MDC Connects: Designing formulations for early stage pre-clinical and clinical studies’

Presented on 20th May 2020 by Alison Foster, Quay Pharma

1. DESIGNING FORMULATIONS FOR PRE-CLINICAL
& EARLY STAGE CLINICAL STUDIES
Dr.Alison Foster, Head of Technical –Pre-Clinical, Quay Pharmaceuticals, Deeside, UK

2. QUAYPHARMA.COM
QUAY PHARMA
•Contract development and clinical manufacturing organisation
•Family owned business, based in UK
•Founded in 2002 by Michael Rubinstein, Prof. Pharmaceutics and Chemistry
•180 + people
•Experts in formulation of molecules for systemic and localised delivery
•Specialist formulators of ‘problem’ molecules, including
•Small molecules
•Live bio-therapeutics
•Antibodies and other large molecules
•GMP clinical manufacture of all products developed
Who are we?
2

3. QUAYPHARMA.COM
•Pre-Clinical Formulation
•Maximise dose and absorption in pre-clinical animal models
•Clinical Formulation
•Pre-Formulation (generate data to enable formulation development, e.g. powder
characterisation, excipient compatibility)
•Formulation (optimise formulation approach and generate early prototypes)
•Feasibility batch (scaled technical batch to mimic GMP process, ICH stability studies)
Development Route
PRE-CLINICAL AND CLINICAL FORMULATION
Pre-clinical
Formulation
API Solid State
Characterisation
DMPK &
Tox
Feasibility
Batch
Pre-
Formulation
Formulation
GMP
Manufacture
Product Development Timeline
3

4. QUAYPHARMA.COM
•Pre-Clinical Formulation
•Maximise dose and absorption in pre-clinical animal models
•Clinical Formulation
•Pre-Formulation (generate data to enable formulation development, e.g. powder
characterisation, excipient compatibility)
•Formulation (optimise formulation approach and generate early prototypes)
•Feasibility batch (scaled technical batch to mimic GMP process, ICH stability studies)
Development Route
PRE-CLINICAL AND CLINICAL FORMULATION
Pre-clinical
Formulation
API Solid State
Characterisation
DMPK &
Tox
Feasibility
Batch
Pre-
Formulation
Formulation
GMP
Manufacture
Product Development Timeline
4

5. QUAYPHARMA.COM
•Pre-Clinical Formulation
•Maximise dose and absorption in pre-clinical animal models
•Clinical Formulation
•Pre-Formulation (generate data to enable formulation development, e.g. powder
characterisation, excipient compatibility)
•Formulation (optimise formulation approach and generate early prototypes)
•Feasibility batch (scaled technical batch to mimic GMP process, ICH stability studies)
Development Route
PRE-CLINICAL AND CLINICAL FORMULATION
Pre-clinical
Formulation
API Solid State
Characterisation
DMPK &
Tox
Feasibility
Batch
Pre-
Formulation
Formulation
GMP
Manufacture
Product Development Timeline
5

6. QUAYPHARMA.COM
•Pre-Clinical Formulation
•Maximise dose and absorption in pre-clinical animal models
•Clinical Formulation
•Pre-Formulation (generate data to enable formulation development, e.g. powder
characterisation, excipient compatibility)
•Formulation (optimise formulation approach and generate early prototypes)
•Feasibility batch (scaled technical batch to mimic GMP process, ICH stability studies)
Development Route
PRE-CLINICAL AND CLINICAL FORMULATION
Pre-clinical
Formulation
API Solid State
Characterisation
DMPK &
Tox
Feasibility
Batch
Pre-
Formulation
Formulation
GMP
Manufacture
Product Development Timeline
6

7. QUAYPHARMA.COM
•Pre-Clinical Formulation
•Maximise dose and absorption in pre-clinical animal models
•Clinical Formulation
•Pre-Formulation (generate data to enable formulation development, e.g. powder
characterisation, excipient compatibility)
•Formulation (optimise formulation approach and generate early prototypes)
•Feasibility batch (scaled technical batch to mimic GMP process, ICH stability studies)
Development Route
PRE-CLINICAL AND CLINICAL FORMULATION
Pre-clinical
Formulation
API Solid State
Characterisation
DMPK &
Tox
Pre-
Formulation
Formulation
GMP
Manufacture
Product Development Timeline
7
Feasibility
Batch

8. PRE-CLINICAL FORMULATION

9. QUAYPHARMA.COM
FORMULATION FOR PRE-CLINICAL STUDIES
•Maximise dose and absorption
•Usually liquid dose required (oral gavage)
•Often a poorly water soluble drug
•Typically very little API available
•Create formulation with minimal time and
effort as ‘proof-of-concept’
•Careful consideration of excipients due to
potential toxic effects in different species
General Considerations
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10. QUAYPHARMA.COM
FORMULATION FOR PRE-CLINICAL STUDIES
•Chemical structure (contain chromophore?)
•Solubility data (water, buffers, solvents)
•LogP, pKa, melting point
•Any Caco-2 data
•Amount API available
•Maximum target dose required
•Intended pre-clinical species
Useful Data to Know
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11. QUAYPHARMA.COM
•Three platforms
•Solubility screening
•Simplest option and starting point
•Includes range of solvent and surfactant solutions, lipids etc
•Solid dispersion and nanoparticles
•If solution or lipid formulation not viable
•More complex route aimed at poorly soluble BCS Class II molecules
•Can bridge to Phase 1 formulation development
•Bespoke -excipient selection based on API
characteristics, animal species and downstream
requirements
•Minimal API
•Rapid turnaround
Quay Platforms
FORMULATION FOR PRE-CLINICAL STUDIES
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12. QUAYPHARMA.COM
FORMULATION FOR PRE-CLINICAL STUDIES
Solubility Screening –Case Study
•Comparison between typical solubility ‘macro’
method and HT screening method
•Maximum 20 mg/mL target in screening
method
•Same trends observed for both methods and
analytical techniques
0
5
10
15
20
25
30
35
40
45
Solubility (mg/mL)
Macro Method UV Macro Method HPLC Screening Method
Macro Method
(UPLC)
Screening Method
(UV)
Amount of API 430 mg 200 mg
Time required 6 days 1.5 days
Lead solvents
Transcutol
Propylene Glycol
PEG 400
10 % SDS
Transcutol
Propylene Glycol
PEG 400
10 % SDS
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13. FORMULATION FOR EARLY CLINICAL
STUDIES

14. QUAYPHARMA.COM
FORMULATION FOR EARLY CLINICAL STUDIES
•Patient health benefits / requirements
•Goal of the Phase I study
•POC only? Bridge to Phase II? As close to final
formulation as possible?
•Preferred route of administration
•Target product profile (essential)
•Success vs. degree of acceptable risk
•Cost/ time(interdependent factors)
•Submission strategy / commercial
considerations
•API availability
•Regulatory timeframe
General Considerations
Time
Cost
Risk
Componentsof the TPP
Indication Patient population
Patient needs/limitationsTarget release profile
Dose range & frequencyTargetabsorption site
(localised vs systemic
delivery)
Balance…..
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15. QUAYPHARMA.COM
FORMULATION FOR EARLY CLINICAL STUDIES
•Physicochemical Characteristics of API –marriage the available data with the
desires of the TPP
•As for pre-clinical studies plus:
•Particle size distribution/shape/density, flow characteristics
•Polymorphic form
•Stability data (including forced degradation studies)
•Biological Characteristics
•Permeability –(such as Caco-2 cell data)
•Potential for efflux
•Existing PK/PD data
•Bioavailability (F), Cmax, T
½
Useful Data to Know
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16. QUAYPHARMA.COM
FORMULATION FOR EARLY CLINICAL STUDIES
•API Classification according to BCS*/DCS** -What are we working with?
Defining the Development Path
*BCS = BiopharmaceuticsClassification System
**DCS = DevelopabilityClassification System
Reproduced from Butler, J. M, Dressman, J. B., J. Pharm.
Sci., 2010,99, 4940
100000
I
Good Solubility
Good Permeability
III
Good Solubility
Poor Permeability
IV
Poor Solubility
Poor Permeability
Dose/solubility ratio 250 500 1000 500010000
Predicted
Peff
in Humans cm/sec x 10
-
4
0.1--
1--
10--
II
Poor Solubility
Good Permeability
IIa
Dissolution
Rate Limited
IIb
Solubility Limited
Using predicted jejunal solubility (e.g. FaSSIF)
Everyone’s favourite!
Most likely….but interesting!
Unlucky!
Not too often…..
Data obtained from pre-clinical
solubility study can help define DCS
Classification together with target dose
from TPP
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17. QUAYPHARMA.COM
FORMULATION FOR EARLY CLINICAL STUDIES
Good Solubility, Good Permeability (Class I)
API in bottle/capsule
Powder in bottle
Standard capsule/tablet (monolithic)
Multi-particulate
Modified release/solutions/suspensions
Advanced technology
Increasing –
duration, cost,
complexity,
risk
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18. QUAYPHARMA.COM
FORMULATION FOR EARLY CLINICAL STUDIES
•Majority of new candidates fall into this category
Low Solubility, Good Permeability (Class II)Dissolution Limited AbsorptionSolubility Limited Absorption
Particle Size
Reduction
Solid
Dispersion
Lipid
Delivery
Micro-environmental
pH Control
Dosage Form
Selection
•Absorption rate drives the selection
of approach
•Higher risk
•Rationale must be based upon
available data (complex decision
tree!)
•Case by case evaluation
•Rapid screening approach available
in pre-clinical platform can help
select formulation options
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19. QUAYPHARMA.COM
FORMULATION FOR EARLY CLINICAL STUDIES
•Additional consideration -has the correct lead compound been selected?
•Could solubility be improved by salt formulation?
•Could permeability be improved by delivery as a pro-drug?
Class III/Class IV Molecules
Class III Compounds
•Can permeation enhancers be
incorporated in formulations?
•Can transit time be reduced to increase
absorption potential?
Class IV Compounds
•Can combinations of permeation
enhancers and solubility enhancing
methods be employed?
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20. QUAYPHARMA.COM
FORMULATION FOR EARLY CLINICAL STUDIES
Balancing Risk vs.Time vs.Cost
Risk
Cost
Time
•More advanced formulation,
easier transition to Phase II/III
•Immediate release to targeted
release
•Bioavailability differences
•Moving from manual to
automated processes
•Speed to clinic
•Enabling technologies
typically more complex
•Availability of technology /
resources (API supply)
•Delay formulation costs for Phase II
•Company value, out-licensing strategy, milestone payments
•IP considerations
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21. QUAYPHARMA.COM
FORMULATION FOR EARLY CLINICAL STUDIES
•Critical factors for selection of appropriate formulation whether for
pre-clinical or clinical studies
•Patient (animal) needs and safety
•Dose to be delivered
•Target release profile
•Complexity of supporting analytical/screening methodologies
•Overall development strategy and timelines
•Readiness to assume risks
•Financial implications
Summary
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22. QUAYPHARMA.COM
CONTACTS
Dr Audrey Vardy
Head of Business Development –Pre-Clinical
[email protected]
Dr Alison Foster
Head of Technical –Pre-Clinical
[email protected]
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