Post on 07-Apr-2018
Technical specifications,
requirements and technical
evaluation of medicines (excluding vaccines)
Atieno Ojoo, Technical Specialist, PharmaceuticalsUNICEF Supply Division, aojoo@unicef.org
Henrik Nielsen, Technical Specialist, PharmaceuticalsUNICEF Supply Division, hnielsen@unicef.org
29th Sept 2016
Source: UNICEF Supply Division
Session outline
• Guiding principles
• Specifications for procurement
• Sourcing
• Technical Requirements
• Dossier and Sample assessments (Technical evaluation)• The Interagency Pharmaceutical Product Questionnaire
• Link with GMP and QA/QC
• Looking into the future
Source: UNICEF Supply Division
Guiding principles
WHO TRS 986 Model Quality Assurance System for procurement agencieshttp://apps.who.int/medicinedocs/en/m/abstract/Js21492en/
WHO TRS 937-WHO Expert Committee on Specifications for Pharmaceutical Preparations
http://apps.who.int/medicinedocs/documents/s14091e/s14091e.pdf
UNICEF IS NOT A REGULATORY AGENCY. DOSSIER and SAMPLE ASSESSMENTS ARE DONE FOR PROCUREMENT PURPOSES-USUALLY IN SPECIFIC CONTEXTS.
End user context
Use at community level• No potable water• No electricity• Low literacy, Low disposable income• Local languages• Few trained health professionals
Cold storage
FPP Specifications
Source: UNICEF Supply Division
The specifications are for procurement and contains information related to:
• Active Pharmaceutical Ingredients
• The Finished Pharmaceutical Product (International Non-proprietary Name)
• Packaging and Labelling
• Usability/fit-for-purpose (Dosage forms, shelf life, stability, dosing devices)
• Context specific requirements e.g packing in kits, color coding
S1505044 Amoxicillin 250mg disp.tab/PAC-(2x10)Amoxicillin 250mg scored dispersible tablets, blister card of 10 dispersible tablets, pack of 2x10.Context specific colour coding
Source of FPP Specifications
• WHO Essential Medicines List– INN, approved dosage forms and dosage strengths• http://www.who.int/medicines/publications/essentialmedicines/en/
• WHO disease specific treatment guidelines – Medicine, dose, dosing frequency, duration of treatment, Route of
administration, Intended level of healthcare use
• Pharmacopoeia– USP, Ph.Int, BP, Ph.Eur– The market place; What is actually available in the marketplace?
• E.g. Paracetamol 125mg/5ml Versus 120mg/5ml?• Cefixime 200mg tablets PACK of 56 Versus pack of 2 or 14
• Where appropriate, user specific requirements for targeted procurement
• See– UNICEF Web catalogue– https://supply.unicef.org/unicef_b2c/app/displayApp/(layout=7.012_1_66_67_115&carea=%24ROOT)/.do?rf=y
Source: UNICEF Supply Division
Identifying Sources for medicines
• UNICEF is interested in diversifying its supplier base and in finding new suppliers that can provide quality goods at competitive prices
• All applications to become a supplier with UNICEF must be made via the United Nations Global Marketplace (UNGM) website http://www.ungm.org. There is no charge for the UNGM service.
• UNICEF reviews supplier applications and determines – Products of relevance to UNICEF
• Placed on Vendor list, can be invited to bids
– Prior to contracts• Financial viability-Copy of audited financial statements, with comparative figures for the
previous year(IN ENGLISH); signed by company's auditing/accounting firm• Ethical issues • Legal issues
INVITEE LISTS for every bid generated from– Request for Expression of interest (REOI)– Vendor list
United Nations agencies participating in the UN Global Marketplace strictly enforce a policy of zero tolerance concerning unethical, unprofessional or fraudulent acts of UN contractors. Accordingly, any registered company that is found to have undertaken unethical, unprofessional or fraudulent activities will be suspended or forbidden from continuing business relations with the United Nations.
Source: UNICEF Supply Division
• Accompanies every bid for pharmaceuticals
• Outlines UNICEFs expectations of safety, efficacy and quality
• Solicits supporting documentation to verify product and manufacturer status
• Based on current international standards and best practice for FPP specifications and the enabling manufacturing environment– http://www.unicef.org/supply/index_41948.html
– http://www.unicef.org/supply/index_52844.html
Source: UNICEF Supply Division
Technical Requirements for
Pharmaceuticals
Source: UNICEF Supply Division
Technical evaluationTechnical Specifications + Technical requirements +Samples
1. Abridged technical evaluation, mainly verification of compliance and usabilityHIV, TB, Malaria
• WHO prequalificationhttp://apps.who.int/prequal/
• USFDA tentative approvalhttp://www.fda.gov/InternationalPrograms/FDABeyondOurBordersForeignOffices/AsiaandAfrica/ucm119231.htm
• Global Fund expert Review Panelhttp://www.theglobalfund.org/en/procurement/quality/pharmaceutical/
• EMA Article 58http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000157.jsp
Other Essential Medicines under WHO prequalification• Diarrhoea-Zinc• Influenza-Oseltamivir, Zanamavir• Neglected tropical diseases-• Reproductive Health-Misoprostol
Products registered by SRA (Stringent Regulatory Authority)• Product registered in SRA country “for export only” undergoes full technical evaluation
Supplier authorizes UNICEF to access information held by WHO PQ, GF ERP, SRA
2. Full UNICEF Dossier and sample evaluation for all other medicines not in any of the categories above
• Complete Interagency Pharmaceutical Product Questionnaire (IAPPQ)• FPP specifications as requested• Monograph (In-House acceptable if no Monograph or tighter than monograph)• Marketing authorization in Country of Manufacture• Valid CoPP• Results of
– FPP stability studies as stated in the WHO/ICH/EU guidelines– Remember to provide data related to batch size, API source used, the actual presentation used in the stability study,– Microbiological testing is a requirement for all testing of FPPs)
– bioequivalence/comparative dissolution as applicable
• COA of 3 production batches – COA model cert from MQAS
• Standards for API- CEP/DMF ( reference to Pharmacopeia/ no requirements for CEP/DMF)
• Manufacture licence ( in country of manufacture )
• Valid WHO-GMP certificate for FPP manufacture site– GMP Inspection can take place after dossier assessment
• API and API manufacturing site oversight
Source: UNICEF Supply Division
Key elements of technical evaluation
• Based on WHO Model Quality Assurance System
• Approved and used by all the agencies below to collect dossier information and documents in a standardized manner.
• Dossier submissions on CD/DVD or electronically,
• Please note only one dossier per CD/DVD
Source: UNICEF Supply Division
Interagency finished pharmaceutical
product questionnaire
ICRF, IFRC, The Union
How to structure the annexes in the Interagency Pharmaceutical products questionnaire
How documents are submitted ensures that product dossiers can be easily identified, stored, retrieved and assessed in and efficient manner.
Source: UNICEF Supply Division
Usability: Tablets do not break as required on score line
Fit-for-purpose, usability • Break marks for solid
tablets• Injectables together
with special diluents• Dose measuring
devices for oral liquidsInstructions for reconstitution, storage, use
• Missing information about stability after reconstitution
Example of storage labelling challengesBasis for label: Stability data [stability
outcome]
Storage statement in SRA product
information (labels)
Then WHO PQ recommended
storage statement
Zone II + accelerated
[FPP is stable at long term conditions, with no
significant change at accelerated]
This medicinal product does not require
any special storage conditions (i.e. no
temperature mentioned). [EU]
Do not store above 25⁰C. Protect
from moisture.
Zone II + Zone IVb + accelerated
[FPP is stable at long term conditions (zones II and
IVb), with no significant change at accelerated]
This medicinal product does not require
any special storage conditions (i.e. no
temperature mentioned). [EU]
Do not store above 30⁰C.
Zone IVa + accelerated
[FPP is stable at long term conditions, with
significant change at accelerated]
Do not store above 30⁰C. [EU] Do not store above 30⁰C. Protect
from moisture. Avoid excursions
above 30⁰C.
Zone II + accelerated
[FPP is stable at long term conditions, with no
significant change at accelerated]
Store at controlled room temperature
(15-30°C). [Canada] OR
Store at 15⁰C to 30⁰C [US, Canada] OR
Store at 25°C; excursions permitted to
15°C to 30°C [US]
Do not store above 25⁰C. Protect
from moisture.
Challenges-Medicines for children
LPV/r oral liquid• Contains >40% alcohol v/v• Cold chain transport &
storage requirements• Needs accurate dosing device• Unpleasant taste
LPV/r Pellets• Safety & acceptability ≥ 6 months • limited evidence 3-6 months• Open capsule, count # pellets, return
remaining pellets to capsule, close capsule
• Mix with semi solid foods,• Unpleasant taste
Heat stability + shelf life+ ease of use
• Liquid dosage forms are preferred for younger children, but pre-formulated liquids or powders for reconstitution have stability challenges, high transport costs and often difficult to administer
Fragmentation of formulation approaches for the same active moiety-creates manufacturing and supply challenges; What to produce? What to buy?
Opportunities for improvement
Focus area Specific Benefits Opportunities for industryHeat stability: Zone IvbLonger shelf life: > 36 months
• Eliminate requirement for mechanized ventilation for warehouses temperature control
• Improved supply chain and better access
• Cost effective to conduct studies at Zone IV b• Variation applications for labelling storage conditions• Product with Zone Ivb and longer shelf life has wider
geographical reach
Dose optimization: Concentrated doses (e.g. Vitamin A, or efavirenz 600mg down to 400mg, Potential for optimizing antibiotic doses, dose frequency, duration of Rx?
• Reduced liquid volume burden to children (Both oral and injectable)• Reduced exposure to unnecessary quantities of drugs• Reduced toxicity and side effects• Reduced cost
• Development of optimized doses and formulations• Clinical studies for optimized doses and formulations
Reformulation: ORS, azithromycin, cefixime, paracetamol dispersible, penicillins; Rectal formulations/suppositories (artesunate); pro-drugs
• Taste masked ORS(i.e not flavoured) to improved uptake• New FSOD forms needed for these medicines for leading childhood
illnesses
• Taste masking for bitter potassium salt in ORS• Dispersible tablet technology exists, can be applied to a
wider range of medicines
Dosing Flexibility: Across weight and age bands; eliminate need for precise dose measurements with dosing devices.
• Improved supply chains• Prescribing flexibility• Addresses users with low literacy levels (No need for precise dose
measurements)- better compliance
• Review existing clinical data, mainly of older drugs for possible dosing based on AGE and/or WEIGHT BANDS ( and not specific weight or BSA)-Therapeutic index?
Improving existing medicines: Gentamicin injection packaging & presentation; Alternative zinc salts to improve taste. Current Zn PQ is sulfate.
• Improved and safe dosing of gentamicin (Narrow therapeutic Index)• Improved taste of Zinc
• Gentamicin requires some R&D work• Alternative, better tasting Zn salts?
Elimination of potentially harmful excipients: (artificial sweeteners, colors, alcohol) especially for long term Rx
• Safer medicines (no long term exposure) • Elimination of colorants• Good evidence for approved excipients, especially on long
term exposure
Optimizing Supply ChainsTransport and handling conditions
• Compliance with GDP guidelines• Improved supply chain and better access
• Labelling of Shipper boxes and pallets with Storage , transport and handling conditions
Optimizing Supply ChainsBar coding
• Reduced liquid volume burden to children (Both oral and injectable)• Reduced exposure to unnecessary quantities of drugs• Reduced toxicity and side effects• Reduced cost
• Development of optimized doses and formulations• Clinical studies for optimized doses and formulations
Optimizing Supply ChainsMonitoring Shipment
• Ensuring quality of product throughout supply chain • Reefer containers• TTS data loggers
Optimizing Supply ChainsElimination of non-functional packaging.
• Improved supply chains• Reduced weight and volumes/reduced freight costs
• Review existing packaging and optimize
Priorities for product development, increasing supply base
Therapeutic area Identified needs Comments
HIV • FDC of ABC+3TC+EFV for paediatric HIV treatment• FDC of NVP+AZT HIV postnatal prophylaxis• Dolutegravir based FDCs
Progress made through IATT optimal formulary. Procurement data shows > 90% of products are ‘optimised formulations’
TB, Hepatitis • PK/PD data for quinolones, new 2nd line products,• Shortening duration of TB therapy• optimising FDCs for Hepatitis, TB and HIV co-infection
Hepatitis B and C medicines quiet costly
malaria • Artesunate Injection• Amodiaquine+ SP dispersible tablets for SMC• Rectal Artesunate for pre-referral severe malaria
Only one WHO PQ source for injectionChallenges with Sulfadoxine API sourcesRectal dosage forms challenging to produce
NTD • Praziquantel reformulation• Miltefosine – dose?• Pentavalent antimonials – PAINFUL injection• Reformulated nifurtimox??
Role of early and independent PK/PD modelling to optimise doseNew products in development with paediatriccomponents
antibiotics Quality sources for • Amoxicillin dispersible tablets• Gentamicin inj 10 mg/ml 2 ml amp• Ampicillin pdr/inj 500 mg vial• Procaine Benzylpenicillin pdr/inj 1MIU/3MIU• Benzathine Benzylpenicillin pdr/inj 2.4 MIU• Cefixime 100 mg dispersible tablets• Azithromycin 200 dispersible tablets• Tetracycline eye ointment 1%/TBE-5g
Limited Sources
others • Suspending agents for extemporaneous preps See new WHO/FIP guideline document
Others • Acetylsalicylic acid tabs 300 mg/500 mg blisters 10x10• Paracetamol 100mg/250 mg dispersible tablets • Miconazole 10 mg mucoadhesive tablets• Dexamethasone inj 4 mg/ml 1ml amp• Nifedipine 10 mg (immediate release) capsules
Limited sources
Property Optimum Minimum
Target populations One dosage form for ages 0 – 6 years Ages 0-2, 2-6, >6
Safety No child toxic excipients No child toxic excipients
Drug attributes Accommodates wide range of doses and drug properties (e.g. solubility)
A set of 3-5 technologies that accommodate 80% / majority of drug types and doses and fixed dose combinations
Weight based dosing Possible to administer the same dosage form across multiple weight bands
Possible to administer the same dosage form across multiple weight bands
Administration considerations* • Easy to administer-minimum manipulation by caregiver• Minimal opportunity for child to reject medication.• Easy to apply with no irritation (non-oral)
Oral, topical, suppository etc.
Administration device consideration • Product does not need device OR appropriate device supplied if needed
• Intuitive-No instructions necessary
Minimum instructions necessary
Taste and texture (oral dosage) Not bitter, child friendly flavor, good mouthfeel Not bitter, acceptable taste
Preparation None Easy administered with water, milk or food
Stability / Shelf Life ICH Zone Ivb/ ≥3 years (36 months) ICH Zone IV/ ≥2 years (24 months)
Packaging Compact light weight, easy to open and administer, inexpensive
Bottles, blisters or sachet etc.
Delivery Channel No special handling requirements Suitable for all climatic zones, low levels of literacy
Disability Braille, “talking patient information”
Looking into the future Sample Target Paediatric Product Profile
UNICEF, WHO, BMGF
*(does not include injectables)
UNICEF VACCINES
Thank you!Technical Specialists
Atieno Ojoo; aojoo@unicef.org
Henrik Nielsen; hnielsen@unicef.org
Natasa Moravcevic; nmoravcevic@unicef.org
Technical Assistants
Chinedum Ogbonna; cogbonna@unicef.org
Karin Martinussen; kmartinussen@unicef.org