Pediatric Delivery Systems for Oral Products · Design History File FMEAs Design Specifications. Prim, Crit 2nd & 2nd Pkg. Trace Matrix Pkg Component / System Specifications Design

Company Confidential © 2018 Eli Lilly and Company

Pediatric Delivery Systems for Oral Products

Matthew S. ThomasEli Lilly and CompanyPackaging/Device Design and DevelopmentMay 3, 2018

Product Research and Development at Lilly

Company Confidential © 2018 Eli Lilly and Company 2

Analytical Development Chemist

Site Packaging Eng. / Global Packaging Eng. / Tech. Service Scientist

Packaging Design and Development Scientist or Engineer

Device Design and Development Scientist or Engineer

Formulation Development Scientist

Design Control and Risk Management for Delivery Systems


21 CFR 820.30, Medical Devices Quality System Regulation, Design ControlsISO 13485, Medical Device Quality Management System Requirements

Development Plan (includes HF Plan, Risk Plan and Deliverables Matrix) Prim, Crit 2nd & 2nd Pkg in Scope

Product Requirements DocumentPrim, Crit 2nd & 2nd Pkg in Scope

Design History File

FMEAs

Design SpecificationsPrim, Crit 2nd & 2nd Pkg Trace Matrix

Pkg Component / System Specifications

Design Reviews / Verification / Validation

Packaging Qualification Plans

Pkg Component and System Qualification Reports

Master Test Plan

Prelim Hazard Analysis

Development History Report

Patient Populations


Pediatric• Infants, children and adolescents

Adult patients with issues swallowing solid oral meds• Adult line-extension• Need to consider bioequivalence of the pediatric product to the

existing adult product

EMA/CHMP/QWP/805880/2012 Rev. 2, Guideline on pharmaceutical development of medicines for paediatric useFDA Guidance, Pediatric Study Plans

Pediatric Oral Dosage Form Options


http://www.pharmacy.umaryland.edu/media/SOP/wwwpharmacyumarylandedu/centers/cersievents/pedsformulation/selen-presentation-notes.pdf

Lilly Experience with Oral Liquid Products


Historical Oral Liquid Medications• Prescription and OTC; Antibiotics, Vitamins

Oral Solution Product• Global launches in the 1980’s and 1990’s

Landscape Research for US, EU & JP Oral Liquid Products• Recent research efforts to understand global landscape

Oral Solution Product• Japan Launch – 2013• European Union and Emerging Market Launches – 2015

Oral Liquid Delivery Systems, Global Landscape


• Glass Bottles• Child Resistant Caps• Foam Liners (PE/PET)• Oral Syringes• Dosing/Transfer Cups• Dosing Spoons

Oral Liquid Delivery System Platform for New Products


8 ounce PET bottle

Child Resistant closure

Peelable induction heat seal liner

3mL oral dosing syringe

24mm Bottle

Adapter Syringe tip cap

CR closure w/peelable induction heat seal liner

24mm Bottle

Adapter

3mL oral dosing syringe

4 ounce PET bottle

1 mL 1.5 mL 2 mL 3 mL

90mL Bottle

75mLBottle

45mL Bottle

30mL Bottle

25mL Bottle

20mL Bottle

69mL Fill54mL Fill

33mL Fill 18mL Fill

Fill Target: Just Below Bottle Shoulder Fill Volume: 30 Day Supply + 20% Overage

Glass Bottle Size 90mL Nominal 75mL Nominal 45mL Nominal 25mL Nominal

Daily Dose 2mL/day 1.5mL/day 1mL/day 0.5mL/day

Days of Supply Target: 30 days Target: 30 days Target: 30 days Target: 30 days

Closure Size 28mm 28mm 28mm 24mm

Bottle Adapter Size 28mm 28mm 28mm 24mm

Dosing Device Size 3mL Oral Syringe 3mL or 1.5mL Oral Syringe 1.5mL or 1mL Oral Syringe 1mL Oral Syringe

90mL Bottle

75mL Bottle

45mL Bottle

25mL Bottle

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwjPva2OsYHSAhUI7yYKHaH9DgoQjRwIBw&url=http://www.comar.com/product-catalog/oral-syringe-adapters-orifice-reducer/&bvm=bv.146496531,d.eWE&psig=AFQjCNG3OBFhuWBMg8nttPiBuHJCWuGkbA&ust=1486673657588120http://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwjPva2OsYHSAhUI7yYKHaH9DgoQjRwIBw&url=http://www.comar.com/product-catalog/oral-syringe-adapters-orifice-reducer/&bvm=bv.146496531,d.eWE&psig=AFQjCNG3OBFhuWBMg8nttPiBuHJCWuGkbA&ust=1486673657588120http://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwjPva2OsYHSAhUI7yYKHaH9DgoQjRwIBw&url=http://www.comar.com/product-catalog/oral-syringe-adapters-orifice-reducer/&bvm=bv.146496531,d.eWE&psig=AFQjCNG3OBFhuWBMg8nttPiBuHJCWuGkbA&ust=1486673657588120

Oral Liquid Delivery Systems, Global Landscape


Global Landscape, Prescription Oral Liquid Products


Two Container Closure / Device Platform Themes:

Single-Dose or Unit-Dose Containers• Predominantly laminated foil pouches• Supports user portability and pharmacy dispensing flexibility

Multi-Use Containers (i.e., bottle) with Device• Glass bottles as well as plastic bottles are prevalent

Bottle/Closure and Pouch Systems for Oral Liquids


PET Bottle and CR closure with peelable induction heat seal (IHS) liner

Glass bottle (type III) and CR closure with foam liner

IHS Liner StructureFoam Liner Structure

Product Contact (e.g., PET, PE)

Barrier Layer (e.g., foil, EVOH)

Printing/Mechanical LayerAdhesive Layer

Adhesive Layer

PET Film

PE Foam

PE Film

PE FilmAdhesive Layer

Pouch Liner Structure

Container Closure System Design and Development


Product Contact Packaging Materials• Formulation screening phase• Food contact requirements• Compendia requirements• Extractable information for packaging materials

Primary / Critical 2nd Packaging Components• Container closure system and delivery device (if applicable)• Child resistant and tamper evident strategies• Anti-counterfeit strategies• Packaging component supply chain qualification

Container Closure Integrity (CCI)• Torque target and range for bottle and closure systems• Seal integrity for seals• Water loss and oxygen ingress studies (if applicable)• Leak studies• Shipping studies

Packaging Line Trials• Target fill volume and fill accuracy• Torque replication at commercial scale for bottle and closure systems• Leak studies conducted at commercial scale

Container Closure System Regulations and Guidance


Product Contact Packaging Materials• USP , Assessment of Extractables Associated with Pharmaceutical Pkg/Delivery• USP , Assessment of Drug Product Leachables for Pkg Delivery Systems• US 21 CFR, List of Indirect Additives used in Food Contact• EU Directive 10/2011, Plastic Materials and Articles Intended to come into Contact w/ Food• USP , Plastic Packaging Systems and their Materials of Construction• USP , Containers – glass• Ph.Eur. 3.1.3, Polyolefins, Ph.Eur. 3.1.15, PET, Ph.Eur. 3.2.1, Glass Containers• USP , Biological reactivity tests, in vitro

Primary / Critical 2nd Packaging Components• FDA Guidance for Industry, Container Closure Systems for Pkg Human Drugs and Biologics• USP , Packaging and Storage Requirements• 16 CFR 1700, Poison Prevention Packaging Act• EMA Guideline, Plastic Immediate Packaging Materials• ISO 12931, Performance criteria for authentication solutions used to combat counterfeiting

Container Closure Integrity (CCI)• USP , Containers – performance testing• ASTM E96/E96M, Standard Test Methods for Water Vapor Transmission of Materials• ISO 15106, Determination of Water Vapour Transmission Rate

Packaging Line Trials• 21 CFRs for Good Manufacturing Practices• ISO Standards for Good Manufacturing Practices

Oral Liquid Syringe and Press In Bottle Adapter (PIBA)


• 5mL, 3mL, 2mL, 1.5mL Oral Syringes• Tip and Blunt (i.e., no tip) Designs

Polystyrene Plunger Rod

• LDPE Barrel and Piston• LDPE contains Erucamide (slip agent)

Oral Liquid Dosing Device Development


Device Materials of Construction and Performance• Product Contact and Mechanical Performance

Mechanical, Chemical and Microbial Testing• Dose Accuracy (gravimetric), In-Use Performance (simulated dosing and glide-force)• Dose Accuracy (potency), In-Use Compatibility• In-Use (microbial)

Human factors (brings all specifications together)• How does the device and CCS interact• What does the device do and how does it interact with the end-user

Oral Liquid Dosing Device Regulations and Guidance


Device Materials of Construction and Performance• US 21 CFR, List of Indirect Additives used in Food Contact• EU Directive 10/2011, Plastic Materials and Articles Intended to come into Contact w/ Food• USP , Plastic Packaging Systems and their Materials of Construction• Ph.Eur. 3.1.3, Polyolefins• ISO-10993, Biological Evaluation of Medical Devices• FDA Guidance, Dosage Delivery Devices for Orally Ingested OTC Liquid Drug Products• EMEA/CHMP/QWP/178621/2004, Suitability of the Graduation of Delivery Devices for Liquid Dosage Forms

Mechanical, Chemical and Microbial Testing• USP, Packaging and Storage Requirements (Includes Dose Accuracy)• USP , Deliverable Volume• Ph.Eur. 2.9.27, Uniformity of Mass of Delivered Doses from Multidose Containers

Human Factors• IEC 62366, Medical devices -- Application of usability engineering to medical devices• FDA Guidance, Applying Human Factors and Usability Engineering to Optimize Medical Device Design• ISO 11540, Writing and marking instruments - Specification for caps to reduce the risk of asphyxiation

Oral Liquid Key Learning Points from Global Submissions


US• Full human factors study report attached to submission• Biocompatibility testing data for dosing device• Performance data for oral dosing device and container closure system

EU• Plastic materials of device and container closure system compliant with EU food contact regulation 10/2011• Certificates of Analysis and ID specifications for the device and the container closure system• In-Process controls established for fill volume and leak testing

JP• Stability and in-use testing considers temperature range of 1C to 30C• Oral liquid syringes and cups not considered devices• Oral liquid syringes should not have tip to avoid potential use with needles

Minitablet Delivery Systems, Global Landscape


Product Molecule Indication Company Country Status Comments

LevetiracetamDesitin

Levetiracetam Epilepsy Desitin Germany marketed 2 mm minitablets, registered as coated granules, 2011

Orfiril long Valporate Epilepsy Desitin Germany marketed SR 2 mm minitablets in capsules and sachet, 1998

Meptin-Mini Tablets

Procaterolhydrochloride

Asthma, Bronchitis, Emphysema

Otsuka Japan Discontinued 4 mm minitablets. Removed from market in 2013

Tekturna Aliskiren fumarate

Hypertension Novartis India BE trial planned

Comparing oral tablet with same dose of mini tablets

Kaletra Lopinavirritonavir

HIV Cipla Uganda BE trial CT in Uganda comparing pediatric dosing with mini-tabs vs. syrup

Kalydeco Ivacaftor Cystic Fibrosis Vertex US marketed Patent application for formulation of mini-tabs, but no evidence of development

Minitablet Delivery System Options Explored


2. MTs in a Single Unit-Dose Delivery System(Stick-Pack/Vial or Tube)

1. Mini-Tablets (MTs) in a Non-Locking Capsule

3. MTs in a Delivery System to Optimize Dose Flexibility (Mechanical Dispensing Device)

Pros• Turnkey CMO option• Standard bottle & blister packaging options• Capsule can be used as a sprinkle or swallowedCons• Limits full dose flexibility of MT platform (versus #3)

Pros• Stick-Pack: Fewer turnkey CMO options than capsule• Vial/Tube: Optimal handlingCons• Both limit full dose flexibility of MT platform (versus #3)

Pros• Optimize dose flexibility and handlingCons• Design and development costs

Minitablet Delivery Systems, Lilly Exploration


Journal Article: Classification of Dosing Device Approaches


Category IVLow flexibilityHigh expenditure

Category IIHigh flexibilityHigh expenditure

Category IIILow flexibilityLow expenditure

Category IHigh flexibilityLow expenditure

https://www.sciencedirect.com/science/article/pii/S0378517310008331

https://www.sciencedirect.com/science/article/pii/S0378517310008331

Journal Article: Dosage Form and Delivery System Ratings


+ Mini-tablets (attractive Pros with Cons that are not impossible to overcome) Pros1. Existing tablet platform can be leveraged2. Optimal dosing flexibility Cons or Challenges1. Dose accuracy, relying on patient to count dose units2. Requires the use of a dosing aid or device

Journal Article: Dosage Form and Delivery System Ratings


+ Capsules*: swallow or sprinkle (existing opportunity for pipeline products) Pros1. Existing capsule platform can be leveraged2. Dose-delivery flexibility3. Dosing aid or device not required Cons or Challenges1. No dose flexibility advantages2. Capsule opening challenges (e.g., interlocking capsule design)

Design Requirements for Minitablet Delivery Systems


DESIGN CRITERIA

Assumptions: Pediatric Delivery, Highly Variable Dosing, Take Home Delivery System

Patie

nt Ne

ed (s

wallo

w-ab

ility)

Dose

Flexib

ility

Fixed

Dose

Comb

o

Usab

ility

COPS

CT Re

adine

ss

Minitablets in Capsule + - + + + +Minitablets in Pouch/Stick-Pack + - + + + +Minitablets in Plastic Vial/Tube + - + + + -Minitablets in Dosing Device + + N/A + - -

Sheet1

DESIGN CRITERIA

Assumptions: Pediatric Delivery, Highly Variable Dosing, Take Home Delivery SystemPatient Need (swallow-ability)Dose FlexibilityFixed Dose ComboUsabilityCOPSCT Readiness

Minitablets in Capsule+-++++

Minitablets in Pouch/Stick-Pack+-++++

Minitablets in Plastic Vial/Tube+-+++-

Minitablets in Dosing Device++N/A+--

High Level Project Timeline

Cross-functional PR&D minitablet workshop meetings Initial minitablet prototyping by Packaging and Device organization User interviews (clinical trial scope) with Lilly Nurses Forum Cross-functional PR&D minitablet delivery system design brainstorm Usability studies with functional prototypes using Lilly employees Pharma pediatric delivery system presentation External patient/HCP engagement study with prototypes First clinical trials with small molecule from Lilly pipeline

• Targeting oncology molecule and/or pediatric presentation• Minitablets provide dose flexibility for oncology products• Minitablets provide “ease of swallowing” with food (e.g., applesauce) for pediatric patients


Pediatric Delivery Systems for Oral ProductsProduct Research and Development at LillyDesign Control and Risk Management for Delivery SystemsPatient PopulationsPediatric Oral Dosage Form OptionsLilly Experience with Oral Liquid ProductsOral Liquid Delivery Systems, Global LandscapeOral Liquid Delivery System Platform for New ProductsOral Liquid Delivery Systems, Global LandscapeGlobal Landscape, Prescription Oral Liquid ProductsBottle/Closure and Pouch Systems for Oral LiquidsContainer Closure System Design and DevelopmentContainer Closure System Regulations and GuidanceOral Liquid Syringe and Press In Bottle Adapter (PIBA) Oral Liquid Dosing Device DevelopmentOral Liquid Dosing Device Regulations and GuidanceOral Liquid Key Learning Points from Global SubmissionsMinitablet Delivery Systems, Global LandscapeMinitablet Delivery System Options ExploredMinitablet Delivery Systems, Lilly ExplorationJournal Article: Classification of Dosing Device ApproachesJournal Article: Dosage Form and Delivery System RatingsJournal Article: Dosage Form and Delivery System RatingsDesign Requirements for Minitablet Delivery SystemsHigh Level Project Timeline

Documents

Pediatric Delivery Systems for Oral Products · Design History File FMEAs Design Specifications. Prim, Crit 2nd & 2nd Pkg. Trace Matrix Pkg Component / System Specifications Design