on the complexity of production planning and scheduling in the pharmaceutical industry: the...
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On the complexity of production planning and scheduling in the pharmaceutical industry: the Delivery Trade-offs Matrix
Samuel Moniz,a,b Ana Paula Barbosa-Póvoa,b Jorge Pinho de Sousa,a,c
aINESC TEC, Rua Dr. Roberto Frias, Porto, PortugalbCentro de Estudos de Gestão, Instituto Superior Técnico, Lisboa, PortugalcFaculdade de Engenharia da Universidade do Porto, Rua Dr. Roberto Frias, Porto, PortugalPSE2015/ESCAPE25| June, 2015
Research and Technological Development | Technology Transfer and Valorisation | Advanced Training | ConsultingPre-incubation of Technology-based Companies
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Agenda
1. The pharmaceutical industry
2. Critical factors for planning and scheduling
3. Scope of planning and scheduling problems
4. Delivery Trade-offs Matrix
5. Challenges and opportunities
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1. The pharmaceutical industry
• The shortage in new drug approval applications
• The uncertainty associated to Research and Development
(R&D) and trials I-III phases
• The pressure of generic drugs
Markets tend to become more complex over time, forcing companies to increase their responsiveness, both in terms of time and cost
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1.1. Some figures …
• Developing cost grew 481% to $802 million from 1970s to
1990s (DiMasi et al., 2003; Hynes III, 2009)
• The duration of the development cycle remained fairly
stable (roughly 15 years) (Kessel,2011)
• The production of the APIs is considered the rate-limiting
step of the supply chain (Shah, 2004)
The current worldwide paradigm imposes a reduction to less than 10 years (Federsel, 2009)
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1.2. Industry trends
• Adoption of continuous processes (Roberge et al., 2005)
• Process Analytical Technology (PAT) (McKenzie, 2006)
• Advanced optimization tools (Grossmann, 2005)
Production planning and scheduling are systematically considered very difficult functions to perform
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1.2. Pharmaceutical Industry System
Main activities
Research and development activities
Development and manufacturing of Active Pharmaceutical
Ingredients (APIs)
Drugs manufacturing
Primary manufacturing
Storage
Distributers StorageHospitals, clinics, pharmacies
Raw Material suppliers
Storage
Storage
Research and Development
Secondary manufacturing
(Shah, 2004)
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1.2. Pharmaceutical Industry System
Main activities
Research and development activities
Development and manufacturing of Active Pharmaceutical
Ingredients (APIs)
Drugs manufacturing
Primary manufacturing
Storage
Distributers StorageHospitals, clinics, pharmacies
Raw Material suppliers
Storage
Storage
Research and Development
Secondary manufacturing
(Shah, 2004)
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Issues
1.Manufacturing in a high regulated market
2.High variability on the demand
4.Pressure created by generic drugs
2. Critical factors for planning and scheduling: Market
3.Large production mixes in the manufacturing sites
Main Decision Areas
1.Pipeline management
2.Capacity planning
3.Supply chain management
(Laínez, Schaefer, & Reklaitis, 2012)
Shah (2004) and Buchholz (2010) pointed out that time-to-market is a critical driver of the pharmaceutical industry
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Issues
1.Process topology: sequential and network processes
2.Regulatory and quality procedures/lots traceability
4.Re-planning and rescheduling are frequent
2.1. Critical factors for planning and scheduling: Processes
Main Decision Areas
1.Product Development
2.Process design/scale-up decisions
3.Processes under development- limited knowledge of the first batches 3.Advanced Process Control
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Issues
1.Resources characteristics
2.Batch versus continuous manufacturing
2.2. Critical factors for planning and scheduling: Plants
Main Decision Areas
1.Plant design: grassroot and retrofit
2.Operating mode: short-term versus campaign mode
3.Inventory management and associated policies
3.Reduction of inventory
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3. Scope of planning and scheduling problems
Process Synthesis
Quantitative
specification of
physicochemical
materials manipulations
Planning and scheduling extended scope
Process Synthesis
Processscale-up
Process design Planning SchedulingProduction
execution and control
“Units independent”
recipe
Processing times,
quantities
Recipe +
Units
R&DOperations Management
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3.1. Scope of planning and scheduling problems
Process Synthesis
Quantitative
specification of
physicochemical
materials manipulations
Planning and scheduling extended scope
Process Synthesis
Processscale-up
Process design Planning SchedulingProduction
execution and control
“Units independent”
recipe
Processing times,
quantities
Recipe +
Units
R&DOperations Management
Process Scale-up and
Process Design
Develop the process
from the laboratory
scale to the industrial
scale
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3.2. Scope of planning and scheduling problems
Process Synthesis
Quantitative
specification of
physicochemical
materials manipulations
Planning and scheduling extended scope
Process Synthesis
Processscale-up
Process design Planning SchedulingProduction
execution and control
“Units independent”
recipe
Processing times,
quantities
Recipe +
Units
R&DOperations Management
Process Scale-UP and
Process Design
Develop the process
from the laboratory
scale to the industrial
scale
Planning and
Scheduling
Resources allocation so
as to minimize costs and
increase the plant
output
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3.3. Scope of planning and scheduling problems
Process Synthesis
Quantitative
specification of
physicochemical
materials manipulations
Planning and scheduling extended scope
Process Synthesis
Processscale-up
Process design Planning SchedulingProduction
execution and control
“Units independent”
recipe
Processing times,
quantities
Recipe +
Units
R&DOperations Management
Process Scale-UP and
Process Design
Develop the process
from the laboratory
scale to the industrial
scale
Planning and
Scheduling
Resources allocation so
as to minimize costs and
increase the plant
output
Production Control
Production dispatching,
control actions and
quality assessment
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3.4. Scope of planning and scheduling problems
The scope of the planning and scheduling functions must be extended to account for design decisions, especially for manufacturing products that are under development
Planning and scheduling extended scope
Process Synthesis
Processscale-up
Process design Planning SchedulingProduction
execution and control
“Units independent”
recipe
Processing times, quantities
Recipe +
Units
R&DOperations Management
Available alternative units
+ -
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3.5. Extended scope of planning and scheduling: How?
Flexible graphical representations of
process design and integration with
scheduling
(Moniz, Barbosa-Póvoa, Pinho de Sousa, &
Duarte, 2014)
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3.5. Extended scope of planning and scheduling: How?
Flexible graphical representations of
process design and integration with
scheduling
(Moniz, Barbosa-Póvoa, Pinho de Sousa, &
Duarte, 2014)
Frameworks for supporting the overall
decision-making process: product
portfolio, capacity planning, planning and
scheduling, process control and safety
and supply chain management
(Venkatasubramanian et al., 2006)
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Trials I-III
R&D
Drug F
Drug F
Drug ADrug A
Drug CDrug C
Drug BDrug B
Commercialization
Drug DDrug D
Drug E
Drug E
Understanding and modelling the
conditions for achieving the global
optimization of these
manufacturing systems is by itself a
hard task
The pharmaceutical industry
should focus on the manufacturing
and delivery issues knowing that
each phase of the development
cycle has different challenges
4. Delivery Trade-offs Matrix
Lot size
Few kilograms
Hundreds of kilograms
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Unc
erta
inty
Low
High
CostH
igh
Low
Shor
t-te
rm
plan
ning
Ca
mpa
ign
plan
ning
Time-to-market Amount delivered
Trials I-III
R&D
II
III IV
Drug F
Drug F
Critical leapDrug ADrug A
Drug CDrug C
Drug BDrug B
Commercialization
IDrug DDrug D
Drug E
Drug E
Exposes the issues that affect the
performance of the manufacturing
systems
Graphical representation of the
portfolio
Helps managing the trade-offs
occurring in the drug development
process
4.1. Delivery Trade-offs Matrix
Lot size
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Unc
erta
inty
Low
High
CostH
igh
Low
Trials I-III
R&D
II
III IV
Drug F
Drug F
Critical leapDrug ADrug A
Drug CDrug C
Drug BDrug B
Commercialization
IDrug DDrug D
Drug E
Drug E
Uncertainty and Costs
1.High uncertainty associated to the
drug structure and to the process design
2.Difficulties in estimating the required
time and resources
3.In the development and
manufacturing of APIs it is common to
allocate production resources 6 to 12
months in advance
4. Critical leap: the first scaled up batch
5. Challenges and opportunities
Opportunity: Simulation-optimization can provide interesting solution methods to combine the stochastic and deterministic parameters of the planning and scheduling problem
Chen, Mockus et al. (2012), Eberle, Sugiyama et al. (2014), Sahay and Ierapetritou (2014)
Lot size
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Unc
erta
inty
Low
High
CostH
igh
Low
Time-to-market Amount delivered
Trials I-III
R&D
II
III IV
Drug F
Drug F
Critical leapDrug ADrug A
Drug CDrug C
Drug BDrug B
Commercialization
IDrug DDrug D
Drug E
Drug E
Time-to-Market and Amount
Delivered
1. The delivery of products to Trials I-III
phases is of extreme importance
2. Fast and robust scalability of the
production processes
3. The inventory in the supply chain
provides flexibility om what concerns to
delivery dates
5.1. Challenges and opportunities
Opportunity: development of comprehensive methods capable of addressing the long–term dimension of the design and scale-up decisions
Varma, Pekny et al. (2008)
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Unc
erta
inty
Low
High
CostH
igh
Low
Shor
t-te
rm
plan
ning
Ca
mpa
ign
plan
ning
Time-to-market Amount delivered
Trials I-III
R&D
II
III IV
Drug F
Drug F
Critical leapDrug ADrug A
Drug CDrug C
Drug BDrug B
Commercialization
IDrug DDrug D
Drug E
Drug E
Operating Mode
1.Heterogeneous demand
2.Mixed planning strategies: short
term mode versus campaign mode
5.2. Challenges and opportunities
Opportunity: solution methods capable of addressing mixed planning strategies
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Final remarks
1. We group the critical factors for planning-scheduling decision-making in 3
categories: market, processes, and plants
2. We propose a representation of R&D and manufacturing trade-offs
3. The integration of process scale-up/design decisions with planning and
scheduling decisions is fundamental to do in the early stages of the drug
development cycle
4. Research addressing integrated decision-making, uncertainty, and knowledge
management is essential to solve extended planning and scheduling
problems
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Thank you!