3rd DVFA Life Science Conference 08 June Biosimilars. BIOCEUTICALS Arzneimittel AG. Epoetin zeta A case study
|
|
- Justina Wiggins
- 8 years ago
- Views:
Transcription
1 3rd DVFA Life Science Conference 08 June 2010 Biosimilars BIOCEUTICALS Arzneimittel AG Epoetin zeta A case study Dr. Michael Mack Member of Executive Board BIOCEUTICALS Arzneimittel AG BIOCEUTICALS Arzneimittel AG, 8. Juni
2 General information By making use of this document the reader acknowledges and agrees to the following: We accept no liability arising from the use of this document. BIOCEUTICALS Arzneimittel AG, Bad Vilbel (in the following BIOCEUTICALS ), has made every effort to make sure that this document contains correct and up-to-date information. However, it accepts no responsibility or guarantee whatsoever in respect of topicality, accuracy and completeness of the information and assumes no obligation to update, complete or correct the information contained therein. The anticipated opportunities and risks to BIOCEUTICALS s activities have been described in detail in the Executive Board s management reports in the annual reports. Current possible opportunities and risks are mentioned in the respective interim report. BIOCEUTICALS s performance indicators are party influenced by one-time special effects and/or effects not arising from the operating business. Disclosure of key figures adjusted for these effects (so called pro forma key figures) by BIOCEUTICALS is only to provide a supplement to the recorded IFRS key figures for a transparent comparison to a relevant period from the previous year. All text, pictures, trademarks, and other information contained in this document are subject to the copyright of BIOCEUTICALS or subject to rights acquired from third parties. Trademark protection may apply even for preparations not indicated as trade marks. This document may not be reproduced in whole or in part without the express written consent of BIOCEUTICALS. Any disputes arising out of or in connection with the content of this document, insofar as they are directed against BIOCEUTICALS, shall be subject to German law, without prejudice to mandatory provisions of foreign law. The place of jurisdiction is Frankfurt am Main to the extent legally permissible. BIOCEUTICALS Arzneimittel AG, 8. Juni
3 Forward-looking statements This BIOCEUTICALS Arzneimittel AG presentation (subsequently "BIOCEUTICALS") contains certain statements regarding future events (as understood in the U.S. Private Securities Litigation Reform Act of 1995) that express the beliefs and expectations of management. Such statements are based on current expectations, estimates and forecasts on the part of company management and imply various known and unknown risks and uncertainties, which may result in actual earnings, the financial situation, growth or performance to be materially different from the estimates expressed or implied in the forward-looking statements. Statements with respect to the future are characterized by the use of words such as expect, intend, plan, anticipate, believe, estimate and similar terms. BIOCEUTICALS is of the opinion that the expectations reflected in forward-looking statements are appropriate; however, it cannot guarantee that these expectations will actually materialize. Risk factors include in particular: The influence of regulation of the pharmaceutical industry; the difficulty in making predictions concerning approvals by the regulatory authorities and other supervisory agencies; the regulatory environment and changes in the health-care policy and in the health care system of various countries; acceptance of and demand for new drugs and new therapies; the influence of competitive products and prices; the availability and costs of the active ingredients used in the production of pharmaceutical products; uncertainty concerning market acceptance when innovative products are introduced, presently being sold or under development; the effect of changes in the customer structure; dependence on strategic alliances; exchange rate and interest rate fluctuations, operating results, as well as other factors detailed in the annual reports and in other Company statements. The above mentioned applies also as far as certain statements within this presentation are made in coordination with STADA Arzneimittel AG with respect to product SILAPO. BIOCEUTICALS not assume any obligation to update these forward-looking statements or adapt them to future events and developments. The BIOCEUTICALS Executive Board: Christof Schumann, Dr. Michael Mack BIOCEUTICALS Arzneimittel AG, 8. Juni
4 Epoetin zeta A case study Contents! BIOCEUTICALS Arzneimittel AG a short overview! Introduction to Epoetin zeta! The regulatory environment past the last 10 years! Regulatory strategy! Development of Epoetin zeta! Control of production a key factor for success! Epoetin zeta in the market! Summary BIOCEUTICALS Arzneimittel AG, 8. Juni
5 Epoetin zeta A case study Contents! BIOCEUTICALS Arzneimittel AG a short overview! Introduction to Epoetin zeta! The regulatory environment past the last 10 years! Regulatory strategy! Development of Epoetin zeta! Control of production a key factor for success! Epoetin zeta in the market! Summary BIOCEUTICALS Arzneimittel AG, 8. Juni
6 BIOCEUTICALS Arzneimittel AG Overview: BIOCEUTICALS Arzneimittel AG, 8. Juni
7 STADA s engagement as of December 31, 2009 STADA Arzneimittel AG No of Shares [%] used credit line [Mio EUR] used capital guarantee [Mio EUR] BIOCEUTICALS Arzneimittel AG, 8. Juni
8 License Contracts Epoetin zeta Hospira Inc., USA! European License and Marketing Agreement (EU)! North American Development and License Agreement (US, Canada) Cell pharm, Germany (a STADA subsidiary)! License and Marketing Agreement (Germany semi exclusive) Hemofarm, Serbia! License and Marketing Agreement (Serbia, Macedonia, Bosnia and Herzegovina, Montenegro, Russia) Nobel Ilac, Turkey! License and Marketing Agreement (Turkey) BIOCEUTICALS Arzneimittel AG, 8. Juni
9 Lower Risk Business Model for Biosimilars High NME Market Potential (Value) Low High B G B Commercialization Risk G Low G = Generics B = non-glycosylated Biosimilars B G = glycosylated Biosimilars NME =New Molecular Entity Source: Biologicals International BIOCEUTICALS Arzneimittel AG, 8. Juni
10 BIOCEUTICALS Generation of Expertise Biotechnological Expertise Development, Manufacturing Implementation of (pre) clinical studies Extensive regulatory discussions Highest quality standards Longer development times Higher development costs Expertise in Biotechnology, in combination with the traditional one, had been established internally and externally within the last ~ 8 years Patent Expertise Business Intelligence Project Management Distribution Efficiency Regulatory Expertise (Generics) Traditional expertise, grown historically within the company BIOCEUTICALS Arzneimittel AG, 8. Juni
11 Epoetin zeta A case study Contents! BIOCEUTICALS Arzneimittel AG a short overview! Introduction to Epoetin zeta! The regulatory environment past the last 10 years! Regulatory strategy! Development of Epoetin zeta! Control of production a key factor for success! Epoetin zeta in the market! Summary BIOCEUTICALS Arzneimittel AG, 8. Juni
12 Introduction to Epoetin zeta Epoetin zeta drug substance! is a recombinant human erythropoietin produced in a CHO cell line! is the active substance in the approved products Silapo and Retacrit Epoetin zeta drug product! Silapo/Retacrit have been developed as a biosimilar product referring to epoetin alfa, authorised in the EU, e.g. under the brand names Eprex (Janssen-Cilag Ltd.) and Erypo (Ortho Biotech, a division of Janssen- Cilag GmbH)! It was shown that quality, safety and efficacy of Epo zeta and Eprex /Erypo are comparable! Indications: renal anaemia and chemotherapy-induced anaemia! Brand new: s.c. application for nephrology (April 2010) BIOCEUTICALS Arzneimittel AG, 8. Juni
13 Epoetin zeta A case study Contents! BIOCEUTICALS Arzneimittel AG a short overview! Introduction to Epoetin zeta! The regulatory environment past the last 10 years! Regulatory strategy! Development of Epoetin zeta! Control of production a key factor for success! Epoeti zeta in the market! Summary BIOCEUTICALS Arzneimittel AG, 8. Juni
14 What kind of product do we have? generic biopharmaceutical subsequententry biologic biocomparable product follow-on biological drug biogeneric multi-source biopharmaceutical biosimilar product second-entry biological drug well-established use essential similarity BIOCEUTICALS Arzneimittel AG, 8. Juni
15 INN Epoetin zeta! An INN identifies a pharmaceutical substance or active pharmaceutical ingredient (API) by a unique name that is globally recognized and is public property. A non-proprietary name is also known as a generic name.! For epoetins, the INN is typically connected with a specific producer clone and hence BIOCEUTICALS concluded that the INN of the reference product (Epoetin alfa) cannot be used.! Moreover, a unique INN was further regarded as advantage for marketing activities ( a biosimilar with an own INN as a standalone feature ).! The INN "Epoetin zeta" was assigned by the WHO.! The issue of allocation an INN has to be distinguished from any scientific data obtained (e.g. comparability of the glyco-profile) and hence this topic is not relevant with respect to the biosimilar -pathway at the EMA. BIOCEUTICALS Arzneimittel AG, 8. Juni
16 Regulatory Environment 2000 Project initiation 2001 The concept of comparability is emerged by the Guideline CPMP/BWP/3207/00 ( )! only applicable for established products! introduces the terminology similarity : [ ] there is a need to consider the necessity for conducting comparability studies for situations where [ ] a biotechnology-derived product claimed to be similar to one already authorised 2003 Directive 2003/63/EC ( ) amends Directive 2001/83/EC! Concept of similar biological medicinal products is introduced into EU legislation by revision of the annex:! Annex I, Part II No. 4: Specific marketing authorisation dossiers and requirements similar biological medicinal products! Legal basis not yet clarified 2004 Directive 2004/27/EC ( ) amends Directive 2001/83/EC! Introduction of a legal basis (Art. 10 para. 4) for biosimilars BIOCEUTICALS Arzneimittel AG, 8. Juni
17 Guidelines on biosimilars 2005 The EMEA publishes an overarching guideline on similar biological medicinal products (CHMP/437/ ) 2006 Two guidelines were finalised for biosimilars concerning quality and non-clinical/clinical issues. In addition, product specific guidelines concerning the non-clinical and clinical requirements were published (Erythropoietin (March 2006), GCSF, Insulin, Somatropin)! June 2006: Submission of marketing authorisation application for Epoetin zeta to the EMEA 2009 Guidelines on LMW Heparins and Interferon alpha Concept paper on monocloncal antibodies 2010 Concept Papers on follicle stimulation hormone (FSH) and interferon beta! The EU was the first regulated region in the world having a defined legal framework for the approval of biosimilars BIOCEUTICALS Arzneimittel AG, 8. Juni
18 Epoetin zeta A case study Contents! BIOCEUTICALS Arzneimittel AG a short overview! Introduction to Epoetin zeta! The regulatory environment past the last 10 years! Regulatory strategy! Development of Epoetin zeta! Control of production a key factor for success! Epoetin zeta in the market! Summary BIOCEUTICALS Arzneimittel AG, 8. Juni
19 Regulatory strategy Right from the start of the development of Epoetin zeta, BIOCEUTICALS followed the at that time nascent concept of similarity. In this context, the following aspects are considered to be the key to success from the regulatory perspective:!stada s expertise and leading role in the field of European regulatory affairs activities for generic medicines!a close collaboration with competent authorities on national and European level due to the lack of existing guidelines!the annotation of draft guidelines during the consultation phase BIOCEUTICALS Arzneimittel AG, 8. Juni
20 Regulatory strategy Nov 2002 Initial scientific advice at BfArM (Germany)! Quality, non-clinical, clinical Jul 2003! Clinical Apr 2004 Follow-up scientific advice at BfArM (Germany) Initial scientific advice at EMEA! Quality, non-clinical, clinical Dec 2005! Clinical Follow-up scientific advice at EMEA Mar 2006 Publication of Guidance on similar medicinal products containing recombinant erythropoietins Jun 2006 Submission of marketing authorisation application to the EMEA Dec 2007 Approval. Product names: Silapo (cellpharm/stada), Retacrit (Hospira) Successful development and registration even without established guidelines! BIOCEUTICALS Arzneimittel AG, 8. Juni
21 The big success! On December 19, 2007, Marketing authorization for Epoetin zeta received from the EU Commission for the treatment of anaemia associated with chronic renal failure (i.v. administration) and chemotherapy.! Epoetin zeta was on the second place in time to market - only few months after the first Epo Biosimilar approval.! Until today only 2 sources for EU-approved Epo Biosimilars exist (Sandoz, BIOCEUTICALS/STADA).! Some of the major players failed so far to reach the market by their own. BIOCEUTICALS Arzneimittel AG, 8. Juni
22 Epoetin zeta A case study Contents! BIOCEUTICALS Arzneimittel AG a short overview! Introduction to Epoetin zeta! The regulatory environment past the last 10 years! Regulatory strategy! Development of Epoetin zeta! Control of production a key factor for success! Epoetin zeta in the market! Summary BIOCEUTICALS Arzneimittel AG, 8. Juni
23 Development Strategies! Own Development, Fully Integrated Control of Success Cost Control EBITDA- Margin 100 % 100 % High Risk High! BIOCEUTICALS! Own Development, Production CMO! Co-Development, Production CMO! In-Licensing 0 % 0 % Low Moderate BIOCEUTICALS Arzneimittel AG, 8. Juni
24 Development of Epoetin zeta (1) Chemistry, Manufacturing and Control (CMC)! CHO host cell line: best established mammalian expression system! GMP-master- and working cell banks: characterization in accordance with the applicable ICH guidelines! cell culture: without serum, proteins, insulin and antibiotics pilot scale process for clinical trial material scale-up for commercialisation! purification: validated multi-step process (incl. virus safety)! fill and finish: 11 presentations from 1,000 IU to 40,000 IU (prefilled syringes) patented formulation (EP ) BIOCEUTICALS Arzneimittel AG, 8. Juni
25 Development of Epoetin zeta (2) Analytics! highly sophisticated analytical methods were/are applied during process development (cell culture, purification and fill-and-finish) within the comparability-exercise for the marketing authorisation application during routine production! the EMA commented the analytical data provided with the marketing authorisation application as follows (citation from the assessment report for Silapo/Retacrit): Very extensive, high quality studies were performed to compare SB309 to the reference product Eprex/Erypo at both the drug substance and the drug product level. Likewise the characterisation of the drug substance and the comparability studies to compare drug substance from different scale manufacturing process is considered high quality with an extreme level of detail applying state-of-the art analytical methods. BIOCEUTICALS Arzneimittel AG, 8. Juni
26 Development of Epoetin zeta (3) Pre-clinical and Clinical Studies Pre-clinical studies:! pharmacodynamic studies (in vitro and in vivo)! toxicological studies (dogs and rats)! local tolerance (rabbits) Pivotal Clinical studies:! Phase I-studies: two comparative pharmacokinetic studies (total: 75 patients)! Phase III-studies: comparative dose titration study (609 patients) comparative study for maintenance therapy i.v. (313 patients) followed by: open follow-up safety trial (745 patients) oncological safety trial (approx. 216 patients) comparative study for maintenance therapy s.c. (462 patients) with open safety follow-up BIOCEUTICALS Arzneimittel AG, 8. Juni
27 Epoetin zeta A case study Contents! BIOCEUTICALS Arzneimittel AG a short overview! Introduction to Epoetin zeta! The regulatory environment past the last 10 years! Regulatory strategy! Development of Epoetin zeta! Control of production a key factor for success! Epoetin zeta in the market! Summary BIOCEUTICALS Arzneimittel AG, 8. Juni
28 Control of production a key factor for success for Biosimilars In order to ensure the commercial supply of Epoetin zeta in the required quantities and quality, BIOCEUTICALS initiated the joint-venture Norbitec GmbH in Norbitec is located at the site of Nordmark Arzneimittel GmbH & Co. KG in Uetersen (near Hamburg). With its engagement in Norbitec, BIOCEUTICALS managed to achieve the following:! key personnel involved in the pilot-scale development of Epoetin zeta could be hired thereby ensuring best possible know-how transfer! with its majority in the advisory board of Norbitec, BIOCEUTICALS is enabled to influence/control management decisions! as the major stakeholder in Norbitec, BIOCEUTICALS does directly benefit from Norbitecs earnings BIOCEUTICALS Arzneimittel AG, 8. Juni
29 Epoetin zeta A case study Contents! BIOCEUTICALS Arzneimittel AG a short overview! Introduction to Epoetin zeta! The regulatory environment past the last 10 years! Regulatory strategy! Development of Epoetin zeta! Control of production a key factor for success! Epoetin zeta in the market! Summary BIOCEUTICALS Arzneimittel AG, 8. Juni
30 Epoetin zeta in the market Marketing hurdles widely spread by some Originators claiming quality and safety deficiencies of all Epoetin Biosimilars......would not meet the Ph. Eur. specifications...would have higher immunogenic risk...would be contaminated with bacterial endotoxines...production process may would lead to higher variations between the batches...would have less experience than the Originators...would have lower potency, etc. This unqualified and incorrect marketing campaign was not a surprise the Generic industry had similar experience with Originators strategies against normal generics 30 years ago. However similar campaigns are still part of the argumentation used by some Originators against Biosimilars. An important statement refering to this kind of campaign made by Nicolas Rossignol from the EU commission pharmaceutical unit is self-explanatory. BIOCEUTICALS Arzneimittel AG, 8. Juni
31 BIOCEUTICALS Arzneimittel AG, 8. Juni
32 ! BIOCEUTICALS as well as STADA always anticipated these kind of hurdles by the Originators.! Thus, their forecast for Biosimilars was always based on a penetration speed significantly lower than for normal generics.! The cellpharm/stada plan for Silapo in Germany is unchanged since years and has a target of 20 Mio. in the third marketing year.! So far Silapo is well in line with German sales of 4,6 Mio. in Y1 (2008) and 13,2 Mio. in Y2 (2009). Thus, cellpharm is aiming in this year 2010 (Y3) for the 20 Mio. sales level.! This sales level could be reached despite intensive competition Today one can find 5 Epo Biosimilars by 2 different product sources and 2 new Epo Originator products by one source (Epoetin theta) in the german market.! For legal reasons we cannot disclose Hospira sales in this presentation. BIOCEUTICALS Arzneimittel AG, 8. Juni
33 ! BIOCEUTICALS is convinced that Biosimilars and especially Epoetin Biosimilars will catch in the long term 5 to 8 years after launch in most markets the same penetration level as it is today usual for generics (e.g. in Germany approx. 60% by value and 80% by volume).! And as more and more Epoetin Biosimilars are recognized as well established and cost-saving products in the EU demonstrating day for day the same therapeutic success but for a lower price than originator products we see the chance for a regulatory breakthrough in the US, too. BIOCEUTICALS Arzneimittel AG, 8. Juni
34 Future Potential Epo-zeta BIOCEUTICALS Arzneimittel AG, 8. Juni
35 Epoetin zeta A case study Contents! BIOCEUTICALS Arzneimittel AG a short overview! Introduction to Epoetin zeta! The regulatory environment past the last 10 years! Regulatory strategy! Development of Epoetin zeta! Control of production a key factor for success! Epo-zeta in the market! Summary BIOCEUTICALS Arzneimittel AG, 8. Juni
36 ! Development of Epoetin zeta, even without established registration guidelines! Epoetin zeta EMA approval within the first wave in Europe! Own Production (drug substance) ramped-up! establishment of out-licensing partnerships and the necessary logistic functions! Basis for development of US dossier (in partnership with Hospira) BIOCEUTICALS Arzneimittel AG, 8. Juni
37 3rd DVFA Life Science Conference 08 June 2010 Biosimilars Thank you for your attention! BIOCEUTICALS Arzneimittel AG, 8. Juni
Lessons for the United States: Biosimilar Market Development Worldwide
Lessons for the United States: Biosimilar Market Development Worldwide Sumant Ramachandra, MD, PhD, MBA Senior Vice President, Chief Scientific Officer Hospira $67B+ of 2012 LMV is expected to face biosimilar
More informationCOMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE (CHMP) GUIDELINE ON SIMILAR BIOLOGICAL MEDICINAL PRODUCTS
European Medicines Agency Evaluation of Medicines for Human Use CHMP/437/04 London, 30 October 2005 COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE (CHMP) GUIDELINE ON SIMILAR BIOLOGICAL MEDICINAL PRODUCTS
More informationBiological. Medicines. A Focus on Biosimilar. Medicines
TM Biological Medicines TM EuropaBio is the voice of the European biotech Industry. It represents the interests of the industry towards the European institutions so that legislation encourages and enables
More informationNon-clinical development of biologics
Aurigon Life Science GmbH Non-clinical development of biologics Requirements, challenges and case studies Committed to Life. Sigrid Messemer vet. med. M4 Seminar March 10 th 2014 Aurigon - your full service
More informationCompany Presentation
Company Presentation DISCLAIMER This document contains forward-looking statements on overall economic development as well as on the business, earnings, financial and asset situation of amp biosimilars
More informationGuideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (revision 1)
22 May 2014 EMA/CHMP/BWP/247713/2012 Committee for Medicinal Products for Human Use (CHMP) Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance:
More informationCOMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE (CHMP) REFLECTION PAPER
European Medicines Agency London 23 April 2009 EMEA/CHMP/BMWP/102046/2006 COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE (CHMP) REFLECTION PAPER NON-CLINICAL AND CLINICAL DEVELOPMENT OF SIMILAR MEDICINAL
More informationEisen en Verplichtingen
Registratie ti van Biosimilars: i il Eisen en Verplichtingen Dr. Thijs J. Giezen Ziekenhuisapotheker, Stichting Apotheek Haarlemse Ziekenhuizen Lid, CHMP Biosimilar Working Party (BMWP), European Medicines
More informationGuideline on non-clinical and clinical development of similar biological medicinal products containing recombinant erythropoietins (Revision)
18 March 2010 EMEA/CHMP/BMWP/301636/2008 Corr.* Committee for Medicinal Products for Human Use (CHMP) Guideline on non-clinical and clinical development of similar biological medicinal products containing
More informationManufacturer of drug substance
Original s and Biosimilars (marketing authorizations in the EU) Date: January 2016 1) Somatropin s ORIGINAL PRODUCTS: Authorization Genentech Genotropin Somatropin Pharmacia/ Pfizer E. coli Humatrope Somatropin
More informationAn Industry Perspective
AIPPI World IP Congress 2014 Workshop Pharma 2 Biosimilar pharmaceutical products An Industry Perspective September 16, 2014 Masahisa Yamaguchi, PhD Department Manager Intellectual Property Dept. Chugai
More informationA Comparison of US and EU Biosimilars Regimes
A Comparison of US and EU Biosimilars Regimes summary statement Economic barriers, along with regulatory complexity and uncertainty, are shaping the biosimilars industry into something entirely different
More informationManagement Report of the Pharmaceutical Market - Part 2
ANNUAL REPORT 2007 1,245.1 1,570.5 180.5 215.5 91.8 105.1 Group sales in million Operating profit in million 2006 2007 2006 2007 Net income in million 2006 2007 Key figures for the Group in million 2007
More informationVolume 2B Notice to Applicants. Medicinal products for human use. Presentation and format of the dossier. Common Technical Document (CTD)
Volume 2B Notice to Applicants Medicinal products for human use Presentation and format of the dossier Common Technical Document (CTD) Introduction Edition June 26 Module 1 Edition May 28 Module 2 Edition
More informationWHITE PAPER. Developing Biosimilars in Emerging Markets: Regulatory and Clinical Considerations
WHITE PAPER Developing Biosimilars in Emerging Markets: Regulatory and Clinical Considerations ppdi.com March 2013 EXECUTIVE SUMMARY Emerging markets in Asia Pacific, Latin America and Eastern Europe are
More informationGUIDELINES ON EVALUATION OF SIMILAR BIOTHERAPEUTIC PRODUCTS (SBPs)
ENGLISH ONLY FINAL EXPERT COMMITTEE ON BIOLOGICAL STANDARDIZATION Geneva, 19 to 23 October 2009 GUIDELINES ON EVALUATION OF SIMILAR BIOTHERAPEUTIC PRODUCTS (SBPs) World Health Organization 2009 All rights
More informationBriefing Paper on Biological and Biosimilar Medicines
Briefing Paper on Biological and Biosimilar Medicines Contents With our thanks IAPO would like to thank all those involved in planning this Toolkit and supporting its development. A full list of acknowledgements
More informationSTADA Interim Report on the First Nine Months
STADA Interim Report on the First Nine Months STADA Interim Report on the First Nine Months of 2010 STADA KEY FIGURES Key figures for the Group in million 1/1 9/30/2010 1/1 9/30/2009 ± % Group sales 1,177.8
More informationBIOTECHNOLOGY OPERATIONS
BIOTECHNOLOGY OPERATIONS Principles and Practices Michael J. Roy TECHNISCHE INFORMATION SBIBLIOTHEK UNIVERSITATSBIBLIOTHEK HANNOVER CRC Press TaylorStFrancis Croup Boca Raton London New York CRC Press
More informationLFB GROUP & SANOFI combine their bioproduction capabilities to provide integrated CMO services for biopharmaceuticals
LFB GROUP & SANOFI combine their bioproduction capabilities to provide integrated CMO services for biopharmaceuticals MAbLaunch TM is a joint bioproduction platform combining LFB Biomanufacturing (LFB
More informationRegulatory Affairs Graduate & Postgraduate Program. Novartis Pharma AG Novartis Animal Health AG
Regulatory Affairs Graduate Postgraduate Program Novartis Pharma AG Novartis Animal Health AG The Regulatory Affairs (RA) Graduate Program is an opportunity to discover the global functions of Drug Regulatory
More informationBiotechpharma company profile
Biotechpharma company profile October 2013 1 History 2004 Biotechpharma UAB established as a proteomic research company in Vilnius, Lithuania 2005 Company became a member of UK s Northway group, investing
More informationEBE Position paper on labelling of biosimilars Summary of Product Characteristics (SmPC) and Patient Information Leaflet (PIL)- draft April 2013
FINAL EBE 21 August 2013 EBE Position paper on labelling of biosimilars Summary of Product Characteristics (SmPC) and Patient Information Leaflet (PIL)- draft April 2013 Introduction This document seeks
More informationGeneral toxicity study designs
General toxicity study designs Jan Willem van der Laan Section on Safety of Medicines and Teratology Centre for Biological Medicines and Medical Technology National Institute for Public Health and the
More informationIntroduction to Drug Naming. Angela G. Long, M.S. Senior Vice President, Global Alliances and Organizational Affairs
Introduction to Drug Naming Angela G. Long, M.S. Senior Vice President, Global Alliances and Organizational Affairs What s in a Name? International Nonproprietary Names (INN) Sponsored by World Health
More informationSiegfried when substance matters Semi-annual report 2008
Siegfried when substance matters Semi-annual report 2008 Key figures Continuing Operations 1 st Half-Year 2008 1 st Half-Year 2007 Difference Change in % Net sales (million CHF) 159.6 157.8 1.8 1.2 Net
More informationBiologics and biosimilars. An overview
Biologics and biosimilars An overview Contents An introduction to biotechnology... 3 A brief history of medicine development... 4 What are biologic medicines?... 5 How are biologic medicines developed?...
More informationPlantForm Corporation
PlantForm Corporation Professor J. Christopher Hall CSO PlantForm Corporation Canada s Top10 Winner Life Sciences 2008/9 Innovator of the Year Guelph, Canada, 2010 Opportunity The introduction of more
More informationLFB GROUP & SANOFI combine their bioproduction capabilities to provide integrated CMO services for biopharmaceuticals
LFB GROUP & SANOFI combine their bioproduction capabilities to provide integrated CMO services for biopharmaceuticals MAbLaunch TM is a joint bioproduction platform combining LFB Biomanufacturing (LFB
More informationEUROPEAN COMMISSION HEALTH AND CONSUMERS DIRECTORATE-GENERAL
Ref. Ares(2011)1044649-03/10/2011 EUROPEAN COMMISSION HEALTH AND CONSUMERS DIRECTORATE-GENERAL Health systems and products Pharmaceuticals SANCO/D3/RSR/iv(2011)ddg1.d3. 1137738 Update 1 October 2011 HANDLING
More informationHealth Care Worldwide. Deutsche Bank European Leveraged Finance Conference June 14, 2013 London
Health Care Worldwide Deutsche Bank European Leveraged Finance Conference June 14, 2013 London Safe Harbor Statement This presentation contains forward-looking statements that are subject to various risks
More informationC 5. chemical development contract research custom synthesis cgmp API manufacturing commercial production. Welcome to
C 5 chemical development contract research custom synthesis cgmp API manufacturing commercial production Welcome to ChemCon Company profile Company profile ChemCon offers outstanding chemical services
More informationImmune-response and adverse reactions: PRCA case example. Nicole Casadevall
Immune-response and adverse reactions: PRCA case example Nicole Casadevall Recombinant human erythropoietin (rhuepo) 1985: EPO gene cloned 1986: first clinical trials in CKD 1988: rhepo is licensed for
More informationPharming Group NV (Euronext: PHARM)
Pharming Group NV (Euronext: PHARM) Sijmen de Vries, MD, MBA Chief Executive Officer Annual General Meeting of Shareholders Leiden, 30 April 2015 1 Safe harbour statement The information contained in this
More informationPost-Approval Change Management: Challenges and Opportunities An FDA Perspective
CMC Workshop From Drug Development to Global Supply to Patients April 15-17, 2013, Washington, DC Post-Approval Change Management: Challenges and Opportunities An FDA Perspective Christine M. V. Moore,
More informationBIOTECH MANUFACTURING SOLUTIONS 4 YOUR SUCCESS. a Novartis company
a Novartis company BIOTECH MANUFACTURING Sandoz GmbH Biotech Cooperations 6250 Kundl Austria Biochemiestrasse10 Phone +43 (0)5338 200 2609 Fax +43 (0)5338 200 442 biotech.cooperations@sandoz.com www.sandoz.com
More informationBiosimilars in the US Health Care Landscape. April 2016 PP-BIO-USA-0093 2016 Pfizer Inc. All rights reserved.
Biosimilars in the US Health Care Landscape April 2016 PP-BIO-USA-0093 2016 Pfizer Inc. All rights reserved. Agenda Introduction to Biologics and Biosimilars Considering the European Biosimilar Experience
More informationHealth Care Worldwide. Citi - European Credit Conference September 24, 2015 - London
Health Care Worldwide Citi - European Credit Conference September 24, 2015 - London Safe Harbor Statement This presentation contains forward-looking statements that are subject to various risks and uncertainties.
More informationTechnology Transfer of CMC Activities for MAb Manufacturing. 2010 ge healthcare (www.gelifesciences.com)
M a n u f a c t u r i n g OPERATIONS Technology Transfer of CMC Activities for MAb Manufacturing by Patricia Seymour, Susan Dana Jones, Howard L. Levine With combined 2009 revenues estimated to be over
More informationRegulatory approval routes in the European System for Medicinal Products
Regulatory approval routes in the European System for Medicinal Products Cardiovascular Combination Pharmacotherapy Global Summit, Melbourne, 8 th May 2014 Presented by: Kevin Blake Human Medicines Research
More informationValneva Reports Preliminary FY 2013 Revenues of EUR 36.0m and Cash Position of EUR 40.2m at End of 2013
Valneva Reports Preliminary FY 2013 Revenues of EUR 36.0m and Cash Position of EUR 40.2m at End of 2013 Revenue Ahead of Guidance and Cash Target Met in First year Following Merger Total revenues and grants
More informationLocalised Cancer Treatment. PCI Biotech. Amphinex a new product for localised cancer treatment
Localised Cancer Treatment PCI Biotech Amphinex a new product for localised cancer treatment Disclaimer This document (the Presentation ) has been produced by PCI Biotech Holding ASA (the Company ). The
More informationICH Topic Q 5 E Comparability of Biotechnological/Biological Products
European Medicines Agency June 2005 CPMP/ICH/5721/03 ICH Topic Q 5 E Comparability of Biotechnological/Biological Products Step 5 NOTE FOR GUIDANCE ON BIOTECHNOLOGICAL/BIOLOGICAL PRODUCTS SUBJECT TO CHANGES
More informationCOMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE (CHMP)
European Medicines Agency Evaluation of Medicines for Human Use London, 10 October 2007 Doc. Ref. COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE (CHMP) GUIDELINE ON POTENCY TESTING OF CELL BASED IMMUNOTHERAPY
More informationWhite Paper The EU Clinical Trials Regulation Main Changes and Challenges
White Paper The EU Clinical Trials Regulation Main Changes and Challenges Table of Contents 1. Introduction... 3 2. Main Changes and Associated Challenges... 4 2.1 Procedure for Initial Authorisation...
More informationWorking with ICH Quality Guidelines - the Canadian Perspective
Working with ICH Quality Guidelines the Canadian Perspective Krishnan Tirunellai, Ph. D. Bureau of Pharmaceutical Sciences Therapeutic Products Directorate Health Canada December 3, 2008 Outline Introduction
More informationBiosimilars Demystified
Biosimilars Demystified Thijs J. Giezen, PhD, PharmD, MSc Hospital Pharmacist, Foundation Pharmacy for Hospitals in Haarlem Member Biosimilar Working Party, European Medicines Agency I attend this conference
More informationBiologics: Specific Drug Safety Challenges. Violetta B. Kyburz
Biologics: Specific Drug Safety Challenges Violetta B. Kyburz 2012 2013 2014 Biologics: Specific Drug Safety Challenges Topics for discussion Particular issues in the preclinical development of biologics
More informationHow To Sell A Share In Amsterdam Molecular Therapy
NOT FOR RELEASE, DISTRIBUTION OR PUBLICATION INTO OR IN THE UNITED STATES, AUSTRALIA, CANADA OR JAPAN 6 June 2007 Amsterdam Molecular Therapeutics announces launch of Initial Public Offering (IPO) on Euronext
More informationEXPERT COMMITTEE ON BIOLOGICAL STANDARDIZATION EXPERT COMMITTEE ON SPECIFICATIONS FOR PHARMACEUTICAL PREPARATIONS Geneva, 18 to 22 October 2010
ENGLISH ONLY EXPERT COMMITTEE ON BIOLOGICAL STANDARDIZATION EXPERT COMMITTEE ON SPECIFICATIONS FOR PHARMACEUTICAL PREPARATIONS Geneva, 18 to 22 October 2010 Proposal to initiate a project to evaluate a
More information1. Name of pharmacopoeia
1 1. Name of pharmacopoeia European Pharmacopoeia 36 Member states (Austria, Belgium, Bosnia and Herzegovina, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece,
More informationSTADA KEY FIGURES. 02 STADA Key Figures. 6 months 2013 Jan. 1 June 30 1) ± % 6 months 2014 Jan. 1 June 30. Key figures for the Group in million
02 STADA Key Figures STADA KEY FIGURES Key figures for the Group in million 6 months 2014 Jan. 1 June 30 6 months 2013 Jan. 1 June 30 1) ± % Group sales 1,002.8 966.8 +4% Generics (core segment) 598.7
More informationGuideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues
1 2 3 03 June May 2013 EMEA/CHMP/BMWP/42832/2005 Rev. 1 Committee for Medicinal Products for Human Use (CHMP) 4 5 6 7 Guideline on similar biological medicinal products containing biotechnology-derived
More informationHealth Care Worldwide
Health Care Worldwide Barclays European High Yield and Leveraged Finance Conference October 30, 2014 London Barclays European High Yield and Leveraged Finance Conference, October 30, 2014 Copyright Page
More informationFORM 6-K. SECURITIES AND EXCHANGE COMMISSION Washington, D.C. 20549. Report of Foreign Private Issuer
FORM 6-K SECURITIES AND EXCHANGE COMMISSION Washington, D.C. 20549 Report of Foreign Private Issuer Pursuant to Rule 13a-16 or 15d-16 under the Securities Exchange Act of 1934 For the month of August 2011
More informationQUESTIONS AND ANSWERS ABOUT THE EDQM ACTIVITIES
QUESTIONS AND ANSWERS ABOUT THE EDQM ACTIVITIES Why are Pharmacopoeias so important in a globalised world? Pharmacopoeias have historically provided collections of medical recipes intended to ensure accurate
More informationCompetitor Analysis: Therapeutic Proteins Biosimilars, Biobetters & Biosuperiors
Brochure More information from http://www.researchandmarkets.com/reports/2540011/ Competitor Analysis: Therapeutic Proteins Biosimilars, Biobetters & Biosuperiors Description: The new Competitive Intelligence
More informationRegulations for Handling Samples and Laboratory Testing from R&D through Phase III Clinical Trials
Regulations for Handling Samples and Laboratory Testing from R&D through Phase III Clinical Trials Ron Hinkel, Director Quality Systems BioReliance Inc. Patti Rossman, President Globiox Purpose Keep pace
More informationStructure of State Regulatory Authorities REGISTRATION CERTIFICATE ISSUING AUTHORITY ROSZDRAVNADZOR
PRESENTATION REGISTRATION OF PHARMACEUTICAL PRODUCTS IN RUSSIA Alyona Chorich, Regulatory Affairs Manager PharmaReg, Moscow 1. Registration in Russia conception. Pharmaceutical products / food supplements
More informationUnedited version adopted by the 45th WHO Expert Committee on specifications for pharmaceutical preparations. World Health Organization 2010
GUIDELINE ON SUBMISSION OF DOCUMENTATION FOR A MULTISOURCE (GENERIC) FINISHED PHARMACEUTICAL PRODUCT (FPP): PREPARATION OF PRODUCT DOSSIERS (PDS) IN COMMON TECHNICAL DOCUMENT (CTD) FORMAT Unedited version
More informationBIOSIMILARS A COMPLETE DEVELOPMENT PLATFORM
BIOSIMILARS A COMPLETE DEVELOPMENT PLATFORM FROM ORIGINATOR THROUGH COMPARABILITY TO MARKET STREAMLINE YOUR R&D, REGULATORY, ANALYTICAL, AND CLINICAL NEEDS WITH ONE PROVIDER The development pathway of
More informationMarketing Authorization Procedures in the European Union Making the Right Choice
Life science i technical bulletin ISSUE N 33 /DECEMBER 2009 Marketing Authorization Procedures in the European Union Making the Right Choice AUTHOR: Arash Ghalamkarpour, PhD, Regulatory Affairs Associate,
More informationINTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE S1A. Current Step 4 version
INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE ICH HARMONISED TRIPARTITE GUIDELINE GUIDELINE ON THE NEED FOR CARCINOGENICITY STUDIES
More informationIncome Statement Format and Disclosures 2007 Conference call for Financial Analysts, November 2007 Ian Bishop
Income Statement Format and Disclosures 2007 Conference call for Financial Analysts, November 2007 Ian Bishop This presentation contains certain forward-looking statements. These forward-looking statements
More informationHealth Care Worldwide
Health Care Worldwide Credit Suisse Global Credit Products Conference September 18, 2014 Miami Credit Suisse Global Credit Products Conference, September 18, 2014 Copyright Page 1 Safe Harbor Statement
More informationGuideline on good pharmacovigilance practices (GVP)
1 2 20 February 2012 EMA/541760/2011 3 4 Guideline on good pharmacovigilance practices (GVP) Module I Pharmacovigilance systems and their quality systems Draft finalised by the Agency in collaboration
More informationFlamel Technologies Announces Second Quarter Results of Fiscal Year 2015
Flamel Technologies Announces Second Quarter Results of Fiscal Year 2015 Product revenue guidance for 2015 of $170-$185 million reaffirmed Conference call with management to take place at 10:00 am ET on
More information9. WestLB Deutschland Conference. Frankfurt November 16, 2011
9. WestLB Deutschland Conference Frankfurt November 16, 2011 Safe Harbour This presentation includes forward-looking statements. Actual results could differ materially from those included in the forward-looking
More informationRADIOPHARMACEUTICALS BASED ON MONOCLONAL ANTIBODIES
RADIOPHARMACEUTICALS BASED ON MONOCLONAL ANTIBODIES Guideline Title Radiopharmaceuticals based on Monoclonal Antibodies Legislative basis Directives 65/65/EEC, 75/318/EEC as amended, Directive 89/343/EEC
More informationEMA Update Clinical Trials
EMA Update Clinical Trials Fergus Sweeney, Head, Compliance and Inspections, European Medicines Agency 16 October 2012 An agency of the European Union Disclaimer The views presented in this presentation/these
More informationCompilation of individual product-specific guidance on demonstration of bioequivalence
17 December 2014 EMA/CHMP/736403/2014 Committee for Medicinal Products for Human Use (CHMP) Compilation of individual product-specific guidance on demonstration of bioequivalence Initial batch of individual
More informationICH Topic S 1 A The Need for Carcinogenicity Studies of Pharmaceuticals. Step 5
European Medicines Agency July 1996 CPMP/ICH/140/95 ICH Topic S 1 A The Need for Carcinogenicity Studies of Pharmaceuticals Step 5 NOTE FOR GUIDANCE ON THE NEED FOR CARCINOGENICITY STUDIES OF PHARMACEUTICALS
More informationPresented at: Jefferies 2015 Global Healthcare Conference
Presented at: Jefferies 2015 Global Healthcare Conference Agenda 1 Overview & Service Platforms 2 Adaptability, Scalability & Expansion Plans 3 Best Practices 4 Blue Chip Customer Base 5 Roadmap of Evolution
More informationPL 17871/0208 UKPAR TABLE OF CONTENTS
Fultium-D 3 3,200 IU Capsules PL 17871/0208 UKPAR TABLE OF CONTENTS Lay Summary Page 2 Scientific discussion Page 4 Steps taken for assessment Page 11 Summary of Product Characteristics Page 12 Patient
More informationBiotest Group. H1 2014 Conference call 12 August 2014
Biotest Group H1 2014 Conference call 12 August 2014 Disclaimer This document contains forward-looking statements on overall economic development as well as on the business, earnings, financial and asset
More informationWILEX AG: Interim management statement on the first quarter of 2016
WILEX AG: Interim management statement on the first quarter of 2016 Munich, Germany, 14 April 2016. WILEX AG (ISIN DE000A11QVV0 / WL6 / FSE) today reported on the first three months of the 2016 financial
More informationEnd of consultation (deadline for comments) 14 October 2009. Adoption by Committee for advanced therapies 15 October 2010
15 October 2010 EMA/CAT/418458/2008/corr. Committee for advanced therapies (CAT) Procedural advice on the certification of quality and nonclinical data for small and medium sized enterprises developing
More informationKempen & Co 4 th Healthcare/Life Sciences Conference. Brussels March 29, 2011
Kempen & Co 4 th Healthcare/Life Sciences Conference Brussels March 29, 2011 Safe Harbour This presentation includes forward-looking statements. Actual results could differ materially from those included
More informationexactly. The need for efficiency in developing effective new therapeutics has never been greater.
exactly. The need for efficiency in developing effective new therapeutics has never been greater. As demands on the global healthcare system increase and treating disease becomes more complex, the research,
More informationDecentralised Procedure. Public Assessment Report. Gadojaco Handvist Gadopentetat Dimeglumin Jacobsen 500 Mikromol/ml Injektionslösung
Bundesinstitut für Arzneimittel und Medizinprodukte Decentralised Procedure Public Assessment Report Gadojaco Handvist Gadopentetat Dimeglumin Jacobsen 500 Mikromol/ml Injektionslösung Gadopentetate dimeglumine
More informationTGN 1412 Welche Änderungen haben sich für die Erstanwendung am Menschen aus Sicht des BfArM ergeben?
TGN 1412 Welche Änderungen haben sich für die Erstanwendung am Menschen aus Sicht des BfArM ergeben? PD Dr. med. Thomas Sudhop Bundesinstitut für Arzneimittel, Bonn Bundesinstitut für Arzneimittel IMP
More informationDecentralised Procedure. Public Assessment Report
Bundesinstitut für Arzneimittel und Medizinprodukte Decentralised Procedure Public Assessment Report ben-u-ron direkt Erdbeer/Vanille 250/500 mg Granulat in Beuteln ben-u-ron direkt Cappuccino 500/1000
More informationRepligen Reports Third Quarter 2015 Financial Results
Repligen Corporation 41 Seyon Street Building #1, Suite 100 Waltham, Massachusetts 02453 Repligen Reports Third Quarter 2015 Financial Results - Product Sales Increase 31% to $19.8 Million - - Conference
More informationHow To Understand The Paediatric Regulation
Paediatric Use Marketing Authorisation (PUMA) from a National Competent Authority Point of View DGRA Annual Congress 2006 Bonn, 10. May 2006 Dr. Susanne Keitel Content PUMA The Future Background Legislative
More informationPHARMACEUTICAL REFERENCE STANDARDS
PHARMACEUTICAL REFERENCE STANDARDS 11 th International Symposium organised by the European Directorate for the Quality of Medicines & HealthCare (EDQM), Council of Europe 3-4 September 2012, Strasbourg,
More informationLuca Romagnoli, Ph.D. Business Development Manager
Modelli innovativi di produzione per lo sviluppo di un processo altamente qualitativo di farmaci biologici Luca Romagnoli, Ph.D. Business Development Manager BIOLOGICAL DRUGS - SOURCES Monoclonal antibodies
More informationAchieving Regulatory Success: Areas of focus for biotechnology companies. Michael J. Schlosser, PhD, DABT April 21, 2013
Achieving Regulatory Success: Areas of focus for biotechnology companies Michael J. Schlosser, PhD, DABT April 21, 2013 Regulatory Success Outline Regulatory Initiatives Regulatory Science Pre-Regulatory
More informationNEW CHEMICAL ENTITIES
NEW CHEMICAL ENTITIES PIONEERING PARTNER FOR PEPTIDES With more than 40 years of expertise in peptide synthesis, a track record in process development, large-scale manufacturing and outstanding product
More informationThe Clinical Trials Directive in the EU: Present and Future Elisabethann Wright, Partner Maurits Lugard, Partner. May 2010
The Clinical Trials Directive in the EU: Present and Future Elisabethann Wright, Partner Maurits Lugard, Partner May 2010 Background (1) The Clinical Trials Directive 2001/20/EC The intention of this Directive
More informationMorphoSys Proprietary Development Update
September 8, 2015 MorphoSys Proprietary Development Update 1 Safe Harbor This presentation includes forward-looking statements. Actual results could differ materially from those included in the forward-looking
More informationChanges to an Approved Product
Changes to an Approved Product Chemistry, Manufacturing and Controls By Khandan Baradaran, PhD and Peggy Berry, MBA, RAC It is a huge achievement for any company to obtain licensing rights to an approved
More informationClinical trials in developing countries submitted to EMEA for regulatory purposes
Clinical trials in developing countries submitted to EMEA for regulatory purposes Rome, UNICRI/AIFA December 2008 Hans-Georg Eichler Agenda Challenges EU regulatory requirements for clinical trials Facts
More informationVOLUME 2A Procedures for marketing authorisation CHAPTER 1 MARKETING AUTHORISATION. November 2005
EUROPEAN COMMISSION ENTERPRISE DIRECTORATE-GENERAL Consumer goods Pharmaceuticals Brussels, ENTR/F2/BL D(2002) NOTICE TO APPLICANTS Revision 3 VOLUME 2A Procedures for marketing authorisation CHAPTER 1
More informationImporting pharmaceutical products to China
Importing pharmaceutical products to China Imported pharmaceutical products need pre-market approval before entering the Chinese market Imported drugs for human use are required to obtain pre-market approval
More informationValentina Gualato, Ph.D. Process Development Scientist
COMPANY PRESENTATION Quality and Innovation Valentina Gualato, Ph.D. Process Development Scientist MISSION areta international is a biotech company dedicated to the contract development and manufacturing
More informationWHO guideline for abbreviated licensing pathways for certain biological therapeutic products
WHO guideline for abbreviated licensing pathways for certain biological therapeutic products - Clinical evaluation - Martina Weise, MD Federal Institute for Drugs and Medical Devices, Germany General considerations
More informationOverview of Drug Development: the Regulatory Process
Overview of Drug Development: the Regulatory Process Roger D. Nolan, PhD Director, Project Operations Calvert Research Institute November, 2006 Adapted from course taught by Cato Research Background: Roger
More informationScientific Challenges for Development of Biosimilar Monoclonal Antibodies. Rafiqul Islam Director, Global Bioanalytical Services Celerion
Scientific Challenges for Development of Biosimilar Monoclonal Antibodies Rafiqul Islam Director, Global Bioanalytical Services Celerion Presentation outline Biosimilars Definitions and Concepts Regulatory
More informationRisk Management Plan (RMP) on Biologicals and NCE
Transformation towards a New Regulatory Paradigm Risk Management Plan (RMP) on Biologicals and NCE Junko SATO International Coordination Officer PMDA, Japan 1 2 Pharmaceuticals and Medical Devices Agency
More informationTesting Services for Large Molecule Drug Development
Testing Services for Large Molecule Drug Development Our mission is to extend our clients capabilities by combining scientific knowledge, capacity, regulatory expertise and flexibility to provide the trusted,
More information