This presentation discusses integrated strategies for overcoming formulation challenges in drug development. It describes Quotient Sciences' approach of integrating formulation development, clinical testing, and manufacturing to accelerate programs and reduce costs. Examples are provided of enhancing solubility for poorly soluble drugs, developing modified release formulations, selecting formulations for first-in-human studies, and formulating peptides for oral delivery. The benefits of this integrated approach include timelines accelerated by over 12 months, significant cost savings, and a greater likelihood of success.

1. Overcoming Complex Formulation
Challenges for Small Molecules & Peptides:
Integrated Strategies for Poor Solubility,
Modified Release, FIH Formulations
and Peptides
Aruna Railkar, Senior Drug Development Consultant

2. Presentation overview
• Industry challenge
• Quotient Sciences and Translational Pharmaceutics
• Integrated development strategies for:
• Poorly soluble drugs
• Modified release product development
• FIH Formulation development and progression to patient supplies
• Peptide development programs
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3. 3
Increasing development costs & complexity

4. • Half life
• Variability
• Dose Proportionality
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Understanding challenges and the target
product profile
Time (Hours)
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Time (Hours)
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Blood
Level
of
Drug
Time (Hours)
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Time (Hours)
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Blood
Level
of
Drug
Dose
Area
under
the
curve
Time (Hours)
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Time (Hours)
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Blood
Level
of
Drug
Time (Hours)
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Time (Hours)
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Blood
Level
of
Drug
Half life Variability Proportionality

5. Traditional industry silos
5

6. Our difference
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7. Our locations
Delivering bespoke programs
to address molecule need
and customer preference
~1300
employees integrated
across two continents
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8. How we work with our customers
Integrated Programs
Turnkey solutions for shortening development times
Tailored services
Individual services to meet customer needs
Candidate Development
Selecting the right molecules for development
Early Development
Accelerating molecules through to proof-of-concept
Late Development
Accelerating products through to commercial manufacture
Formulation
Development
Clinical Trial
Manufacturing
Clinical
Pharmacology
Commercial
Manufacturing
Bioanalysis Data
Sciences
Drug
Development
Consulting
Drug
Substance
8

9. Traditional industry silos
9
Integration through Translational Pharmaceutics
Accelerating drug development
Timeline acceleration of >12 months
Significant reduction in R&D spend
Better decision making
Greater likelihood of success
Simplified supply chain
Unique platform developed in 2008
Used by global pharma and biotech
>400 drug programs completed
Formulation
Development
Late stage /
Commercial
Manufacturing
Drug
Substance
Clinical Trial
Manufacturing
Clinical
Pharmacology
Data
Sciences
Bioanalysis
Rapid
‘Make-Test’
Cycles
1-3 weeks
Reference : DiMasi, J.A., Wilkinson, M. Ther Innov Regul Sci 54, 1453–1460 (2020).
https://doi.org/10.1007/s43441-020-00172-w

10. • Drug product manufacturing integrated with clinical testing
• Simple or complex drug products manufactured in real-time during the
clinical study
• Reduces the “white space” in development
• Managed by highly skilled cross-functional project manager
• Product made in real-time minimises stability data requirements
to enter clinical studies
• Allows reduced batch sizes and reduced API consumption
• Enables rapid ‘make-test’ cycles
• Arising human data used to inform the composition of the next
formulation to be manufactured and dosed
• Reduced probability that a drug will fail in later stage clinical testing due
to sub-optimal formulation performance
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Translational Pharmaceutics
How is it different?
Clinical dosing
Real time
adaptive
manufacture
Typical batch size 250-350 units
Stability ≥7days
Regulatory application
Laboratory
development

11. Translational Pharmaceutics experience
56%
19%
11%
8%
3%
3%
44% Solubility
34% Modified release
8% Non-oral
7% Route switch
3% Taste optimization
4% General product development
Applications Modified release
56% Matrix
19% Coating
11% GR
8% Multiparticulate
3% Lipid matrix
3% Mini-tablet
44%
34%
8%
7%
3% 2%
1%
1%
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12. 12
Solubility enhancement
Processing technologies for poorly soluble compounds
Solubility-enhanced dosage forms
• Amorphous dispersions (SDD, HME)
• Lipidic vehicles
• Particle size reduction
• Complexation
• Spray Drying
• Fluid-Bed Processing
• Roller Compaction
• Hot Melt Extrusion
• Particle Size Reduction
Broad range of technologies and formulation approaches
to address complex solubility challenges

13. 13
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Solubility enhancement- DCS IIb molecule
Post FiH with lipid formulations
Case Study
• Objective: overcome oral PK exposure challenges
associated with the IR tablet
• Non-linear PK, high variability fasted (CV ~60%)
• Positive food effect (AUC, variability)
Background
• Lipid formulation development at Quotient
• Solid dosage form to overcome food effect
• Exposure fasted to match IR in fed state
• 5 period crossover study, n=13 subjects
Project Scope
• SMEDDS formulation successfully identified
• Program duration was a ~ 4 months
Outcome

14. 14
Enhancing drug solubility before Phase II
Case Study
• BCS class II molecule in Phase I
• Poor oral bioavailability & large food effect
• Quotient designed the formulation strategy
Background
• Three formulation technologies developed
• Micronized blend in capsule
• Self-emulsifying lipid-based capsule
• Spray-dried dispersion (SDD) tablet
• Sequential clinical study in 16 healthy volunteers
Results
• Human data selected the simpler & cheaper micronized formulation
• Program delivered data to support future product development
• Timeline from formulation start to clinical PK data was 6 months
Outcome

15. Modified release development
• Modified-release (MR) dosage forms offer drug release characteristics of time course
and/or location that is not accomplished using conventional, immediate release (IR)
formulations
• Different formulation strategies can be used alone (or in combination) to achieve
different release profiles
• Controlled (constant rate)
• Repeat action
• Delayed
• Sustained
• Extended
• Targeted
• Pulsatile (time intervals)
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16. • What does the MR product need to achieve?
• Once a day dosing
• Reduced Cmax
• Reduced Cmax/Cmin ratio
• Match a Ctrough or AUC target for the IR
• Achieve bioequivalence to the IR formulation
• Is targeted delivery required, systemic versus local?
• Which MR technology will achieve the TPP
• Properties of the drug
• How will physiology impact the MR development?
• Where does absorption occur?
• Is there an absorption window?
• Which in vitro/preclinical methods will predict to man?
MR Considerations
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17. • Design spaces can be applied to further enhance
flexibility
• Provides freedom to optimise quantitative
composition of a drug product
• CMC batch data generated from corner points
bracket the entire design space
• No regulatory amendments or notifications
needed
• Drug product manufactured in real-time during
the clinical study
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Design space in formulation optimization

18. Achieving the TPP for MR
• Numerous technologies are available to modify drug release, the difficulty is
identifying the right composition to hit a target in humans
• Design space approach allows within-trial flexibility to adjust the formulation based on
emerging PK (and safety) data
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19. Matrix and minitablet MR formulations
Case study
Background
• Matrix minitab and monolithic tablet formulations evaluated
• 3 Part clinical study, Part A and B investigated target release rates (10 to 24 hour) for the
matrix minitabs (in capsule) and Part C investigated the matrix monolithic tablet
Program design
• GSK2982772 is being developed for the treatment of inflammatory diseases
• IR formulation dosed BID due to a short T1/2 of 2-3 h, requiring MR formulation for QD dosing
• Increase patient compliance and therapeutic outcomes
• Target PK of lower Cmax, similar Ctrough to 60 mg BID dose
Formulation
design space
Drug dose
Drug
release
• Matrix minitabs (80 % release at 12 h) provided a QD profile (delayed Tmax, reduced Cmax
and higher C24 values) when dosed in the fasted state
• Matrix minitab capsule dosed with a high fat meal had an increase in Cmax and AUC and an exposure
profile not suitable for QD dosing
• Matrix monolithic tablet dosed with a standard meal or 1 hour before a meal (high fat or
standard) resulted in an exposure profile suitable for QD dosing
Outcomes
Source: Tompson et al., Pharm Res, 2021 (38:1235-1245)
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Peptide development capabilities
• Expertise
• Oral, parenteral, inhaled, nasal, topical, rectal & vaginal delivery
• GI targeting
• Pre-formulation through proof-of-concept support
• Pre-formulation screening of different technologies
• Formulation strategies to improve oral bioavailability of peptides
• Preclinical and clinical formulation development
• Formulation optimization based on clinical response
• Analytical and bioanalytical assay development and validation across GLP and
GCP domains
• Clinical studies to assist in formulation selection & optimization
• First-in-human studies – including fasted / fed state, timing of food
• Relative bioavailability studies to optimize formulations
• Studies to evaluate change in routes of delivery & Drug-drug interaction (DDI)
studies
• Bioanalytical assay development includes plasma compatibility studies & labware
adsorption studies

21. • Animal models can be poorly predictive
• Variable response in different species
• Formulation ranking
• Absorption enhancers as a drug delivery strategy:
• Absorption and PK can be variable
• Mechanism of action and performance can be API specific
• Volume of fluid on administration has a significant impact on absorption
• Significant food effects observed
• Numerous DDI studies demonstrated requirement for API and absorption enhancer to be co-located for effective
delivery
• API properties:
• Long circulating API reduces steady state variability
• Stability to peptidases and different pH
• Interaction with absorption enhancer
• Target site of absorption may vary depending on delivery system and API used
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Key learnings from clinical experiences

22. 22
FIH assessment of an oral peptide
Case study
• Sponsor advancing oral peptide into Phase I
• Functional excipient was required to achieve target exposure in
animal models
Background
• Multi-part FIH study designed to include optimization of oral exposure
through adjustment of critical formulation parameters.
• Quotient transferred a 3rd party technology for real-time manufacture
of drug product
• IV solution developed and manufactured for absolute bioavailability
assessment
Project Scope
• Study met the goals for SAD and MAD dosing
• Defined the relationship between functional excipient and oral
exposure of the peptide
Outcome
Real-time
manufacturing
Single ascending dose with
formulation adjustments
Absolute bioavailability
Multiple ascending dose

23. 23
Investigating oral peptide delivery using gamma scintigraphy
Case study
• Novo Nordisk advancing oral peptide development (semaglutide w/SNAC)
• Understand tablet disintegration in vivo and correlate with PK
Background & objectives
• Oral tablets labeled with 111Indium
• Water labelled with 99mTc (to outline the stomach)
• 2-way randomized cross-over in 24 healthy volunteers
• Anatomical location of the tablet at the time of erosion & GI transit assessed
by gamma scintigraphy
Project Scope
• Tablet containing oral peptide erodes in the stomach irrespective of water volume
• Lower fluid volume (50 mL vs 240 mL) resulted in reduced rate of tablet erosion,
slower gastric emptying and 70% higher AUC (0-24 hrs) and Cmax levels
• Dosing in fed state further reduces exposure (limited exposure observed in 44%
of subjects, no exposure observed in 56% of subjects)
• Clinically relevant exposure requires administration in the fasted state
Outcomes
1. Baekdal et al, Clinical Pharmacology in Drug Development (2021), 00(0) 1-10

24. 24
Formulation selection and patient supply
Case Study
• Oncology molecule entering FIH study
• Poor solubility requiring assessment of multiple
formulations to ensure exposure in patient trials
Background
• Three formulations developed for evaluation with FIH:
Powder blend, Lipid suspension, Spray dried dispersion
• Flexible product strength enabled to minimize pill burden
• Target inhibition confirmed in healthy volunteers
• Drug product validated for patient trials
Integrated Program
• Drug product suitable for patient supply identified, no
need to transfer product manufacture to CDMO
• Seamless initiation of patient product supply in 12 months
Outcome
In vitro data generation
and PBPK modelling
Formulation development
Global supply to patients
Single Ascending Dose
Healthy Volunteers

25. • Pharma industry is constrained by legacy, silo based, structure
• An integrated service provider can cut through that structure across a
range of drug development capabilities
• Integration of early development can shorten timelines to POC by >12
months
• Identifying the right formulation approach for the drug
• Fit-for-purpose formulations reduce the time in getting into the clinic
• Formulation flexibility in FIH studies drives seamless transition to Phase II drug product
• Supply chains are simplified providing project management efficiencies
• If time can be saved, then R&D spend can be reduced significantly
• Demonstrable savings in direct costs and reduction in development time costs
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Summary

26. quotientsciences.com
Thank You!
Aruna Railkar
Senior Drug Development Consultant
Aruna.railkar@quotientsciences.com