Accelerating Drug Development through Automation

Transcription

1 Accelerating Drug Development through Automation Crystallization Workshop Milan, 7 th June 2018 Dr Edwin Aret Principal Scientist Solid State Chemistry

2 Outline Alcami Solid State Chemistry Drug Development Process Form Selection Case Studies 2

3 Welcome to Alcami Alcami is a world-class contract development and manufacturing organization (CDMO) headquartered in Durham, North Carolina. Alcami provides solutions tailored to small and mid-size pharmaceutical and biotechnology companies. With over 1,000 employees operating at seven sites in the United States and Europe, our combined capabilities include: API development and manufacturing Solid state chemistry Formulation development Analytical development and testing services Launched 2016 Clinical and commercial finished dosage form manufacturing (oral solid dose and parenteral) Packaging and stability services Alcami offers an end-to-end outsourcing opportunity that can be integrated for a less fragmented and faster pathway for products through the clinic toward commercialization, as well as individualized development and manufacturing services. 3

4 Facilities Overview 4

5 Our Approach Easy-to-Work-With Single Program Manager Supported by Project Managers, Quality and Operations Single Master Service Agreement Across All Service Offerings Diversity >100 Early Stage Products in Portfolio >50 Late Stage Products in Portfolio >40 Commercial Products in Portfolio Excellence in Stand Alone Program or Integrated End-to-End Offering Industry Leading Full Service CDMO 7 Sites Globally Science & Technology Integrity Trust >$200M Revenue/Annually Proven technical expertise for optimal right first time process Speed through clinic and launch Technical platforms to address unforeseen molecule constraints & minimize clinical delays Service Offering Solutions Through Clinic to Launch Dedicated to Navigating Companies To Success Invest Back Into Sites- >$20M Annually Regulatory and Safety Expertise Industry Leader in Innovation and Regulatory Changes Multi-Facility Offerings for De- Risked Program and Scale Up Support 1000 Employees 5

6 Solid State Chemistry A Center of Excellence for Crystallization and Solid State Chemistry Process Chemistry Crystallization Study isolate and purify stable solids PhysChem Characterization material identification, stability Solubility Determination in production solvents and buffer solutions Salt Selection suitable form selection, improve solubility Polymorph Study find a form for further development, IP screens Analytical Services Process Development range finding DoE, metastable zone width Particle Habit Engineering control of particle size and shape Pre-formulation dissolution rate, excipient compatibility 6

7 Solid State Chemistry Study of the PhysicoChemical and Mechanical Properties Development Strategy Risk Assessment Target Product Profile Development by combination of DoE, PCA and HTS Route Scouting Range Finding Scale-up Optimization 7

8 Design of Experiments (DoE) DoE provides an overview of the interaction of factors, without the need of testing all possible conditions Continuous factors Temperature, concentration, addition rate, stoichiometry Choose any level / range Discrete factors Reagent, catalyst, ligand, solvent Selection constrained by availability / existence 8

9 Principle Component Analysis (PCA) PCA allows conversion of discreet chemicals into continuous variables e.g. solvents: polarity, polarizability, H-bonding PC2 PC1 9

10 Combining DoE and PCA identify factors and set ranges define solvent space select responses select HTS protocol choose design model data validate predictions 10

11 Drug Development 11

12 Process Development 2 ml 50ml 450 L 1 L 12

13 Process Development MedChem Route Scouting Process -Process R&D -Analytical R&D -Solid State R&D Demo Batch GMP Scale Up Analytical Val. QC/QA Release Typical Deliverables: -Fit Process -Fit Analytical Methods -Target Specs -Material for Analytical Val. Typical Deliverables: -Proof of Concept -Use Test of Raw Mat. -Confirm Specs -Material for Ref. Standard Typical Deliverables: -GMP Batch -Validated Methods -Qualified Reference -Validation Protocols -Validation Reports Typical Deliverables: -CoA -TSE Statement -GMP Compliance -IMPD/IND Support

14 UnchainedLabs Automation dspr (deck Screening Pressure Reactor) Parallel screening 48 * 1 ml Pressure ~5 bar / protected atmosphere Controlled heating / cooling C, stirring e.g. Hydrogenation, cat-screens 14

15 Technobis Crystal 16 Process Chemistry Parallel 16 * 1 ml Stirring, heating-cooling C, turbidity Selection process conditions Metastable zone width Seeding conditions, crystallization behavior 15

16 MSZW data Meta-stable Zone Width: determine the solubility in process solvent(s) at several temperatures. nucleation curve is variable, determined by crystallization conditions Concentration Cooling solubility curve is fixed Temperature

17 Technobis Crystalline Process Chemistry Parallel 8 * 5 ml Stirring, heating-cooling C, turbidity, camera, particle size and shape Selection process conditions Metastable zone width Seeding conditions, crystallization behavior 17

18 Crystalline PSD data Nucleation / crystal growth: 18

19 Crystal Habit Select crystallization conditions to avoid fines, platelets or needles Control for good filtration behavior and consistent dissolution rate Avoid solvent inclusion, amorphous content, agglomerates improved dissolution improved filtration 19

20 Process chemistry Parallel reactor systems 1 Project Database; combined process conditions and (in-situ) analytics MiniTab17 DoE software Optimization, reproducibility, scalability UnchainedLabsScreening Platform Temperature, ph, dosing, seeding Technobis Crystal16 / Crystalline 16 x 2 ml / 8 x 8 ml Database FBRM, turbidity, video, PSD MT-MultiMax/ LabMax 4 x 50 ml / 2 x 250 ml / 1-2 L ELN Filtration rate, drying time 20

21 UnchainedLabs Automation Solid Dispenser Dosing solids in well-plates or glass vials 1 mg 1 g 21

22 Parallel Screening Obtain an overview of the crystallization behavior Produce one suitable form for the stage of development Find and characterize as many forms as time/costs allows Compare critical properties like solubility, stability, bioavailability Heating cooling Stirring / slurry Hot-filtration Anti-solvent addition LC dilution Crystallization 22

23 Protocol Form Selection 23

24 High-Throughput Analytics Analytics: Solids / solution prepared on deck Avoid manual repetitive handling Software integrated Use equipment measurement software Data stored in one project folder (u)hplc XRPD + imaging 24

25 Bruker D8 Discover High-Resolution High-Throughput XRPD four 96 well-plates auto-sampler xyz-screening stage specially designed optics images before and after crystallization plate = XRPD sample holder raw data analysis by Polysnap and TOPAS reduce 2 FTE weeks into 1 day 25

26 Form Selection High-throughput crystallization platform (400 exp./day) Project Database; library, dosing, experimental conditions and analytics UnchainedLabsProtégé Solid Dispense System Bruker D8 Discover HR-HTS XRPD UnchainedLabsCM2 Crystallization Platform Database HPLC / UPLC Technobis Crystal16 / Crystalline FT-IR, DSC, TGA, Microscopy Report / raw data 26

27 Case Studies 27

28 Suzuki cross coupling C-C bond formation Palladium catalyzed cross coupling reaction OR R 1 X + R R 2 B 1 R 2 + RO B OR [Pd] OR OR Organic halide Organo boron 28

29 Suzuki cross coupling # Type A Base Dipea K 2 CO 3 CsCO 3 Et 3 N Dipea K 2 CO 3 CsCO 3 Et 3 N Solvent MeOH MeOH MeOH MeOH DMSO DMSO DMSO DMSO B Base Dipea K 2 CO 3 CsCO 3 Et3N Dipea K 2 CO 3 CsCO 3 Et 3 N Solvent MeOH MeOH MeOH MeOH DMSO DMSO DMSO DMSO C Base Dipea K 2 CO 3 CsCO 3 Et3N Dipea K 2 CO 3 CsCO 3 Et 3 N Solvent MeOH MeOH MeOH MeOH DMSO DMSO DMSO DMSO D Base Dipea K 2 CO 3 CsCO 3 Et3N Dipea K 2 CO 3 CsCO 3 Et 3 N Solvent MeOH MeOH MeOH MeOH DMSO DMSO DMSO DMSO E Base Dipea K 2 CO 3 CsCO 3 Et3N Dipea K 2 CO 3 CsCO 3 Et 3 N Solvent MeOH MeOH MeOH MeOH DMSO DMSO DMSO DMSO F Base Dipea K 2 CO 3 CsCO 3 Et3N Dipea K 2 CO 3 CsCO 3 Et 3 N Solvent MeOH MeOH MeOH MeOH DMSO DMSO DMSO DMSO Variables: solvent (4), base (4), temperature (2), time (2) Responses: conversion, reproducibility 29

30 Suzuki cross coupling Conversion[%] / σ σ DMSO σ IPA σ Ethanol σ Methanol DMSO IPA Ethanol Methanol 65 C 16 hours 90 C 65 C 24 hours 90 C Methanol, inorganic base, 90 C, 24h -> best reaction condition for scaling up 30

31 MSZW data ACN is used as process solvent, poor nucleation control Other solvent? Anti-solvent? 31

32 MSZW data Other solvents: not soluble or solvates Anti-solvent: oiling out Seeding? Cooling Crystallization Seeding Crystalline: Compound oils out, solidifies and clusters of needles grow from it. Seeding gives block-shaped crystals.

33 Filtration issues Material showed filtration issues Isolated using DMSO or DMSO/water Small particles; fines < 20µm Recrystallization experiments new polymorph Isolated using DMSO/methanol, good filtration Advantages new form Improved filtration Thermodynamically more stable Less hygroscopic 33

34 Filtration issues Reaction mixture DMSO Reaction mixture DMSO/MeOH (1/1) 34

35 Case Study - solvent Solubility determination for recrystallization Solvent PCA Solubility (mg/ml) USP classification 2-ethyl-1-butanol < 0.1 Practically insoluble 2-butanol Very slightly soluble Methanol Slightly soluble Water < 0.1 Practically insoluble Dimethylsulfoxide Slightly soluble ethyl salicylate < 0.1 Practically insoluble ethyl acetate Very slightly soluble n-heptane < 0.1 Practically insoluble Anisole Very slightly soluble Cyclohexane < 0.1 Practically insoluble Polarisability (PC1) Polarity (PC2)

36 Case Study - solvent Solubility determination for recrystallization Preferably no high boiling solvents High yield, high purity Polymorph Form A Solvent PCA XRPD Methanol Form A Ethanol Form A 2-Propanol Form A 2-Butanol Form A Ethyl acetate Form A + add. peak Ethyl formate Form A + add. peak Tetrahydrofuran Form A Acetone Form B Formic acid No solids Acetic acid No solids PC PC2 Acid Alcohol Alkylamide Amide Aromatic Aryl Halide CHC Ester HC Ketone Nitrile Nitro Sulfoxide Water -6 36

37 Case Study - solvent Solubility determination for recrystallization 10 solvents provide the overview of the whole solvent space Selection of suitable / alternative process solvents based on PCA Expected solubility behavior based on PCA confirmed No guarantee on polymorphic form Form selection screening still required 37

38 Summary Drug development is troubleshooting and risk management. Streamline the R&D, integrate process development, analytics and solid state chemistry to shorten timelines and strengthen the added value. Have the data accessible and searchable for the project team, not only a report with the conclusions. Use of automation leads to smart experiments for the overview to select optimal conditions. Screen more different factors, not just do more experiments. 38

39 Thank you! Stay connected at alcaminow.com