1 CONTRACT MANUFACTURING EVOLUTION CONTRACT MANUFACTURING EVOLUTION CTP Tecnologie di Processo CTP Tecnologie di Processo è un’azienda certificata: CONTRACT MANUFACTURING EVOLUTION Schema relazione I. La motivazione II. L’analisi e le scelte III. Gli strumenti
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•Leaders positioned in all keycountries with globally designedbusiness systems
Focus•All major pharmacos want to move
to a few attractive (high-volume,high-growth, high barriers to entry)Price pressure
from healthcare
Dry pharma pipelines
Increasing competition for in-licensing
therapeutic areas
Consolidation•Ongoing industry consolidation•Emergence of large global pharma
players with potential scaleadvantages in M&S, R&D, andOperations
from healthcare systems
Increasing shift from Rx to Gx
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CONTRACT MANUFACTURING EVOLUTIONLa motivazione
CAPACITY UTILIZATION*, 2002CAPACITY UTILIZATION*, 2002______________________ROUGH ESTIMATES BASEDROUGH ESTIMATES BASED
ON SITE VISITS**ON SITE VISITS**PercentUnused100%
-65% -73% -69%-56%
Unusedcapacity
Assuming
53%**There are significant
excess capacities
Solids formulation
Liquids formulation
Solids packaging
Liquids packaging
g5 x 2 shifts
* 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
CAPEX DEVELOPMENT FOR MAINTENANCECAPEX DEVELOPMENT FOR MAINTENANCE
CONTRACT MANUFACTURING EVOLUTIONLa motivazione
61
~ 88
EUR millions
Due to network andproduction fragmenta-tion, CapEx dedicated tonetwork maintenance
13% CAGR for CapEx maintenance versus
1% CAGR for productionvolume
~ 25 ~ 29 ~ 35 ~ 41
~ 61
1996 1998 20001994 2002 2004
has grown significantly
ProductionvolumePU, millions 626 717
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CONTRACT MANUFACTURING EVOLUTIONLa motivazione
2013: LA GRANDE GLACIAZIONE 2013: LA GRANDE GLACIAZIONE
Evoluzione fatturato Industria Farmaceutica Internazionale
2007 2008 2009 2010 2011 2012 2013 2014 2015
CONTRACT MANUFACTURING EVOLUTIONLa motivazione
ASPIRATIONS FOR NETWORKASPIRATIONS FOR NETWORKREORGANIZATIONREORGANIZATION
From To
• Fragmented network • Stable and flexible network g
• Complex product portfolio
• Underutilized capacities across sites and technologies
with strong launch capabilities
• Production of rewarded complexity only
• Appropriate capacity utilization of all technologies
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CONTRACT MANUFACTURING EVOLUTIONTYPES OF SITES IN FUTURE NETWORK
1 • Global/regional launch of products• G t th d t l hLaunch sites
Key market presence and
ongoing supply
• Guarantee smooth product launch• Preservation and further development of know-how and
expertise for key technologies (including new technologies)
2 • Focus on continuous, reliable low-cost supply• Production of mature products• Possible differentiation
–Large vs. small productsR /OTC N t l H lth
Competence centers for
specific technologies
–Rx/OTC vs. Natural Health
3• 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
CONTRACT MANUFACTURING EVOLUTIONNETWORK STRATEGIES OF MAIN COMPANIES – EXAMPLES
• Network optimization BMS
AZ • Development of launch site
Abbott • Cost focus (improvement in individual plants, benchmarking)
• Aggressive plant network optimization and coherent supply chain setup to capture lowest possible COGS
– A few plants focused by forms and volumes
– Launch sites
Novartis
• Network optimization and regionalization of Ops responsibility
• Process excellence/lean manufacturing
J&J
GSK • Second round of network optimization
• Multiple productivity and quality improvements per plant
Novo-Nordisk • Application of lean manufacturing across all plants to free up capacity, limit investments, and reduce costs
• Cost focus (plant network, investments)
• Launch capabilities (to some extent forced by Xenical)
Roche
– Truly global Ops responsibility and stringent SCM processes
Pfizer • Focus plant distinctiveness (lean)
Warner-Lambert • Development of launch site
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CONTRACT MANUFACTURING EVOLUTIONII. L’analisi e le scelte
Scegliere la strategia, analizzare l’impatto e Scegliere la strategia, analizzare l’impatto e implementare i miglioramentiimplementare i miglioramentiimplementare i miglioramentiimplementare i miglioramenti
CONTRACT MANUFACTURING EVOLUTIONL’analisi e le scelte
IMPROVEMENT IN MANAGEMENT SYSTEMS AND BUSINESS PROCESSES
Business process excellenceEfficient and fully integrated
•Develop new processes for – Third‐party management–Global network coordination (product/volume allocation)
– Best practice transfer (benchmarking)
Business process excellenceEfficient and fully integrated management systems
•Consolidate and streamline management meeting landscape to two key meetings
•Consolidate current fragmented planning tools in one central fact base for key decisions ( g)
CONTRACT MANUFACTURING EVOLUTIONL’analisi e le scelte
IDENTIFIED IMPROVEMENT MEASURES
Dedicated process engineering function at launch site
Defined quality gates (acceptance criteria) for development process
1
2
ProcessProcess Development Transfer Life cycle optimization
IIMMPPRROOVVEEMMEE Defined quality gates (acceptance criteria) for development process
Own global standards for excipients, materials, and other elements
Cross-functional alignment and management
3
4
NNTT
MMEEAASSUURREESS
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CONTRACT MANUFACTURING EVOLUTIONIII. Gli strumenti
Vantaggi e criticità di alcune scelte.Vantaggi e criticità di alcune scelte.Quali sono e come usare gli strumenti di analisi.Quali sono e come usare gli strumenti di analisi.
I. VERIFICA REGOLATORIAStato autorizzazioni, gap analysis,
integrazioni per importazioni
II. VERIFICA LOGISTICAII. VERIFICA LOGISTICASupply chain
III. VALUTAZIONE ECONOMICACosti fissi, addizionali e variabiliCosti fissi, addizionali e variabili
CONTRACT MANUFACTURING EVOLUTIONGli strumenti
VALUTAZIONE ECONOMICAVALUTAZIONE ECONOMICA
COSTI FISSI
• Costo A.P.I.
• Costo service
COSTI ADDIZIONALI
• Costo convalida interna produttiva/analitica
• Costo di convalida analitica per il rilascio del prodotto
COSTI VARIABILI
• Costo adattamento prodotto requisiti nazionali
• Costo per risk l i d• Costo service
• Costo Materie Prime
• Costo materiali di confezionamento
• Costo trasporto
• Costo di release
del prodotto• Costo stabilità on-going
e PQR• Costo mantenimento
certificazione EU• Costo qualifica interna
supply chain• Costo di adattamento
impianti (eventuali)
analysis prodotto
• Costo mantenimento progetto
• Costo derivante dalla riserva di sicurezza del prodotto
• Costo derivante dalle fluttuazioni monetarie
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CONTRACT MANUFACTURING EVOLUTIONGli strumenti
PRODUCT TECHNOLOGY TRANSFERPRODUCT TECHNOLOGY TRANSFER
Come dare un servizio, fare business ed Come dare un servizio, fare business ed evitare ritardi nello start up produttivoevitare ritardi nello start up produttivo
CONTRACT MANUFACTURING EVOLUTIONGli strumenti
THE MAJOR OBSTACLESTHE MAJOR OBSTACLESN 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• …..
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CONTRACT MANUFACTURING EVOLUTIONGli strumenti
PRODUCT TRANSFER MATERIALPRODUCT TRANSFER MATERIAL
STANDARD
GUIDELINES
•Transfer Standard
•Product transfer between manufacturing sites•Analytical technology transfers between sites
GENERAL PROCESS FLOWCHARTGENERAL PROCESS FLOWCHART
PRE-EVALUATIONPHASE
FEASIBILITYPHASE
PREPARATORY
Data collectionfor a first
appraisal
Preliminaryevaluation
Document preparation Detailed
evaluation Regulatory
ProjectDefinitionDocument
PREPARATORYPHASE
OPERATIONALPHASE
PROJECTCOMPLETION
ProtocolsMaterialsDocumentation Trial batches
and Process qualification Submission
Agency review Market approval(s)
Validation activities
CTP support
Regulatory Support
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CONTRACT MANUFACTURING EVOLUTIONGli strumenti
TRANSFER TEAM ORGANISATIONTRANSFER TEAM ORGANISATION
Analytical Dev.Analytical Dev.
Donor siteDonor site
QualityAssurance
QualityAssurance Equipment
& FacilitiesEquipment& Facilities
&Quality control
&Quality controlFinanceFinance
Manufacturing
IndustrialTechnologyIndustrial
TechnologyRegulatory
AffairsRegulatory
AffairsSupply chainSupply chain
ManufacturingPackaging& Artwork
CONTRACT MANUFACTURING EVOLUTIONGli strumenti
THE PROJECT LEADERTHE 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 andexecute a strategy that delivers the business benefit
PlanningProjectLeader
PlanningLeading
OrganizingControlling
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CONTRACT MANUFACTURING EVOLUTIONGli strumenti
PPLLOOCC ACTIVITES AND DELIVERIESACTIVITES 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 implementationDefine analytical methods transfer strategy
L’Assicurazione di QualitàL Assicurazione di Qualitànella scelta e nella gestione delle attività in outsourcing
Il processo di scelta di un possibile partner a cui affidare attività in outsourcingè un processo multifunzionale che deve essere gestito in accordo al Sistema diQualità sia del Committente sia del Fabbricante.
• Customer Service e Production Service LevelCustomer Service e Production Service Level• Scouting e auditing a fornitori• Implementazione file o software per calcolo costi per offerte e verifica aconsuntivo della redditività
• Implementazione Sistema QA per servizio al cliente (info su change,deviazioni, non conformità, ecc.)
• Adattamento del Regolatorio per supportare il cliente nelle attivitàregolatorie per il trasferimento della produzione e delle analisi relative
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CONTRACT MANUFACTURING EVOLUTIONGli strumenti
Assicurazione di Qualità
In ambito farmaceutico, il processo di selezione di un partner perp p pattività in outsourcing non solo deve tenere conto delle esigenzelogistiche, economiche e/o di fornitura, ma deve anche ottemperareai requisiti regolatori e GMP.
Capitolo 7 “Contract Manufacture andAnalysis” EU GMPAnalysis” – EU GMPCapitolo 6 “Quality Control” – EU GMPAnnex 16 “Certification by a Qualified
Person and Batch Release”
Sviluppo o adattamento di struttura per contrattualistica ecapitolati tecnici
CONTRACT MANUFACTURING EVOLUTIONGli strumenti
Ruolo QA
TechnicalTechnical AgreementAgreement
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 obblighinormativi;
E’ il documento essenziale e di riferimento per la gestione delle attività neltempo;
Deve essere redatto e sottoscritto tra le parti in modo da definirechiaramente, concordare e controllare le attività affidate a terzi;
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Deve essere redatto in modo da definire chiaramente le responsabilitàdelle parti:
• Acquisto materiali (reagenti, colonne, standard)• Modalità di campionamento• 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 dallaQP
Deve essere redatto da personale tecnicamente competente per quantoconcerne gli aspetti tecnici sia tecnologici, sia analitici, sia GMP, sialegali
Il contesto normativo
Technical AgreementTechnical Agreement
Codice civile
Decreto legislativo 14.04.06 n. 219 – codice deimedicinali
Legge 18.06.98 n. 192 – subfornitura
Decreto legislativo 6.09.2005 n. 2006 – codice delconsumo
CTP TECHNICAL AND LEGAL SUPPORT
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CONTRACT MANUFACTURING EVOLUTIONGli strumenti
“Quality by Design” “Quality by Design” per migliorare il servizio al cliente e ridurre i costiper migliorare il servizio al cliente e ridurre i costiper migliorare il servizio al cliente e ridurre i costiper migliorare il servizio al cliente e ridurre i costi
The main problem is variabilityPharmaceutical Products are of good quality. Quality itself is not the issue, butpharmaceutical development and manufacturing could be improved because:Uncontrolled variability in e.g. properties of the starting materials or themanufacturing process affects the quality of the medicinal product.
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CONTRACT MANUFACTURING EVOLUTIONGli strumenti
Quality by DesignScopeScope
How can variability be reduced?By obtaining increased process and product understanding in order toidentify and appropriately manage critical sources of variability and henceachieve “right first time” performance.Need for a shift in paradigm:From compliance
To enhanced product and process understanding
CONTRACT MANUFACTURING EVOLUTIONGli strumenti
D i d t t
Quality by DesignScope
Desired state:• 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 DevelopmentpIdentify critical material and process parameters affecting product quality (usingprior knowledge, risk management tools, DOE, MVA)Understand and if possible express mathematically their relationship with the criticalquality attributesDesign a process measurement system to allow on-line or at-line monitoring ofcritical quality attributesDesign a control system that will allow adjustment of critical quality attributesImplement a quality system that allows continuous improvement
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CONTRACT MANUFACTURING EVOLUTIONGli strumenti
Quality by DesignKey AspectsKey Aspects
ICH Q8: Pharmaceutical DevelopmentICH Q8: Pharmaceutical Development“Quality cannot be tested into products; quality should be
built in by design”
CONTRACT MANUFACTURING EVOLUTIONGli strumenti
Quality by DesignApplications
Pharmaceutical Development- Systematic, establishment of design spaceManufacturing process- Not set, but adjustable within design space- Lifecycle approach to validation: continuous process verification,
alternative strategies to the conventional 3 batches approachP t lProcess controls- PAT tools used with feed forward and feedback controlsProduct specifications- Based on desired product performance with relevant supportive dataControl strategy- Quality controls shifted upstream. Possibility of real-time release or
reduced end-product testing
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CONTRACT MANUFACTURING EVOLUTIONGli strumenti
Quality by DesignToolsTools
Regulatory tools to support the Desired state
Q lit Ri k M tQuality Risk ManagementTrack & Trending
DOCUMENT MANAGEMENT SYSTEM
CONTRACT MANUFACTURING EVOLUTIONGli strumenti
Quality Risk ManagementProcess 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 specificsources of harm (hazards) and to estimate the risk.
Risk evaluation compares the estimated risk against given riskcriteria using a quantitative or qualitative scale to determine thesignificance of the risk.
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CONTRACT MANUFACTURING EVOLUTIONGli strumenti
Quality Risk ManagementApplicationsApplications
1. Development (e.g. Specification Setting, Test Method Selection and processdevelopment).
2. Regulatory scrutiny during pre and post approval.3. As a component of Quality systems (e.g. Auditing, Deviations/Discrepancies,
control, Preventative maintenance and Computerized systems)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
CONTRACT MANUFACTURING EVOLUTIONGli strumenti
Track & TrendingScope
Reference guideline: ICH Q10
To use effective monitoring systems for process performance andproduct quality providing assurance of continued capability ofprocesses.
Identification and implementation of necessary product qualityimprovements, process improvements, variability reduction,innovations, and quality system tools, thereby increasing theability to consistently fulfil quality and financial requirements.Risk Management techniques may be used to identify necessaryareas for improvement.
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CONTRACT MANUFACTURING EVOLUTIONGli strumenti
Track & TrendingApplicationsApplications
Quality and financial toolsAnnual Product Review1. QA – QC Data Monitoring2. Process data Monitoring3. Engineering Data Monitoring5. Change Managing System6. CAPA Managing System7. KPIs System8. Toll Manufacturing Price Evaluation9. “Control panel”
Stream: Stock Reporting and ManagementMonFor: Supplier Performance MonitorScheduler: Production Order CompilerOrdProd: Efficiency in Production
CONTRACT MANUFACTURING EVOLUTION
Track & TrendingApplications
5. KPIs systemName Definition
Quality service level (QSL)Rate of justified complaintsAccident frequency rateCapacity utilization
Capex maint./depr.wPCI*
wMCI*
Yield**
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
(Capex for maintainance)/depreciationsDevelopment of production cost compared to base year, net of product mix changes
and inflation/devaluationDevelopment 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)
%ppmPpm%
%%
%
%
Qua-lity
Cost
Yield**Overall equipment
effectiveness (OEE)Turnover ratio forward (TRF)
Production service level (PSL)Intercompany service level
(ISL)Customer service level (CSL)
(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)
%
–
%
%
%
Time
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CONTRACT MANUFACTURING EVOLUTIONGli strumenti
Track & TrendingFurther development
Problem AnalysisThe Track and Trending activities will lead to the highlighting of the mainproblems affecting quality level, costs, deviations and complaintsOnce highlighted the main problems (i.e. yields, market complaints, assayuncontrolled trends, analytical failure investigations, on hold products, etc.)is suggested to put in place a “Pareto” analysis in order to set up priorities inthe recovery plant e eco e y p a
Problem solvingOnce given priorities and put in place a recovery plan is suggested toevaluate possible causes for each problem highlightedOne possible approach is the “bone fish analysis”Is suggested to involve people of the department / s where the problem issupposed to come from
Track & TrendingFurther development
Quality Output Standardization
In every production plant, during normal production activities, could be highlighted someproducts with defects by automatic checkers or by production or analytical personnelproducts with defects by automatic checkers or by production or analytical personnel.Once highlighted these defects is very important to have in place common and approvedlists for defect evaluations in order to quickly give to the personnel a tool for checking andevaluating the problem and put in action a quick, shared and effective remediationactivity including resampling or reworking.This would lead to a common “Quality Behaviour” in every plant of a multinationalcompany, would reduce the on hold time and costs and would give to personnel a common“Quality Feeling”.
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Data Warehouse and Quality Compliance Assurance System
Track & TrendingFurther development
Q y p yUsually, in every company, there are software up and running; they areoften customized for each department’s needs (AS400, SAP, LIMS, POMS,etc.)
Very often these systems are not connected and lots of data in them haveto be put in at least twice or extracted manually and managed with excelor access files.
Is suggested to have aggsimple software that couldlink all the systems in placeand extract data in order tohave graphics, trends orhighlight quality “alarms”
Data Warehouse and Quality Compliance Assurance SystemEXAMPLE
Track & TrendingFurther development
The QA-Process module contains two separate but integratedapplications that can share data:QA Management ToolGMP Event Monitoring & Tracking of Identification , Recording andmonitoring of process eventsDeviation ManagementComplaint ManagementCAPA ManagementChange ManagementMBR e EBR, Master Batch Record and Electronic Batch RecordAPR & QPR Annual & Quality Product ReviewGMP Production Tool sManagement of Production , Materials and Service Level KPIs