Presentation on theme: "Pharmaceutical Development with Focus on Paediatric formulations"— Presentation transcript:
1 Pharmaceutical Development with Focus on Paediatric formulations WHO/FIP Training WorkshopHyatt Regency HotelSahar Airport RoadAndheri East, Mumbai, India28 April 2008 – 2 May 2008
2 Pharmaceutical Development with Focus on Paediatric formulations World Health OrganizationPharmaceutical Development with Focus on Paediatric formulations1 April, 2017Pharmaceutical packaging – an overview including some considerations for paediatricsPresented by:Name: Simon MillsContact details:
3 World Health Organization 1 April, 2017IntroductionChoosing the most Appropriate Primary PackBlister PacksContainers & ClosuresGeneral OverviewBottlesInhalation / IntraNasal productsRegulatoryUS, EU, PharmacopoeialExtractable & LeachablesPackaging Development considerations through to Launch
4 Specific paediatric considerations World Health Organization1 April, 2017Specific paediatric considerationsAs far as CMC considerations are concerned, paediatric and adult dosage forms can be treated in much the same way. There will be particular areas to focus attention on for paediatric products:There may be lower limits of acceptable levels of impurities, extractables and leachables resulting from product/pack interaction.Extra or novel devices to facilitate dosing or compliance can be associated with paediatric products, e.g. spacers with MDIs, syringes for oral dosing, nebulisers. It will be important to ensure that all contact materials are suitable and well controlled. For new materials/devices, this will necessitate extensive evaluation.Children must be protected from the risk of unsupervised access to medicines – this applies equally to paediatric and adult drug products. The need for child-resistant (CR) packaging will need to be assessed, balanced against the adjudged risk in accidental ingestion of the drug product itself; (some territories insist on CR packs; US requirements detailed in 16 CFR §1700).
5 World Health Organization 1 April, 2017PACKAGING: Choosing the most appropriate packBASIC REQUIREMENTSProtectionstability test conditionsCommercialimagemarket requirements/trendsdosing/patient compliancesecurity/tamper evidencemanufacturingeconomics - COGCompatibilityRegulatoryLegislatione.g. EC Packaging and Packaging Waste DirectiveCorporateGlobal Quality Policies
6 World Health Organization 1 April, 2017PACKAGING: Choosing the most appropriate packADDITIONAL DRIVERS & FUTURE CHALLENGES:Moisture sensitive drugs increasing barrier requirementsNovel delivery systemsEmphasis on speed to marketControl of R&D Expenditure/resource - number of stability studies requiredGlobal - Regional - Local packsAnti-counterfeiting, illegal cross-border tradingPharmacogenomics - Personalised medicinesDemographic change - Ageing population
7 World Health Organization 1 April, 2017PACKAGING: Choosing the most appropriate packSome factors are territory-specific, e.g.Presentatione.g. for solid doseUS prefers bottlesEU/RoW prefer blister packsChild resistance requirementsUSLegal requirement with few exceptionsEU/RoWLegal requirement in only 4 EU member states & for very limited list of productsEnvironmentEU Packaging and Packaging Waste DirectiveUS - no direct equivalent
8 Packaging: WVTRThe water vapour transmission rate (WVTR) through the container is determined by:Container wall thicknessPermeability of the packaging materialDifference between the external and internal relative humidity environmentsDriving force for the water flux through the containerThe theoretical rate of water permeation through a standard 60-cc HDPE bottle when stored at 40C/75%RH has been determined:This equated to an uptake of 1mg of water per day.So, even if a product is packed under low water vapour conditions the relative humidity conditions within the container will re-equilibrate to 50% within 1 day.
9 Packaging: Desiccants Desiccants have been utilised to control the exposure of products to the ingress of moisture.Desiccants vary in their capacity and the rate that they adsorb/absorb ingressed moisture.Silica gel is very efficient at absorbing moisture at high relative humidities, but comparatively poor at lower relative humidities.Molecular sieve desiccants - the opposite scenario prevails.As a consequence, more molecular sieve is required at higher relative humidities, and the greater the handling precautions that are required during packaging operations.Molecular sieve approved in EU for pharmaceuticals, not by FDA in US.Based on the calculated WVTR of known container components and the rate of moisture adsorbed by desiccants, the amount of desiccant that would be required to maintain a specified relative humidity over the product’s shelf-life can be determined.
10 World Health Organization 1 April, 2017PACKAGING: Choosing the most appropriate packBarrier Properties (typical MVTR g/m2/day 38°C/90%RH)Cold Form Aluminium 0.00Aclar ® 33C 0.08Aclar ® UltRxAclar ® 22C 0.22Aclar ® SupRxAclar ® 22APVC/80g PVDC 0.31Aclar ® RxAclar ® 33C 0.42PVC/60g PVDCPVC/40g PVDCPPPVC – 4Aclar ® is a registered trade mark of Allied Signal
11 Packaging: OVTR Pack OVTR (g. mm/(m2. day)) LDPE 241 HDPE 102 Polystyrene127Polycarbonate114Polypropylene89PVC4PET2Similar considerations are relevant to protection of products that are labile to oxidative degradation. The permeability of plastic containers to oxygen ingress has also been evaluated (OVTR), and is summarised here.
12 Packaging Development The theoretical rate of oxygen permeation through a standard 30-cc HDPE bottle when stored in a well sealed container has been determined:This equated to an uptake of 0.2 mMol of oxygen per yearIn addition to permeation through the container walls, the key vulnerability in any container-closure system is the closure.With screw-topped closures, leakage can be significant.Hence for oxidatively labile dosage forms an oxygen-impermeable seal is required and induction heat-sealed containers are particularly useful.Levels of oxygen in the headspace of the container-closure can be significant, and packaging under an inert atmosphere, although doable, is problematical.
13 PACKAGING: First Intent What is First Intent?Preferred range of pack/material options to be used for new productsAgreed between R&D and factoryIdentical global materialsFully aligned with Procurement sourcing strategiesSecure/robust sourcingMinimised R&D resourceSupports supply site transfers (like for like; identical)
14 PACKAGING: First Intent – Blister base MATERIALS (hierarchy of choice based on product stability)Material should preferably be opaque white unless clear is a specific market requirement (e.g. US, Japan)Aclar® should be restricted to applications where cold form is not technically or commercially acceptable due to product or pack size, ie larger products (further guidance to be defined)1. PVC 250m2. PVC/PVDC 250m/60gsm4. PVC/Aclar® UltRx 20003. Cold Form 25 OPA/45 Al/ 60 PVCAclar® is registered trademark of Honeywell Inc
15 First Intent: Bottles and Closures - Benefits CurrentReduction of complexityStandardisation and rationalisation of componentsReduced number of change-overs at factory sitesReduction in resource demandR&D, Pack Dev, Procurement, Sites use ‘off the shelf’ solution for majority of products.Flexibility across factory sites without increased Regulatory activity.Risk MitigationCommercial LeverageFutureReduced Complexity Maintaining Flexibility
16 World Health Organization 1 April, 2017PACKAGING: BottlesBOTTLEGlasstype III (solids)type I (for inhaled solutions)Plasticlow density polyethylene LDPEhigh density polyethylene HDPEpolypropylene PPpolyester PET, PETGCyclo-olefin copolymer (COC)At the opposite extreme - For Perfumes then development of the pack is as important as development of the product.The same is true for pharmaceuticals, and we need to be nearer this end of the spectrum and not the end game.Pack should be developed and tested alongside the productTreat no different to product. As we will see in a minute in numerous cases the same guidelines, eg, ICH Q6A, CPMP DPS and Stability guidelines, are equally applicable to packaging.Perhaps a useful an would be excipient compatibility and to GMP.Just as GMP is not something you can add at the end of a process, if looking for effective ST’s, then same is true for is packaging.
17 World Health Organization 1 April, 2017PACKAGING: ClosuresPlastic - wadless or lined, CR (child resistant), CT (continuous thread), snap fitMetal - screw, ROPPLiner – cork, pulpboard, EPE; flowed in gasketproduct contact materials/facings : PVDC, Saran, Saranex, Melinex, EPE, Vinyl, Foamed PVCInduction heat sealsLet’s start with Packaging is not an end game activity.What do I mean by this?I have worked in this industry for 30 years, most of my career having been spent in packaging. Whilst I have seen many changes in that time, one thing which has tended to remain constant is that for many people in the industry packaging is something that is bolted on at the end, or something which somebody else sorts out for you.
18 PACKAGING: Solid Dose – Blister Packs World Health Organization1 April, 2017PACKAGING: Solid Dose – Blister Packs- Overlacquer- Heat seal lacquer- Print- Aluminium- PrimerTHERMOFORM BLISTERSplastic base webblister formed with aid of heatinglow to high barrierLidding Foil – typically 20 micron AlFilm - eg PVC, PVC/PVDC, PVC/PE/PVDC, PVC/Aclar®At the opposite extreme - For Perfumes then development of the pack is as important as development of the product.The same is true for pharmaceuticals, and we need to be nearer this end of the spectrum and not the end game.Pack should be developed and tested alongside the productTreat no different to product. As we will see in a minute in numerous cases the same guidelines, eg, ICH Q6A, CPMP DPS and Stability guidelines, are equally applicable to packaging.Perhaps a useful an would be excipient compatibility and to GMP.Just as GMP is not something you can add at the end of a process, if looking for effective ST’s, then same is true for is packaging.- PVC- PVDC or Aclar®Product contact layers: For PVC or PVC/Aclar® = PVC For PVC/PVDC = PVDC For Lid foil = heat seal lacquer
19 PACKAGING: Solid Dose – Blister Packs World Health Organization1 April, 2017PACKAGING: Solid Dose – Blister PacksCOLD FORM BLISTERblister formed mechanically (no heat)high barrierLidding FoilFoil Laminate – e.g. OPA/foil/PVC, or OPA/foil/PP- PVC (may be PP)- OPA Film- Aluminium foil- Primer/AdhesiveAt the opposite extreme - For Perfumes then development of the pack is as important as development of the product.The same is true for pharmaceuticals, and we need to be nearer this end of the spectrum and not the end game.Pack should be developed and tested alongside the productTreat no different to product. As we will see in a minute in numerous cases the same guidelines, eg, ICH Q6A, CPMP DPS and Stability guidelines, are equally applicable to packaging.Perhaps a useful an would be excipient compatibility and to GMP.Just as GMP is not something you can add at the end of a process, if looking for effective ST’s, then same is true for is packaging.Product contact layers: For base = PVC (or PP) For lid foil = heat seal lacquer
20 PACKAGING: Solid Dose – Blister Packs World Health Organization1 April, 2017PACKAGING: Solid Dose – Blister PacksTROPICALISED BLISTERthermoform blister plus cold form trayonce tray opened, in use life determined by primary thermoform blisterhigh barrier before useLidding FoilFilm – e.g. PVC, PVC/PVDCAt the opposite extreme - For Perfumes then development of the pack is as important as development of the product.The same is true for pharmaceuticals, and we need to be nearer this end of the spectrum and not the end game.Pack should be developed and tested alongside the productTreat no different to product. As we will see in a minute in numerous cases the same guidelines, eg, ICH Q6A, CPMP DPS and Stability guidelines, are equally applicable to packaging.Perhaps a useful an would be excipient compatibility and to GMP.Just as GMP is not something you can add at the end of a process, if looking for effective ST’s, then same is true for is packaging.Foil Laminate – e.g. OPA/foil/PVCProduct contact layers: For PVC = PVC For PVC/PVDC = PVDC For Lid foil = heat seal lacquer
21 Packaging challenges (4FDC) A 4-API combination anti-TB tablet: Rifampicin 150 mgIsoniazid mgPyrazinamide 400mgEthambutol 275mgTOTAL API weight: 900mgTablet weight: 1.3gThe technical challenges:Big tabletProblem APIs !! Rifampicin is vulnerable to oxidative degradation and hydrolysis, it is light sensitive and it reacts with isoniazid. It also exhibits solid-state polymorphism. Isoniazid reacts with aldehydes/reducing sugars….& rifampicin → major degradant Ethambutol (2HCl) is hygroscopic, attracting moisture into the tablet to form a slightly acidic solution that encourages the rifampicin/isoniazid interaction! Pyrazinamide…..seems to be OK !WHO thought this was a good idea?
22 Packaging challenges (4FDC) The solution:Packaging:Non-permeable (moisture and oxygen) materialDo not remove from primary packaging until useAvoid repackagingProtect from lightAlso:Excipients: no sugar/lactose (isoniazid)Rifampicin used as “as is” powder (no granulation)Maintain low water content of tablets (USP ≤ 3.0%)
23 PACKAGING: IH and IN Products Metered dose inhalerDry Powder InhalersNebulesIntranasal
24 PACKAGING: Key Regulatory Guidance - US Guidance for Industry, Container Closure Systems for Packaging of Human Drugs and BiologicsGuidance for Industry, Changes to an Approved NDA or ANDA
25 PACKAGING: Key Regulatory Guidance - EU Guideline on Dossier Requirements for Type 1A and Type 1B NotificationsCPMP/QWP/4359/03 – Guideline on Plastic Immediate Packaging Materials - specific to plastics onlyKEY POINT TO NOTEEU does NOT have a consolidated container/closure guideline (cf FDA)
26 World Health Organization 1 April, 2017PACKAGING: Food Contact Approval - RelevanceFDA & CPMP (CHMP) RegulatedBaseline Statement of SafetyDefinesacceptable starting materialsacceptable additives and processing aidslimits on residueslimits on leachables (e.g. specific migration limits)Based uponAcceptable or Tolerable Daily Intake in FOOD NOTE: US and EU do not use same calculations
27 EXTRACTABLES and LEACHABLES: Definitions World Health Organization1 April, 2017EXTRACTABLES and LEACHABLES: DefinitionsExtractableCompounds that can be extracted from elastomeric, plastic components or coating of the container and closure system when in the presence of an appropriate solvent(s)LeachableCompounds that leach from the elastomeric, plastic components or coatings of the container and closure system as a result of direct contact with the formulation of the drug product. Can get interaction with a product component to produce an impurity that requires stability monitoring.
28 EXTRACTABLES and LEACHING: Practical examples of Issues World Health OrganizationEXTRACTABLES and LEACHING: Practical examples of Issues1 April, 2017Polyaromatic hydrocarbons (PAH) detected in CFC-filled MDIs (c.1990)Prompted the first concerted efforts to look for leachables in MDIsVanillin detected in solutions for inhalation packed in LDPE containersSource: migration through LDPE container wall from cardboard outer packaging. Protective Al foil laminate overwrap introduced.Di-ethylhexyl phthalate (DEHP)Plasticizer in PVC; detected, for example, in TPN fat emulsions probably via infusion tubing setNeonates have particular sensitivity to DEHP
29 EXTRACTABLES and LEACHING: Considerations World Health Organization1 April, 2017EXTRACTABLES and LEACHING: ConsiderationsClinical concerns:A potentially sensitive, compromised (especially paediatric) patient populationSafety for both acute and chronic administrationRegulatory requirements:FDA requirementsIncluded in CPMP guideline 3AQ10a and CPMP/QWP/4359Extractables: control of quality of packaging materials and robustrelationship with suppliers, e.g. change control.Leachables: comprehensive stability package – long-term storage condition andaccelerated stability assessment for drug product in pack to cover shelf-life ofthe productConsistency in materials/components (Specifications, DMFs)Control of packing material and product manufactureControl for unintended contaminants
30 Packaging Development ObjectiveTo ensure timely and robust selection of the primary pack for clinical trial and commercial supply.Recommended approach:To use, where possible, a limited range of standard, well-characterised pack materials and packs.To ensure thorough testing, characterisation and understanding of these selected pack materials and packs.
31 Phase I – FTIH & Phase II Clinical Supply Objective:Selection of packs for clinical supplyStrategy:Aim to useLimited range of standard, characterised packs, e.g. HDPE bottles for solid dose formsInert packs, e.g. fluororesin laminated injection stoppersPacks and materials chosen to ensure pharmacopoeial and regulatory compliance is well understoodMaterial performance is well characterised or knownPack selection is supported by stability testing for each product
32 Phase II – III, Commercial Pack Development Objective:Identification, development and testing of commercial pack optionsApproach:1. Identify Pack Options2. Material Selection & Testing3. Development Stability Testing4. Controls Defined5. Pack Selection6. Pivotal Stability Testing
33 Pack options are identified to meet: 1. Identify Pack OptionsPack options are identified to meet:Product attributes, e.g. dosage form, physical and chemical robustnessProduct protection needs, e.g. moisture & gas sensitivity, thermal stability, photostability, chemical compatibility, etcClinical requirements, e.g. dosing regimen, titration dosing, route of administration, need for dosing devicePatient requirements, e.g. specific handling requirements, patient handling studiesCommercial requirements, e.g. market presentation, pack sizes, market specific needs, patient handling needsManufacturing requirements, e.g. equipment capability, critical process parametersRegulatory requirements, e.g. material compliance, pharmacopeial monographs
34 2. Material Selection & Testing Product contact materials chosen to meet global and local regulations.Product contact materials, particularly, plastics confirmed as compliant with relevant food contact regulations, e.g. US, EU etcPharmacopoeial compliance established, e.g. USP, Ph Eur, JPPerformance testing conducted, e.g., moisture permeation, light transmissionChemical characterisation, e.g. extractables and leachables studies, especially for parenteral, ophthalmic and inhalation productsToxicological assessment of extractables and leachables conductedMaximise pack and product knowledge and understanding and achieve commercial efficiency by using a limited range of First Intent, preferred pack materials, wherever possible.
35 3. Development Stability Testing Development stability testing used toUnderstand and explore stability in selected pack optionPredict long term stabilityConfirm product protection or need for more protective packs, e.g. need forInclusion of desiccants for moisture protectionHigher barrier blister films or need for foil/foil blistersprotective overwrapConfirm compatibilityIdentify and explore pack/product interactionThese are key data used to make a final pack selection.
36 4. Controls DefinedData from material and product testing used to identify critical quality and process attributes for pack and packaging process, e.g.Need for RH controls during packingNeed for inert gassing of pack headspaceSeal integrity testingNeed for extractables testing as a routine controlManufacturing controls/specifications for the pack components and suppliers, e.g. dimensional and performance specifications, need for clean room manufacture, etc.Manufacturing controls for the packaging process
37 6. Pivotal Stability Testing 5. Pack SelectionData from the previous steps, together with the clinical, patient, commercial and manufacturing requirements, are used to identify and agree the intended market packs.Pivotal stability testing conducted in the selected markets packs, toConfirm compatibility and product stabilitySupport product registration submission6. Pivotal Stability Testing
38 Phase 3 - Launch Between Phase 3 and Launch Secondary packaging is definednote, if needed for product protection, this will be defined with the primary pack and included in pivotal stabilityDefine market presentations, graphics, patient information leafletsConduct line, engineering and technical trials on pack components and equipmentConduct any necessary validation of packaging processes
39 Pack Changes? Recommended aim: to avoid pack changes between pivotal stability and launch by ensuring a Quality-by-Design approach to pack selection and understanding of product stability and packaging.However, changes can occur at late stage due to, for example…Unpredictable outcome in pivotal stability assessmentNewly identified impuritiesRequirement for tighter specification limitsThese tend to drive need for more protective packs, e.g.Inclusion of desiccant in bottle packsNeed for higher barrier (e.g. foil/foil) blister packsBy use of First Intent pack materials and packs, we aim to have a thorough understanding of our materials to minimise impact of change and have readily available, well characterised pack options.
40 World Health Organization Summary1 April, 2017Choosing the most Appropriate Primary PackBlister PacksContainers & ClosuresGeneral OverviewBottlesInhalation/IntraNasal productsRegulatoryUS, EU, PharmacopoeialExtractable/LeachablesPackaging Development considerations through to LaunchANY QUESTIONS PLEASE?