mAbs: Functional Improvements at SPC Shelf Life Limits

Monoclonal antibody (mAb) therapeutics are one of the fastest growing sectors in the pharmaceutical industry and have already established themselves as frontline therapies in oncology.

These drugs are often assigned short shelf lives once prepared for administration, typically 24 to 48 hours.

However, SPCs for some of these drugs recommended they be used immediately following preparation.

Transcript

1. Dr Andrew G Watts Associate Professor of Medicinal Chemistry Department of Pharmacy and Pharmacology University of Bath October 2014
2. 2 Monoclonal Antibodies Functional Improvements at SPC Shelf Life Limits
3. Introduction 3 Monoclonal antibody (mAb) therapeutics are one of the fastest growing sectors in the pharmaceutical industry and have already established themselves as frontline therapies in oncology. These drugs are often assigned short shelf lives once prepared for administration, typically 24 to 48 hours. However, SPC’s for some of these drugs recommend they be used immediately following preparation.
4. Aim 4 To evaluate the physical, chemical and functional stability of several mAb therapeutics used in oncology. - Pertuzumab - Rituximab - Trastuzumab - (Infliximab) Compare the (quality) characteristics of these drugs immediately after preparation with those at the limit of their SPC assigned shelf life.
5. Methods 5 Physical/Chemical/Functional analysis of each antibody was performed using: • visual inspection • SDS-page • pH • SE-HPLC, • circular dichroism (VT-CD) • dynamic light scattering (DLS) • LC-MS • Flowcam imaging (particle counting) • Functional activity (tailored assay) Each antibody was evaluated immediately following preparation as well as at its SPC designated shelf life.
6. Results - Pertuzumab 6 Sub-visible particles Functional activity
7. Methods 7 ‘Flowcam’ imaging (sub-visible particle counting) micro-air bubble silicone oil aggregated protein Quantification and characterisation of sub-visible particles Flow rate: 0.15 ml/min, efficiency: 30.2%, cell: FC100 100 µm x 2000 µm
8. Methods 8 Functional activity – Cell based assay 7.7 Biological activity Assessment of biological properties constitutes an essential step in establishing understanding of the stability profile under specific conditions. The technique should be relevant to the specific biological activity that enables the product to achieve its defined biological effect.
9. Results - Rituximab 9 Sub-visible particles Functional activity
10. Results - Trastuzumab 10 Sub-visible particles Functional activity
11. Results - Infliximab 11 Sub-visible particles Functional activity
12. Degradation Pathways 12
13. Dilution Process 13 Dilution Preparation (reconstitution and dilution): - Rapid change in the chemical micro-environment of the drug - Dilution of A results in a dynamic mixture of B, C, D, E and F.
14. Summary 14 - Multiple stability studies on numerous monoclonal antibodies have been performed. - Higher levels of sub-visible particles and lower levels of functional activity are observed immediately following preparation, as compared to the product at the end of SPC assigned shelf-life. - Dilution of the drug into its ready-to-use form dramatically changes the micro-environment around the API. - Physical changes that occur are dynamic and will reach an equilibrium over time. This has been observed to result in lower particle numbers and improved functional activity.
15. Research team Dr Richard Parry • Principal Scientist • Functional Activity Terry Chapman Dr Monika Ali Khan Physical Stab Dr Andy Watts • Scientific Lead • Chemical Stability Maria Connolly • Programme Lead • Usability
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