MODULE 7:TARGET PRODUCTPROFILES DNDi/Scholars & Gentlemen126
1. INTRODUCTIONTarget product profiles are key strategicdocuments used to communicate summaryrequirements for new products that fulfil apriority need. The purpose of target productprofiles is to guide industry during the drugdevelopment process and serve as a planningtool that can facilitate discussions withregulatory agencies and be updated as newinformation becomes available.The importance of target product profiles residesin their role in identifying the critical attributes ofa product before development begins, to ensurethat the final product is adapted and respondsto the needs of the end-users (Fig. 7.1). Targetproduct profiles can help address issues early inthe product development process and preventlate-stage development failures.Fig. 7.1. A target product profile as a strategicplanning toolResearch MarketresearchThe global community, including WHO, UNAIDS,the Global Fund to Fight AIDS, Tuberculosisand Malaria (Global Fund), the United StatesPresident’s Emergency Plan for AIDS Relief(PEPFAR) and the United Nations Children’s Fund(UNICEF), have a responsibility to define therequirements around paediatric medicines andhave clear, transparent communication to industryon the products that are required to meet theunique needs of children.Some organizations, such as WHO, UNICEF andthe Drugs for Neglected Diseases initiative, havedeveloped target product profiles for specificdesired products such as medicines, diagnosticsand vaccines that have served to guide industryin their own product development process.2 Thetarget product profile describes how the enduser will use the product and is based on suchattributes as indications, targeted population,clinical efficacy, safety and tolerability, stability,route of administration, dosing frequency andcost, along with development timelines.Table 7.1 outlines various properties of targetproduct profiles and the optimum or idealcharacteristics and minimum characteristics.Key properties include the ability to use theproduct across the age spectrum of children andadolescents, ease of administration, heat stability,palatability and swallowability and acceptableproduction costs.Manufacturersand aediatric-hiv/paedhiv-target-product-profile/; https://www.unicef.org/supply/index le/10665/135617/WHO HTM TB 2014.18 eng.pdf;jsessionid 6D9A30EDDBCC978978CF9928FAB921AE?sequence 1127
Table 7.1. Properties of target product profiles128PropertyOptimum or ideal target product profileMinimum target product profileTargetpopulationOne dosage form for ages 0–6 years 6 years: adultAges 0–2, 2–6 and 6 yearsSafety,tolerabilityExcipients selected from already used excipients in thenew drug application or abbreviated new drug applicationand in accordance with the Inactive Ingredients Guide ofthe United States Food and Drug AdministrationLimited use of excipients, minimum toxicity and druginteractionsExcipients selected inaccordance with regulatoryguidelines on inactiveingredientsDrug attributesAccommodates a wide range of doses and drugproperties (such as solubility)Durability – high barrier to resistanceA set of 3–5 technologies thataccommodate 80% or a majorityof drug types and doses andfixed-dose combinationsWeight baseddosingPossible to administer the same dosage form acrossmultiple weight bands1 formulation for children age 6 years;1 formulation for age 6 years: adult (or half a dose)Possible to administer the samedosage form across multipleweight bandsAdministrationconsiderationsEasy to administer – minimum manipulation by thecaregiverMinimal opportunity for child to reject medicationEasy to apply with no irritation (non-oral)Fixed-dose combination, dispersible or small tablet sizeSolid oral dosage formspreferredIf bottle pack, then it shouldhave a child-resistant capAdministrationdeviceconsiderationProduct does not need device or appropriate devicesupplied if neededIntuitive – no use instructions necessaryMinimum instructions necessaryto use device if neededTaste and texture(oral dosage)Palatable, child-friendly flavour, good mouth feelPalatable, acceptable taste andmouth feelManufacturingAccessible development and manufacturing capability inlow- and middle-income countriesRobust and able to deliver medicines of adequate qualityat an affordable priceFeasibility for technology transferLow technology – easy tomanufacture in resource-limitedsettingsCostAcceptable cost to caregivers and fundersLow-cost (total cost of goodsand landed costs) optionsPreparationbeforeadministrationShould not require complex preparation by the end-userbefore administrationInclude recommendations for extemporaneouscompounding in the summary of product characteristicsEasy to prepare and administer,such as with water, milk or foodSuitable for low-literacy settingsHeat stable,longer shelf lifeSuitable for all climatic zones, including InternationalCouncil for Harmonisation Zone IVb (30 C and 75%relative humidity) and 24 month total shelf lifeSee Annex 2, Stability conditions for WHO MemberStates by region (5).No special transport and storage handling requirementsSuitable for the supply chain andend-userNo special transport andstorage handling requirementsorEasy to transport and store
PropertyOptimum or ideal target product profileMinimum target product profilePackagingCompact, light weight, easy to open and administer,inexpensive, easy and low cost to transport,sustainable packagingSameDisabilityFor example, Braille labelling or “talking patient information”Due consideration for end-userdisabilitiesRegulatoryapprovalClear regulatory approval pathways considered up frontboth in source and end-user countriesRegulatory pathways in enduser countries considered upfrontPatentsFull geographical access, open licences, no data exclusivityFeasible to have product monographs in officialpharmacopoeia as soon as possible to produce genericsEquitable geographical accessSources: Special Programme for Research and Training in Tropical Diseases (1), WHO Expert Committee on Specifications forPharmaceutical Preparations: fifty-first report (2), Target product profile – paediatric HIV (3), Lopez et al. (4) and Annex 2,Stability testing of active pharmaceutical ingredients and finished pharmaceutical products (5).Additional considerations in the drug formulationdevelopment process include target candidateprofiles and critical quality attributes. These includevarious drug characteristics that impact whattype of formulations can be manufactured andinclude: solubility and permeability of the activepharmaceutical ingredients (BiopharmaceuticalClassification System classification); bioavailability food effects of the active pharmaceuticalingredients; polymorphism; particle size; stabilityof the active pharmaceutical ingredients; tasteand potential to “mask” taste during manufacture;content of active pharmaceutical ingredientsper dosage form; dose variability versus age;dose accuracy requirements; manufacturability;good technology fit to manufacture the activepharmaceutical ingredients into a finishedpharmaceutical product; possibility to combineseveral active pharmaceutical ingredients intofixed-dose combinations (pharmacokinetics,pharmacodynamics and drug–drug interactions);active pharmaceutical ingredients amenableto age-appropriate simple dosage forms; andenvironmental pollution with active pharmaceuticalingredients during production (6).Table 7.2 outlines the advantages anddisadvantages of various formulations. Oralliquid preparations and oral solid preparationsare the most common formulations used forantiretroviral (ARV) drugs. In general, oral solidpreparations are preferred to liquids since theyrequire less space and are easier to procure andstore. Nevertheless, young children may not beable to swallow solid dosage forms. Dependingon the active pharmaceutical ingredients,granules, pellets or chewable tablets may bedifficult to taste mask, and children may refusethese products because of poor taste (7–13).Liquid formulations allow better accuracy indosing but may be less palatable. Refrigerationmay be required for some liquid formulations,which will increase the difficulty of storage,both during transport and for the end-user. Forspecialized products, more expensive productioncosts or equipment may be required.129
Oral solid preparationsOral liquid preparationsTable 7.2. Advantages and disadvantages of various formulationsActive pharmaceuticalingredientsProcurementIn principle, easy tomanufactureSoluble, chemically stableDifficultYounger age group(unable to swallow)Other particles canbe suspended, likecoated pellets Non-soluble, chemically stable.Better than solutions for activepharmaceutical ingredients thatdo not taste goodDifficultSyrupsYounger age group(unable to swallow)In principle, easy tomanufactureSoluble, chemically stableDifficultEmulsionsYounger age group(unable to swallow)In principle, easy tomanufactureNon-soluble, chemically stableDifficultEffervescenttabletsAll agesDifficult technologyavailableSoluble, non-chemically stableDifficultOral powder,granules andmultiparticulatesystemsBetter suited foryoung ageCan contain beadsor mini-tabletsTechnology readilyavailablePalatable and unpalatable activepharmaceutical ingredientsEasyTabletsOlder children (ableto swallow)In principle, easy tomanufactureSoluble, non-chemically stableEasyChewabletabletsOlder childrenEasy to manufacture.Technology readilyavailableSoluble, non-chemically stable,palatable active All agesIn principle, easy tomanufactureSoluble, non-chemically stable,palatable active pharmaceuticalingredientsEasySplittingtabletsOlder children (ableto swallow)In principle, easy tomanufactureSoluble, non-chemically stable,palatable active pharmaceuticalingredientsDifficult(big size)Solids forreconstitutionYounger age group(unable to swallow)In principle, easy tomanufactureSoluble and non- soluble, nonchemically stableEasyOrallyophilizatesAll agesRequires specificequipmentPalatable active pharmaceuticalingredientsEasyOral filmsLimitation withhigh dosesLimited quantity ofingredientsPalatable active pharmaceuticalingredientsEasyTarget ageFormulationOral solutionYounger age group(unable to swallow)OralsuspensionSource: adapted from: Penazzato et al. (14). 2015 Penazzato M et al.; licensee International AIDS Society.130
ialprecautionsDifficultOnly for acceptable tasteor easy-to-mask activepharmaceutical ingredientsVolumes 5 mlproblematic for children 5 yearsSolventsMeasuring deviceOnly low dosesQuality of waterMeasurementproblemsDifficultSuspensions allow bettertaste-masking thansolutionsVolumes 5 mlproblematic for children 5 yearsClear information onshaking before useMeasuring deviceOnly low dosesDifficultOnly for acceptable tasteor easy-to-mask activepharmaceutical ingredientsVolumes 5 mlproblematic for children 5 yearsProblems measuringOnly low dosesDifficultOnly for acceptable tasteor easy-to-mask activepharmaceutical ingredientsVolumes 5 mlproblematic for children 5 yearsClear information onshaking before useMeasuring deviceOnly low dosesDifficultOnly for acceptable tasteor easy to mask activepharmaceutical ingredientsEasyTaste can be an issue ifadministered directly ormixedCan be administereddirectly in the mouthInformation on food,liquids restrictionsAllows dosing flexibilityVarious strengths neededEasyPalatable and unpalatableactive pharmaceuticalingredientsWell acceptedMay be difficult to swallowdepending on sizeEasyOnly for acceptable tasteor easy to mask activepharmaceutical ingredientsWell acceptedVarious strengthsmay be neededEasyTaste needs to beacceptable or easy to maskWell acceptedVarious strengthsmay be neededWell acceptedDosing instructionsmay be difficultVolumes 5 mlproblematic for children 5 yearsProblems measuringOnly low dosesDifficult (size)EasyTaste needs to beacceptable or easy to maskEasyEasyAlcohol, sugarcontentEffervescenttechnologyrequiredRisk ofaspiration orchokingQuality of waterLyophilizationrequiredTaste needs to beacceptable or easy to maskEquipmentrequired131
2. CHALLENGESThe development of pharmaceutical productsfor children presents additional challenges. Theseproducts need to be adapted to a populationthat is growing, gaining weight and undergoingneurodevelopmental changes, has changingelimination pathways (see the module onpharmacokinetic modelling), relies on caregiversto administer medications and requires specialcharacteristics such as palatability, swallowabilityand dosing flexibility. Lack of stable electricitysupply, difficulty in supplying and storingmedications and additional logistical issues inlow- and middle-income countries contributeto the challenges in designing medicines forchildren, especially those more commonly usedin low- and middle-income countries. Theserequirements and challenges should begin to beconsidered several years before the process ofproduct development.2.1 Target population: developingformulations across the weight andage spectrumThere is a critical need to develop appropriateformulations of medications suitable for useacross the weight bands and age groups ofchildren and adolescents (15,16). Pharmacokineticand safety information as well as appropriatedosing information lags far behind for children,especially neonates (see the modules onpharmacokinetic modelling and trial design) (17).Key questions include: 132How will the limited number of formulationsand dosage strengths available provide theflexibility required for adjusting the dose forgrowing neonates, infants, other childrenand adolescents while drug metabolism andelimination are changing rapidly? Since the acceptability of various dosageforms varies widely with the age of the child(see the module on acceptability), how can itbe ensured that caregivers will administer thecorrect dose and that the child will receive theappropriate dose?Although information is limited on the safe andappropriate use of ARV drugs for neonates,even less information is available for low-birthweight and preterm neonates (18). About 20%of infants born to women living with HIV havelow birth weight or are preterm, and there is verylittle pharmacokinetic and safety information onARV drugs for such neonates. Once a suitabledrug formulation is licensed for use for full-termneonates, the drug is often used for low-birthweight or preterm neonates, for whom thereare no safety or pharmacokinetic data (see themodule on pharmacokinetic modelling). Questionsremain about how appropriate research should besupported for such vulnerable populations.2.2 Adherence: developing formulationsto which people will adhereAdherence to chronic medications is challengingfor most people, but especially adolescents (19).Factors that may influence adherence includethe following: pill size, pill number, frequencyof dosing, volume of solution, palatability, foodrequirement and side-effects attributed tomedications. Although multiclass fixed-dosecombination single-dosage formulations havegreatly simplified treatment regimens, the actualsize of the combination tablet may be an obstacleto adherence. Many people, including adults, havepill aversion and have difficulty swallowing pills.There are limited data on the acceptability ofdifferent dosage forms for younger children andadolescents (see the module on acceptability), but
dispersible tablets, mini-tablets, scored tablets,granules and other flexible dosage forms havebeen promoted as preferred by many people.The physicochemical properties of the activepharmaceutical ingredients determine the rangeof formulations that can be selected. For instance,not all active pharmaceutical ingredients can beformulated into all dosage forms. Pharmaceuticalexcipients may be needed to mask bitter tasteand/or to increase solubility, which may alsoaffect the decision on which formulation isthe most appropriate. The quantity of activepharmaceutical ingredients is also an importantfactor, since it determines the size and volumeof the finished dosage form. The condition to betreated determines the duration of treatment andthe dosage requirements. For ARV drugs used fortreating people living with HIV, the decision on themost appropriate dosage form needs to considerthe importance of good adherence and need forlifelong treatment, and acceptability is thereforean important consideration.Factors related to administration are key whendeciding on the most appropriate dosage form.Drugs for children need to be formulated in adosage form that is easy to administer and thatminimizes potential dosing errors. If measuringadministration devices are required, these haveto be adapted and easy to use.2.3 Costs: development andmanufacturing costs for novel medicationsand formulationsSome medications needed for older children andfor drugs that have no palatability issues can beproduced using conventional formulations suchas tablets and capsules. However, alternativepharmaceutical formulations may be requiredto successfully deliver drugs to children in anacceptable, palatable and easy-to-use manner,but these are more expensive than conventionalformulations. They may require specific equipmentto manufacture, the addition of specific excipientsor the use of measuring devices.For example, oral liquids, tablets and capsules areeasier to manufacture and relatively inexpensive.Other more specific formulations such asgranules, mini-tablets or oral lyophilizates,and 3D printed tablets require dedicatedmanufacturing equipment and may be moreexpensive to produce. Even manufacturingdispersible tablets, which are produced using awell established and frequently used technology,is slightly more expensive than producingconventional tablets.All these factors increase the manufacturingcosts for products that offer less marketreturn in principle (see the module on productcommercialization). Further, the potentiallysmaller market for children means that theeconomies of scale needed to mitigate theadditional costs are difficult to achieve.2.4 Supply chain issuesMedicines for children may need to be shipped toand stored in low- and middle-income countries,where climatic conditions can be hot and dryor hot and humid (5,20). They should be easilytransported, not require refrigeration and bereadily available to the people who need them.Medicines formulated to comply with regulatoryjurisdictions such as the European MedicinesAgency (EMA) or United States Food andDrug Administration (FDA) may not have beensubjected to stability studies for climatic conditionsin countries where they are most needed: hotand humid tropical zones (International Councilon Harmonisation Zone IVa and Zone IVb stabilityconditions). This should be considered whenformulating medicines for children.Factors that are more relevant in low- andmiddle-income countries than in high-incomecountries can affect the procurement and storageof medicines, such as the need for cold-chaintransport and storage. Transporting and storingconventional medicines for children formulatedas oral liquids that may require refrigeration canalso be challenging; instead, one could consider133
developing a tablet for oral solution or suspensionor a dispersible tablet. Bulky products, such as oralliquids, increase shipment costs since they takeup more space, and the cold chain cannot alwaysbe maintained during transport and storage. Theexistence of multiple dosage forms for differentage groups also affects procurement and makesquantifying needs more difficult.2.5 Harmonizing regulatory requirements:regulatory issuesThe lack of harmonization of regulatoryrequirements and pathways across regulatorsis a challenge for drug development. In somecountries, such as India, the national regulatorrequires clinical trials in their populations even ifa product has already been approved in Europe,Japan and the United States of America. Thiscan affect access to medicines for childrenworldwide since Indian generic manufacturers,who supply medicines to most low- and middleincome countries, have greater difficultyobtaining local approval, which then affects priceand development timelines. This not only affectsIndia, since most countries require registrationin the country of origin before the product isauthorized for use elsewhere. Regulatory issuescan also affect supply and logistics. Differencesbetween regulatory requirements for labellingmay lead to a lack of harmonization. Labelswith text differing from that required by localauthorities may be blocked in customs.Some regulatory authorities ask for local clinicaltrials when they consider that existing ones maynot demonstrate safety and efficacy specificallyin their population. This was the case for India,and although the authorities agreed to grant awaiver for products for children WHO identifiedas a priority, this may still be problematic for drugdevelopment (21).1342.6 Product development challenges:formulation development issuesFormulation issues innovators encounter duringdrug development may not be communicatedto the generic manufacturers. The factors thathelp define the dosage form can be groupedinto four categories: (1) factors related tothe physicochemical properties of the activepharmaceutical ingredients and excipients usedin the formulations, (2) factors related to thecondition, dosing and medical need, (3) factorsrelated to transport and procurement and (4)cost factors.The ideal formulations that consider thesefactors and better respond to these challengesare characterized in the target product profilebut may be difficult to develop for cost orfeasibility reasons. The innovator or genericpharmaceutical company may develop the targetproduct profile as the starting-point of productdevelopment, but a supplier may also developthis. Lack of proper communication betweencompanies and suppliers to better understandthe needs, feasibility and costs, as well asthe stages of the development process, maycause delays or even failure when developingformulations for children.
3. SOLUTIONSThis section outlines several solutions andideas for addressing these challenges. Furtherreferences and cross-references to othermodules enable more in-depth analysis.1. regulatory requirement for safety,pharmacokinetic and dosing informationfor life-saving drugs;2. incentives for pharmaceutical companiesand research networks to collaborateon the research needed to obtain thisinformation;3.1 Target population: developingformulations across the age spectrum3. flexible dosage forms that can be safelyadministered to low-birth-weight orpreterm infants; andTo ensure that formulations for children andadolescents are developed so that thesemedications can be used across the agespectrum, additional planning and investigationshould be undertaken. Plan early in the drug development processthe potential need for smaller doses forinfants and other young children. The idealformulation should be heat stable, convenientto use, require simple instructions for use andminimal manipulation to prepare, allow forflexible dosing and not contain potentially toxicexcipients such as ethanol or propylene glycolin high concentrations. Excipients should beselected based on the most recently approvedexcipient guidelines published by the FDA andEMA (22,23).Neonates are very difficult to study,especially low-birth-weight or preterminfants. A mechanism should be developedand encouraged so that this informationbecomes available as more infants receiveempiric therapy, enhanced prophylaxisand early treatment for HIV infection.Pharmacokinetic modelling and simulationscombined with data from older infants andother children can provide an initial potentialdose for medications with good safetyprofiles that can be studied in low-birthweight or preterm infants (see the module onpharmacokinetic modelling). The following aresuggested as potential solutions for obtainingpharmacokinetic and safety data for ARVdrugs for low-birth-weight or preterm infants:4. pressure from organizations and guidelinecommittees to obtain this information. Investigation of drug stability in breast-milk andother solutions and foods should be encouragedas part of formulation development (see themodules on pharmacokinetic modelling andpregnant and breastfeeding women).3.2 Adherence: developing formulationsto which people will adhereIn developing formulations for children, factorsthat relate to people’s preferences should beconsidered. Pill size is important, and manufacturers needto consider acceptability when developingformulations. This is even more importantwhen formulating fixed-dose combinationsthat combine several active ingredients. Before deciding on the formulation and thedevices or instructions that it may require,research should be conducted on what areacceptable formulations in various age groups,both for the patients and caregivers (see themodules on acceptability and communityengagement).Innovative alternatives, such as long-actingformulations, could be considered and developedas alternatives to daily oral medications.135
3.3 Costs: development andmanufacturing costs of novel medicationsand formulationsThe smaller market for drugs for children and thehigher manufacturing costs of many formulationsfor children highlight the importance of limitingthe number of formulations. It is importantto avoid further reducing the market size, tocorrectly quantify the costs in advance and toincrease opportunities for leverage incentives,such as funding for research and developmentand advance market commitments.The following actions could help in identifyingmanufacturing costs and limiting the impact ofunplanned additional expenditure. Each specific target product profile should seta target indicative price. Accurately quantifying and estimating thesize of the market may help in planningthe investment needed to developformulations for children and ensure financialsustainability (see the module on productcommercialization). 136If a supplier, buyer or other stakeholderdevelops the target product profile, sharing thisinformation with the pharmaceutical companiesis important to understand potential obstaclesto product development that may increasecost. Input from manufacturers needs to beconsidered in the final target product profile.This can be done through an open consultationprocess to develop the target product profile,online publication of a draft for comment,industry and stakeholder consultations and,if needed, face-to-face meetings. The targetproduct profile and all product information,including timelines, should be shared inadvance with teams and organizations incharge of procurement, to accelerate productintroduction. Procurement of drugs shouldbe based on identifying the desired drugs anddosage forms, estimating the requirementsfor each drug product for a given period anddetermining what resources are available (24). Rapid product uptake helps in mitigatingfinancial risk and recovering investment.For ARV drugs, this can be done throughthe Antiretroviral Procurement WorkingGroup, which coordinates the demand ofmajor purchasers such as the Global Fund,UNICEF and the Partnership for Supply ChainManagement. Developing a business case for the productneeded and characterized in the targetproduct profile permits measurement of thefinancial risk. Information sharing betweenmanufacturers and suppliers is also key in thisstep, since it enables investment to be adaptedto the expected return.3.4 Supply chain issuesThe following actions could avoid supply-relatedproblems for formulations for children. Stability studies must demonstrate thestability of the medicinal product throughoutits intended shelf life under the climaticconditions prevalent in the target countries.For global supply, product stability should besystematically conducted in the most stringentconditions (climatic zone IVa, 30 2 C and65 5% relative humidity or IVb, 30 2 Cand 75 5% relative humidity) unless thecharacteristics of the active pharmaceuticalingredient typically do not support suchconditions (5,20). Products should be labelled with actualstorage temperatures. Stating that a productdoes not require special storage conditions isunacceptable for use in countries where theseproducts are most needed. Heat-stable products that do not require coldchain or end-user refrigeration are ideal. Age-appropriate solid oral dosage forms ormedicines in appropriate packaging greatlyreduce weights and volumes and therebyshipping and storage costs.
3.5 Harmonizing regulatory requirements:regulatory issues that affect supply andlogistics Efforts to ensure harmonized regulatoryrequirements should be increased. Theseefforts include the following. Efficient collaboration between regulatoryagencies and manufacturers would greatlyreduce the costs and delays involved in bothdrug development and supply and logistics. Improving the harmonization of regulatoryrequirements and pathways and regulatoryinterpretation of stability studies acrossregulators can positively affect drugdevelopment and supply and logistics. Specific country regulatory requirementsneed to be considered early in the drugdevelopment process to avoid additionalhurdles and obstacles to importation and incountry approvals. WHO and other global health agenciesshould consider how to leverage influence toencourage the regulatory agencies to betterharmonize their requirements.3.6 Product development challengesThe following product development challengesshould be considered. Regardless of whether a manufactureror a supplier develops the target productprofile, communication between the partiesinvolved is important, to understand whetherthe proposed target product profile coversthe requirements and whether it is feasibleindustrially. Precise knowledge of
Table 7.1. Properties of target product profiles Property Optimum or ideal target product profile Minimum target product profile Target population
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