Medicines for children in developing countries: from challenges to specifications Atieno Ojoo Technical Specialist, Pharmaceuticals UNICEF Supply Division, Copenhagen, Denmark WHO PreQ; EU generic manufacturers meeting 261109, Copenhagen, Denmark

EU generic manufacturers meeting 261109, Copenhagen, Denmark Presentation outline Safety, efficacy and quality of medicines is a prerequisite before looking for appropriate formulations-UNICEF technical requirements for pharmaceutical products Without access and affordability, any medicine will not reach the intended beneficiary- Medicines do not work in those who do not take them UNICEF EU generic manufacturers meeting 261109, Copenhagen, Denmark

EU generic manufacturers meeting 261109, Copenhagen, Denmark Causes of death in under 5s World Health Statistics 2007 http://www.who.int/child_adolescent_health/data/child/en/index.html UNICEF EU generic manufacturers meeting 261109, Copenhagen, Denmark

Some success stories 2006 U5M <10 million (9.7m in 2006) 2007 1st WHO paediatric EML 1st Paediatric ARV FDCs 2008 1st Paediatric ACT antimalarial FDC U5M <8.8 million 2009 2nd Paediatric ACT Antimalarial FDC BUT Its not yet time to celebrate ! UNICEF EU generic manufacturers meeting 261109, Copenhagen, Denmark

Health worker challenges Weight & height measurements often not taken Busy clinics No weight and height measuring devices No suitable dose measuring & administration devices What is a teaspoonful? Any spoon? No spacers for MD Inhalers (Cost issue) Reconstitution of powders for oral suspension/liquid Challenge if bottles not marked Water supply challenges no cold storage Repackaging No clean bottles - patients have to bring own bottles, no measuring/counting devices no labels No standard methods for extemporaneous preparations Reformulating existing (adult) formulations In house manufacture, lack of critical ingredients Quality concerns UNICEF EU generic manufacturers meeting 261109, Copenhagen, Denmark

EU generic manufacturers meeting 261109, Copenhagen, Denmark Solutions? Splitting tabs or dividing caps powder 1/8 of Frusemide 40mg=5mg. How? Challenge if tablet is coated, not scored UNICEF EU generic manufacturers meeting 261109, Copenhagen, Denmark

Current solution: ½, ¼, 1/8 tablets UNICEF EU generic manufacturers meeting 261109, Copenhagen, Denmark

Patient/caregiver challenges Palatability-Child refuses to take medicine Too much liquid volume per dose Child vomits, not sure how much to re-administer No storage space for bulky liquids Also significant if caregiver has to carry and walk long distances Difficult to follow Instructions Mix with apple or apple-grape juice or applesauce or yoghurt Open capsule and sprinkle contents over a spoonful of applesauce, or yoghurt, consume immediately Crush tablets and mix with condensed milk prior to administration Break tablets into 8 equal pieces (How?) Dissolve tablet water, then administer by dropper, oral syringe (not provided) or drink directly To be swallowed whole- not to be chewed School going children-scheduling of when to give medicines? UNICEF EU generic manufacturers meeting 261109, Copenhagen, Denmark

EU generic manufacturers meeting 261109, Copenhagen, Denmark Challenges for HIV+ children Adult Child: too many bottles UNICEF EU generic manufacturers meeting 261109, Copenhagen, Denmark

EU generic manufacturers meeting 261109, Copenhagen, Denmark No cold storage Quote “ two years ago, I was involved in a study…….in children and adolescents. One of the subjects, a 5 year old boy, had to commute daily accompanied by either of his parents to the hospital to take the drug, which was a suspension that needed to be stored in a refrigerator. The family did not have a refrigerator and did not have electricity connection either, so we could not even donate a refrigerator as there was provision for this” UNICEF EU generic manufacturers meeting 261109, Copenhagen, Denmark

EU generic manufacturers meeting 261109, Copenhagen, Denmark WHO-UNICEF joint plan Work on a global project to make paediatric medicines a priority Add missing essential formulations to the Model list in 2009; advise on doses Develop EML for children (2007-8) Update treatment guidelines (2007-9) Develop paediatric prescribing information – a formulary Develop effective methods for provision of information at the point of care Collaborate with regulatory authorities to encourage appropriate drug development and approval processes in all regulatory authorities Develop quality standards for paediatric medicines Public development support for missing essential medicines for children Advocate for the development of paediatric medicines by the industry Develop a system for enhancing safety monitoring of medicines in children Provide guidance on procurement and supply of paediatric medicines UNICEF EU generic manufacturers meeting 261109, Copenhagen, Denmark

Ideal paediatric medicine Route of administration: Oral most frequently used Dosage form? SODF** Liquids? Sufficient bioavailability Dose uniformity Non toxic excipients Acceptable organoleptic properties: Taste Dosing aids Ease of administration for both parent and child Clear product information/instructions Cost effective Does not require cold storage Minimum steps of manipulation before use ** Chewable, fast melts, effervescent, granules, sprinkles, soluble tablets,, sublingual, etc If scored Must break easily without use of additional devices Validated for equal distribution of actives within each split portion Stability of split tablets- portions that have to be stored for use later UNICEF EU generic manufacturers meeting 261109, Copenhagen, Denmark

We need the support of manufacturers Solid oral dosage forms that can me made into liquid at the time of use Dispersible tablets, effervescents, solubles Reduce requirements for additional water Fast melts, sublingual, lollipops Reduce requirements for cold storage Course of therapy individual patient packs No bulk packs for repacking Provide information on sources and prices of paediatric medicines http://www.unicef.org/supply/index_47129.html. Suitable formulations needed for Anti-infectives Micronutrients, vitamins & minerals Antiepileptics Cardiovascular medicines ACT antimalarials HIV & TB Medicines UNICEF EU generic manufacturers meeting 261109, Copenhagen, Denmark

Coated particles in tablet form for preparing suspension Courtesy of J. Breitkreutz UNICEF EU generic manufacturers meeting 261109, Copenhagen, Denmark

Example of win-win strategies Reduced input costs for solid formulations Vs liquid formulations Most Solid dose manufacture technology already exists Reduced need for excipients, less safety concerns Reduced complexity Going green/reducing carbon foot prints while meeting developing country end user needs Drug product with no cold storage requirements Reduced freight loads-reduced cost No need to transport water around the world! UNICEF EU generic manufacturers meeting 261109, Copenhagen, Denmark

EU generic manufacturers meeting 261109, Copenhagen, Denmark Thank you UNICEF EU generic manufacturers meeting 261109, Copenhagen, Denmark