peter york | april 2008 1 |1 | pharmaceutical development with focus on paediatric formulations...

Peter York | April 20081 |

Pharmaceutical Development with Focus on Paediatric formulations


WHO/FIP Training Workshop Hyatt Regency Hotel

Sahar Airport Road

Andheri East, Mumbai, India

28 April 2008 – 2 May 2008




Presented by:

Name: Peter York

Contact details:

[email protected]


Pharmaceutical Development with Focus on Paediatric Formulations -

Dosage form design and manufacture

Pharmaceutical Development with Focus on Paediatric Formulations -

Dosage form design and manufactureIn this presentation:

Design of paediatric medicines – underlying principles

Critical factors related to API(s) properties

Formulation and manufacturing plan

Factors for formulation selection and design

Challenges for ‘forward thinking’ with paediatric medicines


Medicinal ProductsMedicinal Products

ACTIVE COMPOUND (API) MEDICINE

(MOLECULES, QUALITY

MACROMOLECULE) SAFETY

EFFICACY

EXCIPIENTS MANUFACTURE


Medicinal ProductsMedicinal Products

PHYSICAL ADMINISTRATION REQUIRED PATIENTFORM ROUTE TIME OF AGE

ONSET ACTION/PERIOD OF DRUG DELIVERY

SOLIDS ORAL SECONDS PRETERM INFANTS

SEMI-SOLIDS PARENTERAL MINUTES TERM INFANTS (0 – 28 DAYS)

LIQUIDS TOPICAL/RECTAL HOURS INFANTS, TODDLERS

(>28 DAYS – 23 MONTHS)

RESPIRATORY DAYS CHILDREN(2 – 11 YRS)

EYE, EAR WEEKS/ ADOLESCENTS (12 – 16/18 YRS)

MONTHS

ADULTS


Design of MedicinesDesign of Medicines

PRIMARY FACTORS TO CONSIDER

API properties (e.g. solubility, absorption characteristics, BCS, stability, dose ……)

Route of administration (linked to API pharmacology/ therapeutics, pharmacokinetics, intended patient population (age etc)….)

Selection of type of dosage form (linked to selection of functional excipients)

Awareness of manufacturing process (GMP, efficiency, exposure to manufacturing ‘stresses’ ….)

Sourcing of quality APIs and excipients


Paediatric Medicines and Specific Dosage Forms

Paediatric Medicines and Specific Dosage Forms

SOLIDS

• powders, granules, pellets

• capsules, DPIs, implants

• tablets, dispersible tablets, bilayer tablets

SEMI-SOLIDS

• suppositories• dermatologicals

LIQUIDS

• syrups, solutions, suspensions• pareterals• MDIs


Focus – Paediatric Medicines (HIV/AIDS, Malaria and TB)

Focus – Paediatric Medicines (HIV/AIDS, Malaria and TB)

SOLIDS

• powders, granules, pellets

• capsules, DPIs, implants

• tablets - dispersible, bilayer, chewable, buffered

SEMI-SOLIDS

• suppositories• dermatologicals

LIQUIDS

• syrups, solutions, suspensions• parenterals• MDIs


Paediatric medicines for HIV/AIDS, malaria and TB – additional issues

Paediatric medicines for HIV/AIDS, malaria and TB – additional issues

Continuous changes of medicine dispositional parameters

Dose, ADME, PK,…..

Dose ratios for fixed dose combinations (FDCs)

‘Extemporaneous’ dispensing (eg dilutions, ‘fractioning’ of adult dosage form, packaging, stability….)

Compliance

Stability, transport challenges for liquid formulations


WHO Model List of Essential Medicines for Children (Oct 2007)


Antituberculosis medicines

ethambutol: oral liquid (25mg/ml); tablet (100mg, 400mg)

isoniazid: oral liquid (50mg/5ml); tablet (50mg (scored), 100mg, 300mg)

pyrazinamide: oral liquid (30mg/ml); tablet (150mg (dispersible, scored), 400mg)

rifampicin: oral liquid (20mg/ml); capsule and tablet (150mg, 300mg)

rifampicin+isoniazid+pyrazinamide: tablet 60mg+30mg+150mg

streptomycin: powder for injection (1g (as sulphate)in vial)




Intended for children up to 12 years of age

Core list – minimum medicine needs for a basic health care system

Specialized list – essential medicines for priority diseases for which specialized diagnostic/monitoring, specialist medical care, and/or specialist training are needed

http://www.who.int/medicines/publications/essentialmedicines/en/index.html


WHO Model List of Essential Medicines for Children (October 2007)

WHO Model List of Essential Medicines for Children (October 2007)

Antiretrovirals

‘Subcommittee recommends and endorses the use of fixed-dose combinations and the development of new fixed-dose combinations, including modified dosage forms, non-refrigerated products and paediatric dosage forms with assured pharmaceutical quality’

Nucleoside/nucleotide reverse transcriptase inhibitors

eg abacavir: oral liquid (100mg/5ml (as sulphate)), tablet (300mg (as sulphate))

eg didanosine: buffered powder for oral liquid (100mg, 167mg, 250mg packets), capsule (unbuffered enteric-coated 125mg, 200mg, 250mg, 400mg), tablet (buffered,chewable, dispersible 25mg, 50mg, 100mg, 150mg, 200mg)

• Non nucleotiside reverse transcriptase inhibitors

eg efavirenz: capsule (50mg,100mg, 200mg), oral liquid (150mg/5ml), tablet 600mg

• Protease inhibitors

eg ritonavir: oral liquid (400mg/5ml), oral solid dosage fom (100mg)




Antiretrovirals

Fixed dose combinations (FDC)

stavudine+lamivudine+nevirapine: tablets (30mg+150mg+200mg)

zidovudine+lamivudine: tablets (300mg+150mg)

zidovudine+lamuvidine+nevirapine: tablets (300mg+150mg+200mg)




Antimalarial medicines

For curative treatment

‘Medicines for the treatment of P. falciparum malaria cases should be used in combination. The list currently recommends combinations according to treatment guidelines. The Subcommittee recognizes that not all of these FDCs exist and encourages their development and rigorous testing. The Subcommittee also encourages development and testing of rectal dosage forms.’

eg amodiaquine: tablet (153mg or 200mg (as HCl)); to be used in combination with artesunate 50mg

doxycycline: capsule (100mg (as HCl)), tablet (dispersible 100mg as monohydrate); for use only in combination with quinine

quinine: injection (300mg (as HCl)/ml as 2 ml ampoule, tablet (300mg (as sulphate or bisulphate); used in combination with doxycycline


Active Pharmaceutical Ingredient(s)Active Pharmaceutical Ingredient(s)

Sourcing – patented and generic compounds

Specifications and standards– pharmacopoeial monographs (BP, USP, IP, EP); reference

standards– focus on chemical identification and purity– increasing awareness of need to monitor physical,

crystallographic and ‘functional’ properties

Other sources of information –– scientific literature, www, innovator product information.


API Routine Testing – ‘Good Practice’ API Routine Testing – ‘Good Practice’

Provide assurance of quality and safety

Verification of CoA and magnitude of testing programme

Sampling programme/isolated quarantine storage areas

Retention/storage of batch samples

Training programmes for staff, SOPs, GLP and validation of methods

‘Confidence’ in consistent quality of supply from chosen suppliers


API Properties – Formulation Design and Processing (1)


50% of new APIs, and many others, have very low aqueous solubility which can constrain drug dissolution (ie rate of solution) and thereby limit bioavailability

Many APIs exhibit polymorphism (also solvation – hydration) – alternative molecular packing of the same chemical in crystalline material leading to different properties such as dissolution rate)

Moisture content control – hygroscopic material often difficult to process (eg tabletting); change in hydration state (eg during wet granulation)

Respiratory drug delivery – DPIs and suspension MDIs require drug particle size (aerodynamic) of 1 – 5 microns

All above are also examples of QUALITY issues when formulating and processing APIs; may require additional testing and/or control procedures




Additional validated testing methods may be required to guide and direct formulation design, e.g. pH solubility profile

Pharmacopoeia now introducing general guidance chapters, information, testing methods …..

Properties being introduced include

– particle sizing (laser light diffraction method)– crystallinity (by x-ray powder diffraction)– amorphous content (by x-ray powder diffraction)– wettability (by liquid penetrating methods)


API properties – particle sizeAPI properties – particle size

Many substances poorly aqueous soluble (BCS Class II and IV)

Reduce particle size to maximise dissolution (also for BCS Class III)

Such compounds routinely micronised – potential for chemical and crystallographic damage which can compromise stability and intra- and inter-batch consistency

Potential issues for liquid suspension formulations (eg particle size changes on stability)


API Properties - PolymorphismAPI Properties - Polymorphism

e.g carbamazepine, ritonavir

Representation of two polymorphic forms of a crystal consisting of a molecule represented by a ‘hockey-stick’ shape


Ritonavir – Issue of PolymorphismRitonavir – Issue of Polymorphism

Ritonavir (originator Abbott) – HIV protease inhibitor

Norvir product introduced in 1996 as ‘semi-solid’ capsule preparation containing a ‘solid-solution’ of drug in PEG

Summer 1998 – capsule supplies threatened as a new much less soluble crystal form of ritonavir precipitated in the capsule

Drug dissolution was slowed down, compromising bioavailability

Product was withdrawn and reformulated in soft elastic capsule form with new form of ritonavir

(Baur et al, Pharm Res 18 (6) 859-866 (2001))




Alternative pre-treatment and processing of APIs (eg alternative final solvent used during final crystallisation step during synthesis of API; use of crystallisation rather than milling process for particle size reduction ) can lead to different surface properties of particles, such as interparticle cohesion and surface ‘charge’

These phenomena can lead to different secondary processing behaviour and potentially variation in product performance


API Properties – Characteristics to be considered when formulating medicines

API Properties – Characteristics to be considered when formulating medicines


API Property Classification – inter-dependencies between ‘groupings’

API Property Classification – inter-dependencies between ‘groupings’



(Development pharmaceutics)


Design of a Paediatric Dosage Form (1)Design of a Paediatric Dosage Form (1)

Define API(s) and dosage regime

Consider – route of administration - suitable dosage form

What are pharmacokinetic Determine relevant properties of characteristics of API(s)?) API(s)- t50, Cmax, AUC - physicochemical, crystallographic- BCS (for oral products - stability under ‘stress’ conditions- BA/BD issue - compatibility with second API

and/or common excipient

-Select dosage form and strength

Development pharmaceutics;formulation and

manufacturing plan


Design of a Paediatric Dosage Form (2)Design of a Paediatric Dosage Form (2)

Selection dosage form and strength

Consider suitable formulations and manufacturing processes

Prototype formulations andmanufacturing route,

and prototype packaging

Optimisation techniquesValidation (formulation and

Manufacturing process)

Selection final formulation

Define ‘design space’, process control

Sources of information

Innovator literature

Company experience

Other literature sources Testing

Phys/chem stability)Dissolution(

Relevant product tests

)Pilot BE study(

DoE AI tools


Design of a Paediatric Dosage FormDesign of a Paediatric Dosage Form

Select final formulation,manufacturing process

and packaging

Process scale-up studies/batchesConfirmatory stability (dissolution) studies

(BE study)

Documentation for prequalification/ registration dossiers


Factors influencing formulation selection and design


Paediatric medicines- liquid formulationsPaediatric medicines- liquid formulations

Solutions, syrups

-preferably avoid sugar and alcohol in formulations

-drug solubility (dose/volume), stability, pH,

-API(s) compatibility with vehicle/liquid diluents

-taste (taste masking), colour, flavour

- single dose vs multidose (preservatives etc)

Suspensions (and liquids products reconstituted from powders/granules)

- as above

- viscosity, API(s) particle sedimentation volume/redispersion

- suspending/flocculating agents

- particle size/crystallinity changes on storage/shelf life


Paediatric medicines – solid formulationsPaediatric medicines – solid formulations

API(s) compatibility with excipients/other active(s) (need to separate APIs?)

Selection of ‘appropriate’ functional excipients

API dose and/or physicochemical properties may direct selection of manufacturing route (eg direct compression for low dose products, heat/light sensitive APIs…)

Key product performance test is dissolution of drug(s)– QC test (meet specification, batch reproducibility…)– Potential ‘surrogate’ test for in vivo performance, but ivivc (in vitro/in vivo

correlations) remain challenging for most solid dosage forms– Critical test for BE waivers (BCS Class I and III)


Paediatric medicines - all dosage formsPaediatric medicines - all dosage forms

Stability indicating assay for shelf-life testing

Establish sensitivity of API(s) to applied ‘stresses’ during selected manufacturing processes

Packing is an integral component of the medicinal product


ChallengesChallenges

Quality, safe and efficacious medicines, appropriately designed medicines for children

Clinical pharmacology; dose versus age; clinical trial evidence aiding dose and design criteria

ADME/PK/pharmacogenetics knowledge/data base for APIs

Elimination of ‘dose-risk’ at point of delivery (administration) of medicine

‘Innovative’ yet ‘pragmatic’ solutions to dose dilution, and dose ratio options for FDC products




In this presentation:

Design of paediatric medicines – underlying principles



Factors influencing formulation selection and design

Challenges for ‘forward thinking’ with paediatric medicines

peter york | april 2008 1 |1 | pharmaceutical development with focus on paediatric formulations...

Documents

design of paediatric

paediatric medicines

peter york contact details

liquid formulations

mgml tablet

oral liquid 50mg5ml

yrs months adults slide

dispersible tablets