICs are consistently high enough to cause oxytocin to

degrade• Degraded oxytocin won’t be as effective as it should be, or not at all, resulting in poor

maternal health outcomes.

MisoprostolTablets

• Misoprostol tablets are subject to degradation when exposed to moisture• During manufacture of

API• During manufacture of

FPP• When inappropriately

packaged

Summary of results of 345 samples

• Of 304 samples of misoprostol FPPs 143 (47.0%) were OOS; and 41 samples of misoprostol from combination kits of which 6 (14.6%) were OOS.

• Out of 345 samples, 138 (40.0%) contained less than 90% labelled content, many significantly. One in 10 had less than 30% content!

• Samples packaged in plastic/aluminium were far more susceptible to degradation, 57 out of 74 (77.0%) contained less than 90% labelled content as opposed to 81 out of 270 (30.)%) packaged in aluminium/aluminium

Analysis of 345 samples of misoprostol products

0.00%

10.00%

20.00%

30.00%

40.00%

50.00%

60.00%

70.00%

80.00%

90.00%

100.00%

110.00%

120.00%

130.00%

0 200 400 600 800 1000 1200

Mis

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t (%

LA)

Time (days)

Generics - pl/alu

Generics - alu/alu

SRA, PQd, ERP

"Counterfeit/no miso"

Important findings

• Misoprostol degrades as a result of moisture – packagingand manufacturing can both contribute

• At one year:• Samples packaged in plastic/alu blisters, 5 of 54 (9%) remained

within specifications. Samples packaged in alu/alu blisters, 94 of 133 (71%) remained within specifications.

• Product packaged in plastic/alu starts to deteriorate at 6 months and most show significant degradation at one year.

But, packaging in alu/alu is not a guarantee of lack of degradation. Number of products packaged in alu/alu do show degradation – due to manufacturing environment/ inadequate control of humidity and/or delayed blister packaging.

Procurement and supply of uterotonics

In 2017, Concept Foundation undertook research to interrogate the supply chain for uterotonics. Respondents were:

• UN organisations involved in the procurement of uterotonics.

• International wholesalers specializing in medicines supply to public (and private) sectors of low and middle-income countries.

• International NGOs known to have large procurement organisations and operations covering maternal health:

• MEG• UNFPA• IDA Foundation• UNICEF• IFRC• Imres• Missionpharma• MSF• Action Medeor• DPSA• MSI

Significant procurement of uterotonics

Table 1: Significant procurement of uterotonics in 2016:

Organisation Medicine Quantity

MEG Oxytocin 10IU 4,500,000*

UNFPA Oxytocin 10IU 2,653,943#

Imres Oxytocin 10IU 1,500,000*

IDA Foundation Oxytocin 10IU 1,120,500

IDA Foundation Ergometrine 438,900#

UNFPA Misoprostol 2,253,150

DPSA for Nigeria All uterotonics In excess of £1M per year

# Based on UNFPA Planned Procurement for 2016. Actual procurement may have been as low as 847,649 for oxytocin and as

high as 2,582,553 for misoprostol, according to the Procurement Statistics table included in the 2017 RFP for Medicines Supply

issued in July by UNFPA. However, these tables were found to contain errors including duplication and incoherent

information.

* Supply includes private and public sectors.

Volume of uterotonics supplied by international organisations represents less than 20% of the total volumes for LMICs

0% of the total volumes for LMICs

h of the total volumes for LMICs

0% of the total volumes for LMICs

Pricing

Minimum and maximum prices from international agencies/wholesalers. Research indicates local purchase prices at lower rates in most LMICs.

Table 2: Minimum and maximum prices for uterotonics

Medicine Item Min. Price

$ Organisation

Max. Price $

Organisation

Oxytocin 10IU Ampoule 0.0785 Missionpharma 0.28 UNFPA

Oxytocin 5IU Ampoule 0.135 Imres 0.423 Action Medeor Intl.

Misoprostol Tablet 0.09 Missionpharma 0.83 Action Medeor Intl.

Methylergometrine maleate 0.2mg

Ampoule 0.08 IDA Foundation 0.35 Imres

0% of the total volumes for LMICs

0% of the total volumes for LMICs

Funding

• International funding (provided by donors) does support maternal health commodity purchases through general health financing

• Very little direct donor support for MH commodities – hence limited role of international procurement organisations

• Countries are required to develop their own health budgets, allocating funds as they see fit to maternal health programs and medicines

Processes

• Vary considerably across institution:• Type of contract with manufacturers – long term agreements,

single supply contracts, work orders etc.• Physical product route – manufacturer to central (European)

warehouse to customer, manufacturer direct to customer-common in manufacturing countries.

• Frequency, regularity and size of purchases.• Product registration requirements – use of wholesalers or

international agencies can get around product registration requirements in some countries (to be identified through procurement mapping research). Some wholesalers assist with product registration.

Uterotonics

• Oxytocin, misoprostol and ergometrine are main uterotonics being procured for use in LMIC’s for the prevention and treatment of post-partum haemorrhage.

• Oxytocin and ergometrine require refrigeration and medically trained staff for parenteral administration.

• Misoprostol can be kept at room temperature and is suitable for administration outside a medical facility due to its tablet formulation.

Issues encountered by institutions procuring uterotonics

• Heat stability – some will not procure goods which require cold-chain if they cannot guarantee cold chain all the way to the facility. Additionally, information relative to the heat stability of oxytocin is often unclear and sometimes procurers also unclear

• Short shelf-life – most agencies and organisations will require a product to have minimum 75% remaining shelf-life when it is received, some require 95% and a minimum of two years.

• Extra cost involved with transporting and storing products requiring cold-chain (which are usually transported by air), resulting in a less-competitively priced product.

• High presence of low-quality uterotonics available locally at very low prices.

• Regulatory aspects – Lack of registrations of QA products, due to lack of market for QA products!

Public sector procurement map

Conclusions

• The key uterotonics oxytocin and misoprostol are products which areprone to degradation if not manufactured, packaged and transported under adequate conditions

• Both products are primarily purchased at country level via fragmented and highly diverse supply chains from multiple manufacturers at extremely low prices.

• Purchasing by international agencies with policies and procedures to ensure product quality is limited. Major donors provide limited support for the procurement

• Substantial evidence exists that many products used in LMICs are sub-standard