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.

Technical Specifications

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

Technical

requirements or

standards

• 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

Technical

evaluation

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