CU Chemie Uetikon GmbH

Transcription

1 CU Chemie Uetikon GmbH Challenges in API manufacturing UETIKN Dr. Hendrik Baumann, Commercial Director

2 First of all... UETIKN... CNGRATULATINS to the 5th anniversary of Rapid Pharma Development and best wishes for the future from the whole team of CU Chemie Uetikon GmbH 2

3 ur areas of activity UETIKN Custom Synthesis - for all clinical phases of pharmaceutical development - from development through production to registration API's with (proprietary) Drug Master Files (DMF) or Certificate of Suitability (CEP) in Full compliance with international quality standards like cgmp, IS 9001:2000 Special Intermediates of high purity and High Performance Chemicals for the Electronic Industry, Cosmetics or Nuttrition 3

4 About us: CU Chemie Uetikon GmbH UETIKN Lahr o CU Chemie Uetikon GmbH - a German CM with long presence and excellent reputation in the market o Located in Lahr, southwest Germany, directly linked to the major hubs of the Pharmaceutical and Chemical Industries o Easy access by train, car and through major airports like Frankfurt, Paris, Basel or Zurich o Aquisition of 90% of CU Chemie Uetikon GmbH by Barclays Private Equity (since 2012 Equistone Switzerland). Management holds 10% of the company shares o Successful inspection by CFEPRIS (Mexico) o Most recent successful FDA inspection o Successful re-certification according to IS 9001:2008 o Purchase of additional land reserves (about 2,500 m 2 ) o Extension of the GMP kilo-lab with a Cryoreactor o Completion and operational start of two additional production trains in the MPA P3 plant, one equipped with a cryogenic reactor (-90 C). o GMP-inspection by German authorities and GMP certification o Start operation of a state-of-the-art GMP production plant (MPA P3) with initially 2 production trains o Erection and start operation of the GMP kilo-lab and upgrading of further laboratory infrastructure in Lahr o Initial operation of a thermal waste gas treatment plant o Acquisition First certification of the business according activities to IS by 9001 CPH-Group o First successful FDA inspection o Start of chemical operation by the predecessor of Uetikon in Lahr 4

5 Key Financials UETIKN o Key figures 2011: 108 employees and a capacity of 91,5 m 3 reactor volume o Turnover 2011: 32,3 MEUR o Project success rate: o > 200 inquiries ("Paperevaluation") o 175 registered projects with sample o 31 projects in pilot production and/or commercialisation o Turnover with new projects in 2011 >10% 5

6 Business Model: Custom Synthesis UETIKN The API manufacturing is a highly regulated business Key for success is the smart combination of modern technologies with efficiant processes development and implementation. Worldmarket Pharma: utsourcing Pharma: Chem. API/Adv.Intermediates: 790 Mrd.$*) 168 Mrd.$**) 12 Mrd.$**) 55% of the current APIs or key intermediates are outsourced to CM's *) **) IMS Health 2008 *) Frost&Sullivan 6

7 Business Model: Custom Synthesis UETIKN "This is a business model where you are guaranteed to lose your entire orderbook of business every 8 years. "Speed, Endurance und Experience" are key for success and excellent customer relationship the basis for a sustainable business. Number of competitors worldwide >1000; nobody has more than 3% of market share. The successful players are small-midsized companies (SME's) or departments of big companies (BASF-rgamol for example) 7

8 verview: API supply chain UETIKN GMP mg - g 1-20 kg kg > 500 kg Discovery Preclinical Clinical Launch Di IND* NDA** CMC for clinical trials CMC for Launch *) Investigational New Drug Application **) New Drug Application 8

9 Process Development: TCQ triangle UETIKN Time Medchem Supply Early Phase or Clinical Phase Supply API supply Cost Quality Launch and Late Phase Supply 9

10 Challenge 1: Reduction of complexity UETIKN Heat reactants, cool down and filter off the crystalls Reaction in DMF Quench into Water Filter and Dry Reaction in THF Add Heptane and Crystallize Filter and Dry How to get there? Suspend in EtAc Filter Crystalline API yield 83-87% Start at the end of the process Crystallize from THF/Heptane Filter and Dry Crystalline API yield 70-75% Lit.: rg Proc Res & Dev 2001,

11 Challenge 2: Plant utilisation UETIKN Multipurpose plants are more expensive than dedicated plants. As more dedicated products are available, as lower the CG are. For an SME it is important to have a "base load" of repeating products to cover costs and to guarantee an average utilisation of >50%. "Ideal" plant size for CM's is between m 3 of capacity with vessels of max. 6m 3. There must be a mix of new projects (small volume, small batch size), with established projects (medium volume, max. batchsize) and proprietary products (medium-high volume, ideal batchsize). 11

12 Challenge 2: Plant utilisation UETIKN Firma Sales Mitarbeiter Kesselvol. Umsatz pro MA Umsatz pro m 3 (Mill. EUR) (m 3 ) (TEUR) (TEUR) Cerbios CU Chemie Uetikon GmbH Helsinn (Biasca, CS only) Rohner Chem Siegfried Bachem/Sochinaz Valsynthese (SSE Group) Dottikon Exklusive* The most of the successful CM's have an average turnover per employee of >250 TEUR/MA and an average turnover of >300 TEUR/m 3 per reactor volume. Backward integration (to Asia) and foreward integration (to FDF) are strategic questions for future success of CM's. 12

13 Challenge 3: "simple" Hydrogenation UETIKN Target: Reduction of the Carbonylgroup without reduction of the aromatic system. R H 2 R R R R R Result of the development: R R More or less no literature available, if available "exotic" conditions like loop reactor, FeCoCr-catalysts etc. Catalyst producers offering standard portfolio only. R 13

14 Challenge 3: "simple" Hydrogenation UETIKN We have tested more than 50 different catalyst systems. Always reduction of the aromatic systems or no reduction or masses of impurities. Brainstorming results: Back to old school Solution: Reduction in HCl/Fe or Zn yields perfect product and a competitive process. A simple system which is easy applicable in the current production, no additional equipment necessary and product quality is sufficiant. 14

15 Challenge 4: "green" Chemistry UETIKN Due to increasing legislation and environmental protection many of the good old "recipes" are not longer applicable or the limits in the end product are extremely low (LD). Examples: Halogenated solvents, xidation with Chromium or Permanganate, heavy metals as catalysts, alkylation agents etc. 15

16 Challenge 4: "green" Chemistry UETIKN Literature Route #1 J. Med. Chem. 1992, 5, ; W2007/ and W2008/ NaBH 4 MeH yield: 90% Expensive H NaH MeI, DMF yield: 80% p-tsh Acetone H 2 yield: 91% Literature Route #2 Tetrahedron Lett. 1994, 35, ; J. rg. Chem. 1961, 26, H H 2, Rh/Al 2 3 H K 2 Cr 2 7 H 2 S 4 MEHQ - hydroquinone monomethyl ether 16

17 Challenge 4: "green" Chemistry UETIKN 1. Use of a catalytic reduction step 2. Using cheap MEHQ as starting material 3. Use of a mild oxidation reagent, no chromium salt! H H 2, Ni/NiH-cat NaCl TEMP H 0 C, H 2 yield: 95% yield: 60% Bleach and TEMP are versatile green reagents for xidation reactions H N tbu NaCl TEMP MTBE N tbu yield: 87% 17

18 Summary UETIKN Custom Synthesis is and was a challenging business. "Speed, Endurance und Experience" are key for success and excellent customer relationship is the basis for a sustainable business. Big is not beautiful. The CM market is more or less saturated and the CAGR in Pharma is estimated with 3,6% for That means gaining market share will only be possible by displacement of competitors. Technology is self understanding, customer intimacy is key for survival in that business. 18

19 Summary UETIKN A successful CM is able to deliver all CMC services which are necessary for a successful launch of the API Drug Master File Chemistry Manufacturing Control Knowledge and Experience Don t build a house without an architect 19