Specific Challenges in Large-Scale Manufacturing of Peptide as API s Presentation at TIDES Conference, Las Vegas, April 25 29, 2004

Transcription

1 Specific Challenges in Large-Scale Manufacturing of Peptide as API s Presentation at TIDES Conference, Las Vegas, April 25 29, 2004 Oleg Werbitzky

2 Slide 2 Agenda Market environment Current manufacturing technologies Peptide solid phase manufacturing in Fmoc-strategy Purification and Isolation of peptides Summary

3 Slide 3 Peptides today: status and evolution (I) Still a niche market : less then <1% of the total pharmaceutical market Reasons: Poor physical and chemical stability (enzymatic and chemical degradation) Limited bioavailability (short half-life, unstable through oral delivery) Expensive and difficult to manufacture

4 Slide 4 Peptides today: status and evolution (II) But the current and the predicted growth rates (ca.15%) of the peptide market are higher than the growth rate of the global API market! Drivers: Market General need for additional new API s Technologies Drug discovery technologies Drug delivery technologies Manufacturing technologies: SPPS, recombinant (leading to the availability of large quantities at reduced costs)

5 Slide 5 Peptides today: status and evolution (III) Questions: How does this market and technology driven evolution reflect on the complexity of the target peptides and on the future API demands?

6 Slide 6 Criteria for the complexity/difficulty of a synthetic peptide Criteria Easy Medium Hard Lengt h of peptide < 10 AA AA > 20 AA Degree of modification Unmodified linear peptide C or N- terminal modification Cyclic peptides S-S bridges Modifications on side chains Unnatural amino acids Difficult coupling building blocks Sequence Difficult sequence Potential side-reactions (e.g. isomerisation or re-arrangements, reaction on sidechain functionalities) No risk of sidereactions High risk of side reactions Purity requirement > 90% > 95% > 98% Potential solubility problems High risk of β-sheet formation Stability Stable Limited stability under processing conditions

7 Slide 7 Characterisitics of recently launched peptide API s Product Length Product characteristics Estimated API Demand Bivalirudin 20 Relatively long peptide 1 unnatural amino acid > 100 kg Eptifibatide (Integriline) 7 Peptide amide Cyclic peptide, S-S bridge 2 unnatural building blocks 100 kg Enfuvirtide (T-20) 36 Long peptide, peptide amide N-Terminus modified >500 kg ( > 1 to?) Desirudin 65 Very long peptide (recombinant) Teriparatide 34 Long peptide, (recombinant) Thymosin alpha 1 (Zadaxin) 28 Long peptide, > 100 kg (?) Abarelix 10 6 unnatural amino acids, Peptide amide N-Terminus modified 10 kg Ganarelix 10 5 unnatural amino acids, Peptide amide N-Terminus modified 10 kg

8 Slide 8 Peptides today: status and evolution (IV) Peptides in development: About 200 different drug development programs are currently ongoing. Among them many complex and high volume compounds can be identified. e.g. GLP-1 analogs: about 6 compounds in clinical development (30-44 AA). For several of them a demand at maturity of multi 100 kg is predicted.

9 Slide 9 Peptides today: changing environment Conclusions: Target compounds getting more complex More products with higher demand But also additional new factors: Increasing cost pressure Reduced time to the market expectations To successfully face these upcoming challenges, the industry will have to develop and provide appropriate manufacturing solutions.

10 Slide 10 Agenda Market environment Current manufacturing technologies Peptide solid phase manufacturing in Fmoc-strategy Purification and Isolation of peptides

11 Slide 11 Peptide Manufacturing Technology Stages of development Development Phase Phase Growth Growth Phase Phase Maturity MaturityPhase Decay Phase Extraction Semi Transgenic Methods Solution Phase Solid Phase Recombinant Hybrid Chemistry synthesis (Combination of Chemistry and Fermentation)

12 Slide 12 Criteria for the complexity/difficulty of a synthetic peptide Technology Liquid phase Solid phase and hybridal approach Recombinant and semi-synthesis Process development Long Rapid Very long Cost of goods High High Low Advantages - Similar to standard organic chemistry - Straightforward approach to longer peptides Practically no limitations in scale and amounts - Established technology - Excellent scalability Limitations Very laborious, will remain an expensive technology High material flows at large scale Unnatural sequences potentially problematic

13 Slide 13 Peptides today: changing environment Conclusions: The solution phase synthesis remains an important manufacturing technology for peptides of the classical type (short peptide, low volumes, high price acceptable). For larger amounts of longer peptides the solid phase/hybridal approach is probably the most attractive option. The recombinant synthesis is particularly interesting for very large amounts of long peptides composed of natural amino acids.

14 Slide 14 Agenda Market environment Current manufacturing technologies Peptide solid phase manufacturing in Fmoc-strategy Purification and Isolation of peptides

15 Slide 15 Peptide manufacturing in Fmoc-strategy T-20 changed the world of peptide manufacturing: The suitability of the Fmoc-chemistry and particularly of the hybridal approach for the production of long peptides was demonstrated An industrial process scalable to a multi metric ton scale was successfully developed and introduced A general approach for the analytical characterisation of an API of this origin was established and successfully implemented The project had also a highly positive impact on the raw materials situation for Fmoc synthesis (resin, amino acids) : Better availability Better quality Competitive cost of goods

16 Concepts of of solid phase and hybrid synthesis Slide 16

17 Slide 17 Process development: essential steps Sequence Selection Route selection Process qualification Proof of concept Identification of major issues Primary optimisation of reaction conditions Assessment of impurity profile Further optimisation of reaction parameters (loading, coupling conditions, throughput etc.) Identification of critical parameters Definition of operating ranges

18 Slide 18 Solid phase synthesis: laboratory equipment Large laboratory scale 1 liter vessel, g Resin 8 Well Reaction Block 20 ml Max working volume 1g Resin (0.5 mmol)

19 Slide 19 Process development (I): Proof of concept First Experiment SPPS synthesis XT-001 (20+mer peptide): Purity 61% 19 impurities >0.5%

20 Slide 20 Process development (II): Process Optimisation Second Experiment SPPS synthesis XT-001 (20+mer peptide): Purity 86% 13 impurities >0.25%

21 Slide 21 Industrial Peptide manufacturing 250 l SPPS-Reactor 800 l SPPS-Reactor Solid phase reactor

22 Slide 22 Industrial Manufacturing: Optimised process on 800l scale CX-0031 (10+ mer peptide): Purity 95% 8 impurities >0.1%

23 Slide 23 Industrial Manufacturing: Batch to Batch reproducibility CX-0032 (15+ mer peptide): Purity 97% 4 impurities >0.1%

24 Slide 24 SPPS manufacturing of peptides in Fmoc Conclusions: The manufacturing of peptides on solid phase in Fmoc strategy is an extremely powerful and cost efficient technology, which already has demonstrated its potential for the large scale manufacturing of long and complex peptides. The development of an industrial process using this technology is rapid. The key for success is a profound understanding of the specific chemical problems, this generally requires a significant analytical support.

25 Slide 25 Agenda Market environment Current manufacturing technologies Peptide solid phase manufacturing in Fmoc-strategy Purification and Isolation of peptides Summary

26 Slide 26 The production universe for APIs: Purification Industrial chromatography remains a very significant cost contributor. Purities >98% quite often require two HPLC purification steps. It is definitely worthwhile to invest additional efforts into process development to obtain better qualities of crude material HPLC System

27 Slide 27 Chromatography: Development Screening of separation phases and optimisation of chromatographic conditions can be very efficient using highly automated systems.

28 Industrial Peptide manufacturing: Isolation Slide 28

29 Slide 29 Isolation of peptide API s Lyophilisation Spray Drying Filtration/ Drying Advantages - Very mild method - Continuous process (typically high productivity) -Standard equipment can be used -Easily scalable - Few unit operations -Desalting or solvent exchange may be omitted Limitations -Batch process (typically low productivity) -High investment in specific equipmentt -Potential stability issues -High investment in specific equipment - Potential limitations by solubility properties of the product -Many unit operations -Potential stability issues

30 Slide 30 Comparative study: Lyophilisation vs. Spray Drying XP-003, lyophilised XP-003, spray dried

31 Slide 31 Summary Market analysis indicate that the peptide field is evolving into the direction of more complex compounds and to larger amounts of API. The manufacturing industry is already anticipating this evolution and is putting significant efforts to establish appropriated manufacturing technologies, in terms of modern concepts in process development, analytical support and manufacturing technologies. The future has already began!

32 Slide 32 Acknowledgements LONZA TIDES TEAM: Matthieu Giraud Stéphane Varray Anne-Sophie Droz Daniel Bourgin Dirk Oehlers Jens Donath Volker Niedan Verena Jung Johannes Brass

33 TIDES R&D and Manufacturing at Visp, CH Slide 33