In our final webinar of the MDC Connects Series 2021 | A Guide to Complex Medicines. This slide deck takes a closer look at the advantages of good formulation. Claire Patterson, Seda Pharmaceutical Development Services

1. Claire Patterson, Senior Principal Scientist
22 June 2021
Formulating Complex Medicines:
A simple solution?

2. Formulating Complex Medicines
• Few complex medicines are suitable for oral absorption –
they simply wouldn’t survive the conditions in the GI
tract, and biopharmaceutical properties may prevent oral
absorption.
• The majority of complex medicines are parenterals
• Typically IV, IM, SC, or intratumoural
• Formulation can play varying roles in complex medicines
• Vehicle in which the active-conjugate or is
dispersed
or
• Complex carrier system e.g. Liposomal formulation
or polymeric nanoparticles where formulation is
fundamental to delivering the active to the site of
action

3. Solution, or
concentrate for
dilution
Lyophile for
reconstitution
• Vehicles for drug conjugates e.g.
• Products must be sterile, and therefore presented as an unpreserved frozen
solution/concentrate for dilution, or lyophile for reconstitution with a commercially available
(e.g. saline or dextrose) or custom diluent
• Buffer (pH selected for maximal stability (physical and chemical) and tolerability
• Tonicity modifier
• Cryoprotectant
• Solvents/solubilisers
• Stabilisers
Typical Formulation Components (Vehicle)
ADCs Polymer conjugates Dendrimers
Or

4. Drug Product Specification
• In addition to the generic specification clauses required for a
parenteral product, there are further considerations for complex
medicines/nanos
• Develop assays EARLY to characterise these potential critical
attributes of the formulation
• Particle size and distribution
• Aggregation/Structural Conformation including
functionality
• API release (must distinguish free and conjugated drug) –
not trivial and highly dependent on product
characteristics. Methods may include:
• HPLC
• Dialysis
• SEC
• It is not a simple solution!
Test
Description
Identity
Assay
Related substances (degradants)
Particulate matter
Sterility
Uniformity of content
pH
Antimicrobial/Antioxidant preservative content
Osmolarity
Reconstitution time
Example clauses from a generic parenteral
specification (not exhaustive)

5. API release
• Example: a drug-polymer conjugate with a hydrolytically sensitive
linker (also pH sensitive)
• Select a formulation buffer with appropriate pH, ionic strength, and
counterions to maximise stability (chemical and physical)
• API release needs to be considered from manufacture to the point of
administration to the patient
• API release prior to administration can drastically affect safety and
efficacy
Impact of %Released on
Simulated PK profiles
DS
Manufacture
and storage
DP
manufacture
and storage
Reconstitution In-use period Infusion start In vivo
e.g. SITUA method

6. Mathematical modelling in formulation design
• Optimisation of linker design to control
release rate for balance of safety/efficacy
• Close collaboration between CMC/biopharm
and DMPK scientists.
• Methods to quantify total/released, not just in
plasma but in relevant organs e.g. tumour are
crucial to build this understanding.
https://doi.org/10.1038/s42003-020-01631-8

7. Aggregation
• Example: ADC solution
• May undergo irreversible aggregation and
loss of biological activity and increased
immunogenicity
• Formulation should be designed to
minimise aggregation
• pH, additives e.g. arginine
• Important to have methods to detect
aggregation in the formulation e.g. SEC or
functional assays

8. Drug Delivery Systems
• Drug is encapsulated for protection from biological
environment, to cross biological barriers and release API
at the site of action.
• May also include targeting ligands and other surface
functionalisation
• ADME
• For conventional medicines, formulation influences
absorption only
• Absorption, distribution, metabolism and elimination
are all impacted by complex formulations
Liposomes
Inorganic NPs
Micelles Polymeric NPs Lipid NPs Polymersomes

9. Surface
charge
Size
Stealth
layer
Material
properties
Stability
API
release
Potential Critical Quality Attributes of Nanomedicines
Aggregation
Biodistribution
Pharmacokinetics
Recommended reference: A Quality by Design Approach to Developing and Manufacturing
Polymeric Nanoparticle Drug Products | SpringerLink

10. What could possibly go wrong?
• The NCL (Nanotechnology Characterisation Laboratory) published a case
study on impact of batch to batch variability on biodistribution and toxicity
• Two batches of PEGylated gold nanoparticle
• Batch 1 showed unexpected severe inflammatory lung lesions
• Batch 2 only minimal to mild lung inflammation
• Comparable in terms of size (DLS and TEM), surface charge (zeta potential)
• Batch 1 showed higher degree of protein binding by 2D-PAGE, suggesting
dissociation of the PEG with time.
Common Pitfalls in
Nanotechnology: Lessons Learned
from NCI’s Nanotechnology
Characterization Laboratory
(nih.gov)

11. Conclusions
• Can't emphasise enough the importance of
understanding critical material and process
attributes and monitoring/controlling these
throughout development, from a much earlier
stage than for conventional medicines.
• Develop methods to measure
• Particle size and aggregation
• Conformation/Functionality
• API release
• A biscuit dunked too long is no longer a biscuit!

12. Seda Pharmaceutical
Development Services
Block 21, Alderley Park
Alderley Edge Cheshire
SK10 4TG
E: enquiries@sedapds.com
W: www.sedapds.com