Practical Considerations in Developing High Concentration Antibody Formulations

Transcription

1 Practical Considerations in Developing High Concentration Antibody Formulations Qingyan Hu Formulation Development Group Regeneron Pharmaceuticals DDF Summit, Aug 2017

2 Outline High concentration antibody formulation challenges Case Studies High concentration formulation storage stability challenge Selection of manufacturing process for high viscosity product DoE-based model for understanding formulation viscosity space Summary

3 Protein concentrations in FDA-approved antibody drug products There is a general trend toward increasing protein concentration in commercial formulations Increasing number of high concentration drugs (> 100 mg/ml) Source data was transcribed from approved drug labels, and analyzed by Regeneron formulation scientists.

4 Why high concentration formulations? - Reduce drug substance volume for processing and storage - Reduce delivery volume - Enable high dose subcutaneous (SC) delivery - Potential for device delivery and self-administration - Switch from commercialized IV product to SC product - Increase dose to improve efficacy

5 General properties of high concentration formulations Contains high concentration of solubilized antibody Reversible aggregation - dissociate upon dilution Irreversible aggregation Solubility limit, precipitation Antibody buffering effect Increased interaction between the molecules Potentially colored solution High viscosity Large viscosity variation over antibody concentration variation Temperature dependence of viscosity Shear thinning or shear thickening Monomer + Monomer Dimer

6 Challenges with high concentration formulations Stability challenges Increased aggregation at high antibody concentration Precipitation Analytical challenges Analysis at high antibody concentration avoiding dilution Manufacturing challenges (Drug substance and Drug product) ph and buffer concentration shift due to Gibbs-Donnan and excluded volume effect Filtration/pumping/filling issues due to increased viscosity Drug product (DP) and administration challenges Syringeability, injectability Device (such as auto injector) performance vs formulation variation and storage Clinical blinding the appearance difference with placebo

7 Terms used in this presentation Purified mab UF/DF, buffer Final Concentrated Pool (FCP) Buffer/Excipient Drug Substance (DS) Buffer/Excipient Surfactant Drug Product (DP) Fill Formulated Drug Substance (FDS)

8 Case Study 1 Formulated Drug Substance (FDS) Storage Stability Challenge mab1 DP in vials Two formulations 50 mg/ml for IV 175 mg/ml for SC Stability challenge for high concentration (175 mg/ml) formulation Frozen storage stability for formulated drug substance (FDS, bulk)

9 mab1 DP formulation, 50 mg/ml and 175 mg/ml at 5 ºC mab1 DP formulated with 3% stabilizer A Identical excipient compositions 50 mg/ml and 175 mg/ml DP are both stable for at least 18 months (< 1.0% HMW increase) at 5ºC

10 mab1 FDS formulation, 50 mg/ml and 175 mg/ml; frozen storage 50 mg/ml FDS frozen storage 175 mg/ml FDS frozen storage mab1 formulations with 3% stabilizer A Significant increase in %HMW of 175mg/mL formulation at frozen storage at - 20ºC and - 30ºC, compared to frozen storage of 50 mg/ml formulation. 175 mg/ml FDS should be stored at -80ºC if this formulation progresses to clinic. Same formulation except protein concentration difference Lower stabilizer/protein ratio in the high concentration mab1 formulation

11 Effect of stabilizer types and stabilizer/antibody ratios on 175 mg/ml FDS frozen storage stability 175 mg/ml FDS 175 mg/ml FDS 2% Stabilizer B 175 mg/ml FDS 2% Stabilizer B 3% stabilizer A (previous slide), and 2% stabilizer B could not provide sufficient stabilization to high concentration mab1 at -30ºC or -20ºC Increasing stabilizer/mab1 ratio improves high concentration formulation frozen storage stability

12 Learnings from the high concentration formulation frozen stability challenge High protein concentration formulations can face frozen storage stability challenges if the formulation is optimized at a lower protein concentration, or optimized based on 5 ⁰C or accelerated stability Stabilizers developed and optimized for high concentration DP formulation (2-8 ºC storage) may not provide sufficient stabilization for frozen storage of FDS at the preferred storage condition Stability data generated at intermediate concentrations (<100 mg/ml) may not be successfully extrapolated to high concentrations under frozen storage conditions For high concentration formulations, increasing the stabilizer amount could minimize the stability risk during FDS frozen storage

13 Case Study 2 Manufacturing Challenge for a High Concentration Formulation mab2 late stage formulation 150 mg/ml for SC injection Using phase 1 formulation with 150 mg/ml mab2, viscosity > 40 cp (20 ºC) With viscosity reducer and formulation optimization, 150 mg/ml DP viscosity ~ cp Developing a feasible manufacturing process

14 Typical DP Manufacturing Scheme Purified mab UF/DF, buffer Final Concentrated Pool (FCP) Buffer/Excipient Drug Substance (DS) Buffer/Excipient Surfactant Drug Product (DP) Fill Formulated Drug Substance (FDS)

15 Challenges for high viscosity mab2 when using typical manufacturing scheme Purified mab UF/DF, buffer Final Concentrated Pool (FCP) Buffer/Excipient Drug Substance (DS) Buffer/Excipient Surfactant Drug Product (DP) Fill Formulated Drug Substance (FDS) High viscosity FCP, difficult to process Due to Gibbs-Donnan effect : i. Buffer accumulated in FCP; ii. Not able to reach 10 mm set target buffer concentration; iii. Large ph shift onnan_effect#/media/file:gibbs-donnan-en.svg

16 Manufacturing scheme for mab2 Purified mab UF/DF, buffer/ viscosity reducer Final Concentrated Pool (FCP) Buffer/Excipient Drug Substance (DS) Viscosity reducer also acts as a charge balance agent Able to reach 10 mm set target buffer concentration Minimal ph shift Drug Product (DP) Manageable viscosity for FCP processing; able to achieve high FCP concentration Development work required for concentration control of the viscosity reducer in FCP Fill Formulated Drug Substance (FDS)

17 Effect of viscosity reducer on UF/DF process UF/DF buffer Final Concentrated Pool ph [Buffer] (mm) Viscosity Reducer (mm) ph (ΔpH) [Buffer] (mm) [Protein] (mg/ml) Viscosity Reducer (mm) (+ 0.7) (+ 1.0) (+ 0.1)

18 Learnings from the high concentration formulation UF/DF Gibbs-Donnan effects is much more pronounced in high concentration formulations during UF/DF. Viscosity reducer can be added during the UF/DF process for high concentration formulations, not only to reduce the viscosity, but also to minimize buffer concentration and ph shift.

19 Case Study 3 Understanding Drug Product Viscosity Space for Device Development mab3 High concentration DP (150 mg/ml) Formulation for a DP with prefilled syringe and auto-injector Target viscosity 10 cp (at 20⁰C) Maximum viscosity < 15 cp (at 20 ⁰C) DoE study to characterize viscosity in the formulation design space Generate a model for formulation design space Optimize formulation to meet the viscosity development target Excipient concentration control to ensure DP viscosity within target

20 DoE study to understand formulation viscosity - Study design Factors included in DoE study design ph Protein concentration Excipient concentrations Storage time Temperature Response Viscosity Stability (HMW, Charge variants) Osmolality

21 Empirical fitting indicates mab3 concentration, temperature and excipient 2 concentration are the major factors impacting the viscosity Viscosity Experimental Formulation viscosity vs. excipient concentration, mab3 concentrations, ph, temperature and time Intercept mab Conc Temp Excipient 2 ΔpH Excipient 2*ΔpH Excipient 2*mAb conc Time (40C) Excipient 1 Excipient 1*Excipient 2 ΔpH*ΔpH

22 Viscosity Formulation viscosity model has been constructed [11.60, 12.09] Excipient 1 Excipient 2 mab3 conc Time (40ºC) ΔpH Temperature

23 Formulation robustness: Simulation indicates that variation in excipient concentrations have minimum impact on the selected formulation Excipient 1 Excipient 2 [mab3] ph With wide variability, ±20% for excipient 1, ± 10% excipient 2, ± 10% for mab3 concentration, ±0.3 ph unit under normal distribution, simulation indicated that 99.9% product viscosity is between within cp at 20ºC.

24 Learnings from the formulation optimization and viscosity modeling by DoE DoE is a powerful tool to derive the viscosity model within the formulation design space The viscosity model for mab3 high concentration formulation effectively describes the impact of formulation compositions, temperature and storage time on viscosity Formulation robustness (with respect to viscosity) can be assessed in the model. The model is helpful for setting up excipient control limits in high concentration formulations to meet a viscosity target.

25 Summary Three case studies for developing high concentration formulations have been presented, addressing challenges with FDS stability, the manufacturing process, and viscosity. Although the learnings are from specific mabs, they may be generally applicable to high protein concentration formulation development. High concentration formulation can face frozen storage stability challenges if the formulation is optimized at a lower protein concentration, or optimized based on 5 ⁰C or accelerated stability. Changes in manufacturing process may be necessary for high protein concentration formulations due to high viscosity and pronounced Gibbs-Donnan effects (and excluded volume effect). DoE is an effective tool for modeling the high concentration formulation space.

26 Acknowledgements Dingjiang Liu Mohammed Shameem Jonathan Wert Ka Po Chu Qunhui Liu Dan Dix Thomas Daly Regeneron Formulation Development Group

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