On the complexity of production planning and scheduling in the pharmaceutical industry: the Delivery Trade-offs Matrix

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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

June 2015 PSE2015/ESCAPE25 2

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


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


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)


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


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)


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)


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


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


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


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


3.1. Scope of planning and scheduling problems

Process Synthesis

Quantitative

specification of

physicochemical



Process Synthesis

Processscale-up




recipe

Processing times,

quantities

Recipe +

Units


Process Scale-up and

Process Design

Develop the process

from the laboratory

scale to the industrial

scale



Process Synthesis

Quantitative

specification of

physicochemical



Process Synthesis

Processscale-up




recipe

Processing times,

quantities

Recipe +

Units


Process Scale-UP and

Process Design

Develop the process

from the laboratory


scale

Planning and

Scheduling

Resources allocation so

as to minimize costs and

increase the plant

output



Process Synthesis

Quantitative

specification of

physicochemical



Process Synthesis

Processscale-up




recipe

Processing times,

quantities

Recipe +

Units


Process Scale-UP and

Process Design

Develop the process

from the laboratory


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



The scope of the planning and scheduling functions must be extended to account for design decisions, especially for manufacturing products that are under development


Process Synthesis

Processscale-up




recipe

Processing times, quantities

Recipe +

Units


Available alternative units

+ -


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)


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)


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


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


Unc

erta

inty

Low

High

CostH

igh

Low

Trials I-III

R&D

II

III IV

Drug F

Drug F


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


Unc

erta

inty

Low

High

CostH

igh

Low


Trials I-III

R&D

II

III IV

Drug F

Drug F


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)


Unc

erta

inty

Low

High

CostH

igh

Low

Shor

t-te

rm

plan

ning

Ca

mpa

ign

plan

ning


Trials I-III

R&D

II

III IV

Drug F

Drug F


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


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


Thank you!

Science

On the complexity of production planning and scheduling in the pharmaceutical industry: the Delivery Trade-offs Matrix