Transcript Guidelines

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
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Peter York | April 2008
Pharmaceutical Development with Focus
on Paediatric formulations
Presented by:
Name: Peter York
Contact details:
[email protected]
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Peter York | April 2008
Pharmaceutical Development with Focus on Paediatric
Formulations Dosage form design and manufacture
In 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
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Peter York | April 2008
Medicinal Products
ACTIVE COMPOUND (API)
MEDICINE
(MOLECULES,
 QUALITY
MACROMOLECULE)
 SAFETY
 EFFICACY
EXCIPIENTS
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Peter York | April 2008
MANUFACTURE
Medicinal Products
PHYSICAL
FORM
ADMINISTRATION
ROUTE
REQUIRED
TIME OF
ONSET ACTION/
PERIOD OF
DRUG DELIVERY
PATIENT
AGE
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
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Peter York | April 2008
Design 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
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Peter York | April 2008
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
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Peter York | April 2008
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
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Peter York | April 2008
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
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Peter York | April 2008
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)
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Peter York | April 2008
WHO Model List of Essential Medicines for
Children (Oct 2007)
 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
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Peter York | April 2008
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)
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Peter York | April 2008
WHO Model List of Essential Medicines for
Children (Oct 2007)
 Antiretrovirals
 Fixed dose combinations (FDC)
stavudine+lamivudine+nevirapine: tablets
(30mg+150mg+200mg)
zidovudine+lamivudine: tablets (300mg+150mg)
zidovudine+lamuvidine+nevirapine: tablets
(300mg+150mg+200mg)
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Peter York | April 2008
WHO Model List of Essential Medicines for
Children (Oct 2007)
 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
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Peter York | April 2008
Critical factors related to API(s) properties
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Peter York | April 2008
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.
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Peter York | April 2008
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
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Peter York | April 2008
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
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Peter York | April 2008
API Properties – Formulation Design and
Processing (2)
 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
–
–
–
–
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particle sizing (laser light diffraction method)
crystallinity (by x-ray powder diffraction)
amorphous content (by x-ray powder diffraction)
wettability (by liquid penetrating methods)
Peter York | April 2008
API 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)
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Peter York | April 2008
API Properties - Polymorphism
Representation of two
polymorphic forms of a
crystal consisting of a
molecule represented by a
‘hockey-stick’ shape
 e.g carbamazepine, ritonavir
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Peter York | April 2008
Ritonavir – 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))
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Peter York | April 2008
API Properties – Formulation Design
and Processing (3)
 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
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Peter York | April 2008
API Properties – Characteristics
to be considered when formulating medicines
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Peter York | April 2008
API Property Classification –
inter-dependencies between ‘groupings’
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Peter York | April 2008
Formulation and manufacturing plan
(Development pharmaceutics)
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Peter York | April 2008
Design of a Paediatric Dosage Form (1)
Development
pharmaceutics;
formulation and
manufacturing plan
Define API(s) and dosage regime
Consider – route of administration
- suitable dosage form
What are pharmacokinetic
characteristics of API(s)?)
- t50, Cmax, AUC
- BCS (for oral products
- BA/BD issue
Determine relevant properties of
API(s)
- physicochemical, crystallographic
- stability under ‘stress’ conditions
- compatibility with second API
and/or common excipient
Select dosage form and strength -
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Peter York | April 2008
Design of a Paediatric Dosage Form (2)
Sources of
information
Innovator literature
Selection dosage form and strength
Consider suitable formulations and
manufacturing processes
Company
experience
Other literature
sources
Define ‘design
space’, process
control
Prototype formulations and
manufacturing route,
and prototype packaging
Optimisation techniques
Validation (formulation and
Manufacturing process)
Selection final formulation
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Peter York | April 2008
Testing
Phys/chem stability
(Dissolution)
DoE
AI
tools
Relevant product
tests
(Pilot BE study)
Design of a Paediatric Dosage Form
Select final formulation,
manufacturing process
and packaging
Process scale-up studies/batches
Confirmatory stability (dissolution) studies
(BE study)
Documentation for prequalification/ registration dossiers
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Peter York | April 2008
Factors influencing formulation selection
and design
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Peter York | April 2008
Paediatric 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
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Peter York | April 2008
Paediatric 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)
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Peter York | April 2008
Paediatric 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
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Peter York | April 2008
Challenges
 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
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Peter York | April 2008
Pharmaceutical Development with Focus
on Paediatric formulations
In this presentation:
 Design of paediatric medicines – underlying
principles
 Critical factors related to API(s) properties
 Formulation and manufacturing plan
 Factors influencing formulation selection and design
 Challenges for ‘forward thinking’ with paediatric
medicines
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Peter York | April 2008