L analisi e le scelte

Transcript

1 CTP Tecnologie di Processo è un azienda certificata: CTP Tecnologie di Processo Schema relazione I. La motivazione II. L analisi e le scelte III. 1

2 I. La motivazione La situazione mondiale, le strategie del futuro La motivazione RANKING BY ETHICAL DRUG SALES Vs

3 La motivazione THE BLOCKBUSTER MODEL La motivazione R&D cost, Dev.times, NME output and Sales world growth from 1993 to 2003 R&D Expenditure Development times NME output Sales ex Ind Year 3

4 La motivazione Table 1: The leading pharmaceutical companies will lose between 14% and 41% of their existing revenues as a result of patent expires Company AstraZeneca Share of Revenues (%) Arimidex $2.2bn Seroquel $4.7bn Symbicort $3.7bn 38 US Plavix $4.8bn BMS Avapro $1.3bn Abilify $2.1bn 30 GSK Advair $3.8bn Avandia $2.5bn 23 Eli Lilly Zyprexa $4.8bn 22 Merck Cozaar/ Hyzaar $3.2bn Singulair $4.5bn 22 Novartis Femara $1.1bn Diovan $6.0bn 14 Pfizer Aricept $800m Sanofi-Aventis Taxotere $2bn Lipitor $12.1bn Viagra $4.5bn Xalatan US Plavix Avapro $1.6bn $3.8bn $2.1bn Detrol $860m Geodon $1.1bn 41 Lovenox $3.1bn 34 La motivazione Dry pharma pipelines Increasing competition for in-licensing Price pressure from healthcare systems Increasing shift from Rx to Gx Globalization Focus Consolidation Innovation and product introduction no longer affordable at country/region level Leaders positioned in all key countries with globally designed business systems All major pharmacos want to move to a few attractive (high-volume, high-growth, high barriers to entry) therapeutic areas Ongoing industry consolidation Emergence of large global pharma players with potential scale advantages in M&S, R&D, and Operations 4

5 La motivazione CAPACITY UTILIZATION*, 2002 Percent 100% ROUGH ESTIMATES BASED ON SITE VISITS** Unused capacity 53%** -65% -73% -69% -56% There are significant excess capacities Assuming 5 x 2 shifts Solids formulation Liquids formulation Solids packaging Liquids packaging * Defined as actual output divided by output of machine running at technical limit during full shift time ** Capacity utilization calculated as machine utilization time divided by maximum running time adapted to 5 x 2 shifts EUR millions La motivazione CAPEX DEVELOPMENT FOR MAINTENANCE 13% CAGR for CapEx maintenance versus 1% CAGR for production volume ~ 25 ~ 29 ~ 35 ~ 41 ~ 61 ~ 88 Due to network and production fragmentation, CapEx dedicated to network maintenance has grown significantly Production volume PU, millions

6 La motivazione 2013: LA GRANDE GLACIAZIONE Evoluzione fatturato Industria Farmaceutica Internazionale La motivazione ASPIRATIONS FOR NETWORK REORGANIZATION From Fragmented network Complex product portfolio Underutilized capacities across sites and technologies To Stable and flexible network with strong launch capabilities Production of rewarded complexity only Appropriate capacity utilization of all technologies 6

7 TYPES OF SITES IN FUTURE NETWORK 1 Global/regional launch of products Launch sites Guarantee smooth product launch Preservation and further development of know-how and expertise for key technologies (including new technologies) 2 Key market Focus on continuous, reliable low-cost supply presence and Production of mature products ongoing supply Possible differentiation Large vs. small products Rx/OTC R/OTCvs. Natural Health 3 Competence centers for specific technologies Global competence center for selected technologies Product launch and ongoing supply combined on-site Potential key technologies (es.) Respiratory drugs and devices Sterile application forms NETWORK STRATEGIES OF MAIN COMPANIES EXAMPLES Abbott AZ BMS GSK J&J Novartis Cost focus (improvement in individual plants, benchmarking) Development of launch site Network optimization Second round of network optimization Multiple productivity and quality improvements per plant Network optimization and regionalization of Ops responsibility Process excellence/lean manufacturing Aggressive plant network optimization and coherent supply chain setup to capture lowest possible COGS A few plants focused by forms and volumes Launch sites Truly global Ops responsibility and stringent SCM processes Novo-Nordisk Pfizer Roche Warner- Lambert Application of lean manufacturing across all plants to free up capacity, limit investments, and reduce costs Focus plant distinctiveness (lean) Cost focus (plant network, investments) Launch capabilities (to some extent forced by Xenical) Development of launch site 7

8 II. L analisi e le scelte Scegliere la strategia, analizzare l impatto e implementare i miglioramenti L analisi e le scelte IMPROVEMENT IN MANAGEMENT SYSTEMS AND BUSINESS PROCESSES Efficient and fully integrated management systems Business process excellence Consolidate and streamline management meeting landscape to two key meetings Consolidate current fragmented planning tools in one central fact base for key decisions ( g) CIVISO QbD Develop new processes for Third party management Global network coordination (product/volume allocation) Best practice transfer (benchmarking) Optimize existing processes Annual discussion Global asset management (corporate invest process) Personnel development 8

9 L analisi e le scelte Possibili approcci al contract manufacturing L analisi e le scelte CSO Contract t Support Organization + CMO Contract Manufacturing Organization Integrazione di un processo frammentato CMSO Contract Manufacturing and Support Organization Single-source provider from manufacturing through commercial manufacture 9

10 L analisi e le scelte CMSO Contract Manufacturing and Support Organization Analytical development and validation Industrial productions Formulation development Dossier writing Client idea Generic product Client product Process development Raw materials sourcing Pilot batches Production for clinical trials Stability studies CMSO NEEDS L analisi e le scelte CTP SUPPORT Analytical development and validation Industrial productions Formulation development Dossier writing CMSO LIFE CYCLE CTP SYSTEM INTEGRATED COMPETENCES Process development Raw materials sourcing Pilot batches Production for clinical trials Stability studies 10

11 L analisi e le scelte Passare da un concetto di PRODOTTO ad un concetto di SERVIZIO Quello che per noi è normale attività per gli altri è un PROBLEMA Ciò che per gli altri è un PROBLEMA per VOI deve essere un BUSINESS Diventare partner STRATEGICI e non solo TATTICI CLIENTI TARGET Piccole e Medie Aziende prevalentemente commerciali magari senza stabilimento produttivo Grandi Aziende che vogliono delocalizzare produzioni mature o di nicchia L analisi e le scelte Excelvision, Unither, Pharma Stulln, Ursapharm, SIFI, Tubilux, Farmigea, COC, Moorfields, Vianex, Holopack, Catalent, Montefarmaco, Nycomed, PharmaSter, Wockhardt, Patheon, Fareva, Haupt, Abbott, FDC-India, Promed, Etc Il mercato dei terzisti è un mercato altamente competitivo 11

12 L analisi e le scelte Il mercato dei terzisti è un mercato altamente competitivo WHY MOVING PRODUCTS? GENERAL Market changes Product life cycles Optimizing production between locations Mergers & Acquisitions ECONOMIC International cost competition Tax advantages Supply Chain rationalization SEARCH FOR PRODUCTION EFFECTIVENESS L analisi e le scelte IDENTIFIED IMPROVEMENT MEASURES Process Development Transfer Life cycle optimization I M P R O V E M E N T M E A S U R E S Dedicated process engineering function at launch site Defined quality gates (acceptance criteria) for development process Own global standards for excipients, materials, and other elements Cross-functional alignment and management 12

13 III. Vantaggi e criticità di alcune scelte. Quali sono e come usare gli strumenti di analisi. TERZIARIZZAZIONE DELLA PRODUZIONE DEL FARMACO NEI PAESI EXTRA E.U. Paesi Low Cost Esclusione dei Paesi: Usa Canada Australia Islanda Giappone Paesi consolidati: Turchia India Cina Paesi emergenti: Vietnam Tunisia Marocco Algeria Sud Corea 13

14 I. VERIFICA REGOLATORIA Stato autorizzazioni, gap analysis, integrazioni per importazioni II. VERIFICA LOGISTICA Supply chain III. VALUTAZIONE ECONOMICA Costi fissi, addizionali e variabili VALUTAZIONE ECONOMICA COSTI ADDIZIONALI Costo convalida interna produttiva/analitica Costo di convalida analitica per il rilascio del prodotto Costo stabilità on-going e PQR Costo mantenimento certificazione EU Costo qualifica interna supply chain Costo di adattamento impianti (eventuali) COSTI FISSI Costo A.P.I. Costo service Costo Materie Prime Costo materiali di confezionamento Costo trasporto Costo di release COSTI VARIABILI Costo adattamento prodotto requisiti nazionali Costo per risk analysis prodotto Costo mantenimento progetto Costo derivante dalla riserva di sicurezza del prodotto Costo derivante dalle fluttuazioni monetarie 14

15 PRODUCT TECHNOLOGY TRANSFER Come dare un servizio, fare business ed evitare ritardi nello start up produttivo THE MAJOR OBSTACLES N t f t f / j t No management of transfer / no project manager No consistent transfer team Regulatory requirements unclear Priority for production in the plant Ineffective communications between functions Poor definition of the target Industrial strategy unclear Process not transferable Vague definition of the tasks Cultural misunderstanding Unavailability of people Unrealistic timelines and lack of cost evaluation No integration of the receiving site expectations Lack of training.. 15

16 PRODUCT TRANSFER MATERIAL STANDARD Transfer Standard GUIDELINES Product transfer between manufacturing sites Analytical technology transfers between sites STANDARD DOCUMENTS Pre-evaluation document Project Definition Document (PDD) Transfer Activity Monitoring Document (TAMD) Monthly report SUPPORT DOCUMENTS Training material GENERAL PROCESS FLOWCHART PRE-EVALUATION PHASE Data collection for a first appraisal CTP support FEASIBILITY PHASE Preliminary evaluation Detailed evaluation Project Definition Document Document preparation PREPARATORY PHASE Protocols Materials Documentation Validation activities OPERATIONAL PHASE PROJECT COMPLETION Trial batches and Process qualification Submission Regulatory Support Agency review Market approval(s) 16

17 TRANSFER TEAM ORGANISATION Donor site Finance Analytical Dev. & Quality control Quality Assurance Equipment & Facilities Manufacturing Industrial Technology Regulatory Affairs Supply chain Packaging & Artwork THE PROJECT LEADER Expert named from CTP Team Leads a group of individuals from different functional areas (within receiving site but also from external) to develop and execute a strategy that delivers the business benefit Project Leader Planning Leading Organizing Controlling 17

18 PLOC ACTIVITES AND DELIVERIES Define products to be transferred (formulations, packs, markets, volumes) Audit receiving site Establish current status for regulatory and quality issues Define process in receiving site Define regulatory strategy Define capital and revenue costs of implementation Define analytical methods transfer strategy Identify supply chain issues Establish project schedule Confirm project profitability Prepare documentation, SOPs, methods, equipment, Assicurazione di Qualità L Assicurazione di Qualità nella scelta e nella gestione delle attività in outsourcing Il processo di scelta di un possibile partner a cui affidare attività in outsourcing è un processo multifunzionale che deve essere gestito in accordo al Sistema di Qualità sia del Committente sia del Fabbricante. Customer Service e Production Service Level Customer Service e Production Service Level Scouting e auditing a fornitori Implementazione file o software per calcolo costi per offerte e verifica a consuntivo della redditività Implementazione Sistema QA per servizio al cliente (info su change, deviazioni, non conformità, ecc.) Adattamento del Regolatorio per supportare il cliente nelle attività regolatorie per il trasferimento della produzione e delle analisi relative 18

19 Assicurazione di Qualità In ambito farmaceutico, il processo di selezione di un partner per attività in outsourcing non solo deve tenere conto delle esigenze logistiche, economiche e/o di fornitura, ma deve anche ottemperare ai requisiti regolatori e GMP. Capitolo 7 Contract Manufacture and Analysis EU GMP Capitolo 6 Quality Control EU GMP Annex 16 Certification by a Qualified Person and Batch Release Sviluppo o adattamento di struttura per contrattualistica e capitolati tecnici Ruolo QA Technical Agreement La sottoscrizione di un Technical Agreement tra le parti: Sancisce la conclusione del processo di selezione del partner esterno; E un elemento essenziale ed irrinunciabile per ottemperare agli obblighi normativi; E il documento essenziale e di riferimento per la gestione delle attività nel tempo; Deve essere redatto e sottoscritto tra le parti in modo da definire chiaramente, concordare e controllare le attività affidate a terzi; 19

20 Deve essere redatto in modo da definire chiaramente le responsabilità delle parti: Acquisto materiali (reagenti, colonne, standard) Modalità di campionamento Invio e conservazione dei campioni di analisi Analisi (redazione ed approvazione metodiche e specifiche) Conservazione dei campioni d archivio Conservazione dei dati analitici Rilascio (modalità di certificazione e rilascio) Modalità di gestione di OOS, deviazioni e change Modalità di gestione di difettosità e/o reclami Deve chiaramente indicare le modalità seguite nel rilascio dei lotti dalla QP Deve essere redatto da personale tecnicamente competente per quanto concerne gli aspetti tecnici sia tecnologici, sia analitici, sia GMP, sia legali Technical Agreement Il contesto normativo Codice civile Decreto legislativo n. 219 codice dei medicinali Legge n. 192 subfornitura Decreto legislativo n codice del consumo CTP TECHNICAL AND LEGAL SUPPORT 20

21 Quality by Design per migliorare il servizio al cliente e ridurre i costi Quality by Design Quality Risk Management Track & Trending DOCUMENT MANAGEMENT SYSTEM Quality by Design Scope The main problem is variability Pharmaceutical Products are of good quality. Quality itself is not the issue, but pharmaceutical development and manufacturing could be improved because: Uncontrolled variability in e.g. properties of the starting materials or the manufacturing process affects the quality of the medicinal product. 21

22 Quality by Design Scope How can variability be reduced? By obtaining increased process and product understanding in order to identify and appropriately manage critical sources of variability and hence achieve right first time performance. Need for a shift in paradigm: From compliance To enhanced product and process understanding Quality by Design Scope Desired state: t Product quality and performance achieved and assured by design of effective and efficient manufacturing processes Product specifications based on mechanistic understanding of how formulation and process factors impact product performance Continuous "real time" quality assurance How to deliver the desired state? Invest in Pharmaceutical Development p Identify critical material and process parameters affecting product quality (using prior knowledge, risk management tools, DOE, MVA) Understand and if possible express mathematically their relationship with the critical quality attributes Design a process measurement system to allow on-line or at-line monitoring of critical quality attributes Design a control system that will allow adjustment of critical quality attributes Implement a quality system that allows continuous improvement 22

23 Quality by Design Key Aspects ICH Q8: Pharmaceutical Development Quality cannot be tested into products; quality should be built in by design Quality by Design Applications Pharmaceutical Development - Systematic, establishment of design space Manufacturing process - Not set, but adjustable within design space - Lifecycle approach to validation: continuous process verification, alternative strategies to the conventional 3 batches approach P t l Process controls - PAT tools used with feed forward and feedback controls Product specifications - Based on desired product performance with relevant supportive data Control strategy - Quality controls shifted upstream. Possibility of real-time release or reduced end-product testing 23

24 Quality by Design Tools Regulatory tools to support the Desired state Quality Risk Management Track & Trending DOCUMENT MANAGEMENT SYSTEM Quality Risk Management Process flow Risk Assessment What can go wrong? What is the likelihood (probability) it would go wrong? What are the consequences? Risk analysis is a systematic use of information to identify specific sources of harm (hazards) and to estimate the risk. Risk evaluation compares the estimated risk against given risk criteria using a quantitative or qualitative scale to determine the significance of the risk. 24

25 Quality Risk Management Applications 1. Development (e.g. Specification Setting, Test Method Selection and process development). 2. Regulatory scrutiny during pre and post approval. 3. As a component of Quality systems (e.g. Auditing, Deviations/Discrepancies, Complaints & Recall Management, Change management) 4. Facility systems management (e.g. Design, Hygiene, Qualification, environmental control, Preventative maintenance and Computerized systems) 5. Materials Management (e.g. Supply chain, Assessment and evaluation of suppliers and contract manufacturers, procurement and release of material) 6. Production (e.g. PAT, Validation, in-process sampling, testing, reporting and trending) 7. Laboratory controls (e.g. validation, testing, methods development, stability). 8. Packaging and labeling (e.g. Selection of container closure system and label controls). 9. Regulatory Authority Activities Track & Trending Scope Reference guideline: ICH Q10 To use effective monitoring systems for process performance and product quality providing assurance of continued capability of processes. Identification and implementation of necessary product quality improvements, process improvements, variability reduction, innovations, and quality system tools, thereby increasing the ability to consistently fulfil quality and financial requirements. Risk Management techniques may be used to identify necessary areas for improvement. 25

26 Quality and financial tools Track & Trending Applications Annual Product Review 1. QA QC Data Monitoring 2. Process data Monitoring 3. Engineering Data Monitoring 5. Change Managing System 6. CAPA Managing System 7. KPIs System 8. Toll Manufacturing Price Evaluation 9. Control panel Stream: Stock Reporting and Management MonFor: Supplier Performance Monitor Scheduler: Production Order Compiler OrdProd: Efficiency in Production 5. KPIs system Track & Trending Applications Quality Cost Time Name Quality service level (QSL) Rate of justified complaints Accident frequency rate Capacity utilization Capex maint./depr. wpci* wmci* Yield** Overall equipment effectiveness (OEE) Turnover ratio forward (TRF) Production service level (PSL) Intercompany service level (ISL) Customer service level (CSL) Definition 1 - (Rejected + reworked + reanalysed batches)/total batches (no. of total complaints)/(total PU produced) (no. of severe accidents)/(total labor hours) (Running time)/8,760 hours % ppm Ppm % % (Capex for maintainance)/depreciations % Development of production cost compared to base year, net of product mix changes and inflation/devaluation % Development of material cost from 3rd parties compared to base year, net of product mix changes % (Value of employed material in endproduct)/(total value of employed material) % (Real running time)/(available capacity) 4 x (projected deliveries in month M+1, M+2 and M+3)/(total inventory at end of month M), deliveries/inventory valued at COG % Average of classified deviation in days for all items between requirement date and date of stock availability % (Number of correctly fulfilled intercompany order lines)/(total number of intercompany order lines) % (Number of correctly fulfilled customer order lines)/(total number of customer order lines) 26

27 Track & Trending Further development Problem Analysis The Track and Trending activities will lead to the highlighting of the main problems affecting quality level, costs, deviations and complaints Once highlighted the main problems (i.e. yields, market complaints, assay uncontrolled trends, analytical failure investigations, on hold products, etc.) is suggested to put in place a Pareto analysis in order to set up priorities in the recovery e plan pa Problem solving Once given priorities and put in place a recovery plan is suggested to evaluate possible causes for each problem highlighted One possible approach is the bone fish analysis Is suggested to involve people of the department / s where the problem is supposed to come from Track & Trending Further development Quality Output Standardization In every production plant, during normal production activities, could be highlighted some products with defects by automatic checkers or by production or analytical personnel. Once highlighted these defects is very important to have in place common and approved lists for defect evaluations in order to quickly give to the personnel a tool for checking and evaluating the problem and put in action a quick, shared and effective remediation activity including resampling or reworking. This would lead to a common Quality Behaviour in every plant of a multinational company, would reduce the on hold time and costs and would give to personnel a common Quality Feeling. 27

28 Track & Trending Further development Data Warehouse and Quality Compliance Assurance System Usually, in every company, there are software up and running; they are often customized for each department s needs (AS400, SAP, LIMS, POMS, etc.) Very often these systems are not connected and lots of data in them have to be put in at least twice or extracted manually and managed with excel or access files. Is suggested to have a simple software that could link all the systems in place and extract data in order to have graphics, trends or highlight quality alarms Track & Trending Further development Data Warehouse and Quality Compliance Assurance System EXAMPLE The QA-Process module contains two separate but integrated applications that can share data: QA Management Tool GMP Event Monitoring & Tracking of Identification, Recording and monitoring of process events Deviation Management Complaint Management CAPA Management Change Management MBR e EBR, Master Batch Record and Electronic Batch Record APR & QPR Annual & Quality Product Review GMP Production Tool s Management of Production, Materials and Service Level KPIs 28

29 Executive Summary Slide DISPONIBILIDAD DEL MATERIAL DE LAS CONFERENCIAS 29