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Dr Tom Sam
Secretary
FIP’s Industrial Pharmacy Section
The impact of Quality by Design
on Modern Manufacturing
FIP - Who we are
The International Pharmaceutical Federation
(FIP) is the global Federation of national
associations of pharmacists and pharmaceutical
scientists.
Through our 127 Member Organisations in over
80 countries FIP represents more than one
million pharmacists and pharmaceutical
scientists worldwide.
2
FIP has 127 member organisations
?!
Board of Pharmaceutical Practice
Board of Pharmaceutical Science
Cooperation with WHO
FIP’s Industrial Pharmacy Section
www.fip.org/industrial_pharmacy
www.fip.org
Dr Tom Sam
Head Medical Devices & EU API support Global CMC Regulatory Affairs
MSD
The impact of Quality by Design
on Modern Manufacturing
THE STATE OF THE PHARMACEUTICAL
INDUSTRY
Where is it going?
• Global Sales growing at <5%
• R & D costs rising but with low productivity
• Development is complex with large clinical trials and
high late stage failure
• Sales are constrained by few “new” products and
competitive global markets
• Distribution is global and security & integrity of supply
is a challenge
• Structure of industry evolves with consolidation,
partnerships and outsourcing
Prof. Cooney, MIT, presentation PBP World meeting, Istanbul, 2012
Multiple lenses on Product and
Process Development & Operation
• The Discovery Lens – The pipeline has been flat over 50 years
– Increased potency and decreased dose
– Use of molecular diagnostics in prescribing therapy
– Platform technologies: monoclonal antibodies and vaccines
– High cost of discovery for a “flat discovery pipeline”
FAILURE is expensive
• The Market Lens – Patent expiry Generic vs. innovator products
– Country by country regulatory filing to access global markets
– Global manufacturing
– Pressure to reduce price and increase access
– Security and integrity of supply chain
8
Prof. Cooney, MIT, presentation PBP World meeting, Istanbul, 2012
Multiple lenses on Product and Process Development & Operation
• The Clinical Lens – Increasing molecular complexity
– Large number of drug candidates in “clinical analysis”
– Personalized medicine with companion diagnostics
– Biosimilar versus Biobetter products
• The Regulatory Lens – Focus on risk
– Quality by Design
– Post marketing surveillance
– Compliance
– Global production, distribution and harmonization
9
Prof. Cooney, MIT, presentation PBP World meeting, Istanbul, 2012
Assessing the Critical Challenges going forward
• Discovery is linked to the target assay and not the patient
• Discovery, development, regulation and manufacturing is
constrained by analytics
• There has always been and always will be variance
• Markets are increasingly global and security and integrity
of supply must evolve in synchrony
• We operate in intellectual and organizational silos but we
must communicate
• Acknowledging, managing and accepting risk is a cultural
and intellectual challenge
10
Prof. Cooney, MIT, presentation PBP World meeting, Istanbul, 2012
THE PATH FORWARD IS CHALLENGING
BIOTECHNOLOGY &
PHARMACEUTICAL
INDUSTRY R&D
PRODUCTIVITY
COST OF MANUFACTURING
PRICING PRESSURES
PATENT
EXPIRATION
11
Quality by Design:
Changing the Model
“QbD requires a through understanding of a
product and its process of manufacture …
For QbD, the product and process
knowledge base must include an
understanding of variability in raw materials,
the relationship between a process and
product critical quality attributes, and the
association between CQAs and a product’s
clinical properties.”*
*A. S. Rathorne & H. Winkle Nat. Biotech. Jan 2009
12
QbD - a Systematic Approach to Product and Process Design through
ANALYTICS • Target Product Profile (QTPP)
• Determine critical quality attributes (CQAs)
• Link raw material attributes and process
parameters to CQAs
• Conduct a risk assessment
• Develop a design space
• Develop a PAT strategy – linking measurement to
theory
• Design and implement a control strategy
• Manage the product life cycle with continuous
improvement.
13
What is Quality by Design ?
From quality by testing to …
What is Quality by Design ?
….. to quality by design !
What is Quality by Design ?
Quality by Design “Quality cannot be tested into the system”
2 /Q11
Opportunities to apply Quality Risk Management
Knowledge management Technical
Transfer
Patient
Needs
Business
needs
Product
design
Control
Strategy
Manu-
facturing
Process
design
Re
se
arc
h a
nd
cli
nic
al s
tud
ies
Co
mm
erc
ial
Man
ufa
ctu
ring
PAI Inspections
Quality
Target Product
Profile (QTPP)
Critical
Quality Attribute
(CQA)
Critical Process
Parameter
(CPP)
Technical
Regulatory
Filing & Review
Performance
Review &
Change Control
Opportunities to apply Quality Risk Management
GMP Inspections
approx.
life cycle
time
1/4
3/4
Process understanding
Co
urt
es
y F
igu
re:
Ste
ph
an
Rö
nn
ing
er,
Ro
ch
e
See a
lso
ICH
Q-I
WG
tra
inin
g s
lid
es
It is important to have one integral systematic approach towards QRM
across the development and manufacturing departments
Pharmaceutical Development
Technology Transfer
Commercial Manufacturing
Product Discontinuation
Investigational products GMP
The PQS introduces a life cycle perspective
Management Responsibilities
Process Performance & Product Quality Monitoring System
Corrective Action / Preventive Action / CAPA System
Change Management System
Management Review
PQS
elements
a. Knowledge Management
b. Quality Risk Management
enablers
Pharmaceutical Quality System
Source: Quality system elements from the Q10 graph
List of PIC/S members America
• Canada
• Argentina
• USA
• Brazil • (Mexico)
Africa
• South Africa
• (Nigeria)** • (Uganda)
• (Zambia)
• (Zimbabwe)
Australia
• Australia
• New Zealand
membership requested
* application expected in 2012
interested countries/parties
** pre-assession
Asia
• Malaysia
• Singapore
• Indonesia
• Iran
• Japan
• Philippines
• South Korea*
• Thailand (?) • (China)
• (Chinese Taipei)
• (Hong Kong, China)
• (Oman)
• (Saudi Arabia)
Europe
• Austria
• Belgium
• Cyprus
• Czech Republic
(H/V)
• Denmark
• Estonia
• Finland
• France (H/V)
• Germany
• Greece
• Hungary (H/V)
• Iceland
• Ireland
• Israel
• Italy
• Latvia
• Liechtenstein
• Lithuania
• Malta
• Netherlands
• Norway
• Poland
• Portugal
• Romania
• Slovak Republic
• Spain
• Sweden
• Switzerland
• United Kingdom (H/V)
• Ukraine
• Slovenia • (Armenia)**
• (Bulgaria)
• (Croatia)
• (Georgia)
• (Hungary)
• (Russia)
• (Serbia)
• (Turkey)
Partner
• EDQM
• EMEA
• UNICEF
• WHO • (ASEAN)
Application of risk assessment in GMP inspections
• A simple and flexible Quality Risk
Management tool for the frequency
of GMP based inspections
implementing a risk ranking
approach
• Rating of manufacturing sites
based on an estimated risk that
they may pose to patients,
consumers, animals and users of
medicines and product quality
IFPMA RPTS meeting, Copenhagen, March 2012
PIC/S Expert Circle on QRM: http://www.picscheme.org/bo/commun/upload/document/pi-037-1-
recommendation-on-risk-based-inspection-planning-copy2.pdf .
• Applied by inspectorates this will
recommend
– A frequency for routine inspections at a site
– The scope of the next inspection in terms of
focus and depth
• Documentation by site – Preliminary Information
– Intrinsic Risk (i.e. complexity of the site, its
processes and products, and the criticality of
the products manufactured)
– Compliance risk and previous site inspection
performance
– Overall risk rating
– Inspection frequency
– Scope of the next Inspection
– ‘Who and when’
IFPMA RPTS meeting, Copenhagen, March 2012
PIC/S Expert Circle on QRM: http://www.picscheme.org/bo/commun/upload/document/pi-037-1-
recommendation-on-risk-based-inspection-planning-copy2.pdf .
Application of risk assessment in GMP inspections (2)
MSD/Merck Fully Supports QbD
• MSD/Merck has embraced QbD as a strategic initiative
on how we develop and manufacture products
– QbD provides a consistent framework for developing high
quality products that provide benefits to our patients and
meet our customer’s needs
– QbD promotes systematic, scientific and risk-based
approaches to product and process development
• MSD/Merck is executing a company-wide QbD strategy
and playbook
• All of MSD’s/Merck’s development programs now follow
the QbD approach
– Work processes are established to realize MSD’s/Merck’s
QbD strategy
MSD/Merck Experiences with QbD
• Initial QbD filing in 2006 as part of FDA QbD pilot program – Led to real-time release testing approval on a high-volume
product
– Since registered in 80+ markets world-wide
• Subsequently used QbD approach in development on all programs, introducing innovative elements such as – use of PAT for feed-back and feed-forward control
– use of models for stability evaluations
– filing and approval of dimensionless scalable design spaces and control strategies
– clinically relevant specifications
• Company-wide approach includes small molecules as well as biologics/vaccine products
Experiences with QbD Product
• Longest running example with 6 years of production
• High-volume tablet product – Actual production was multiple times initial forecast
• Very robust process resulted in: – No process-related atypicals in initial manufacturing site
in 5 years
– Efficient manufacturing including real-time release testing (75% reduction in Quality Cycle Time)
– Volume increase supported with limited manufacturing capacity
– Successful transfer to two subsequent manufacturing sites
The Journey to Operational Excellence
is Enabled by Quality by Design
Demonstrated Benefits of QbD
1. Enhanced Process Understanding
2. Higher Process Capability
3. Better Product Quality
4. Increased Flexibility to Implement
Continuous Improvement Changes
5. Value!
Note that much of the QbD investment occurs in process development,
and the benefit is realized in commercial manufacturing
1. Higher Process Capability
Gerry Migliaccio, 2011
2. Higher Process Capability
Gerry Migliaccio, 2011
KQA = key quality attribute
2. Higher Process Capability
Quality by Design results in a robust
process and enables rapid
improvements in process capability
Gerry Migliaccio, 2011
In process improvement efforts, the process performance index Ppk
is an estimate of the process capability of a process during its initial set-up,
before it has been brought into a state of statistical control.
3. Better Product Quality
2007 deviation rates for three tablet products
manufactured in same facility
QbD resulted in a lower deviation rate in the 1st year after launch
than achieved through traditional continuous improvement efforts !
Gerry Migliaccio, 2011
4. Increased Flexibility
• Demand for 1st QbD product was 4X forecast
• Due to a well‐developed design space, the
site was able to increase productivity by 66%
by optimizing process parameters within the
design space –
no regulatory filing required.
• Further improvements were made by
expanding the design space with appropriate
regulatory submissions.
Gerry Migliaccio, 2011
5. The QbD Value Proposition
– Product/Process design
– “Lean by Design” equals $$$
– Process/Product robustness
– Reduce defects, rejections, investigations
– Process control
– Reduce testing, inventory costs
– Improved yields, Cost of Goods
– Regulatory flexibility (QbD Filing)
– Continuous improvement
• But where do we go from here ??
Gerry Migliaccio, 2011
Real-time Release Testing
Real Time Release Testing
• Shift of analytical control from an off‐line, post‐ manufacturing approach to an approach where data is generated during manufacturing.
• RTRT does not mean less testing, in fact it often means more analytical data is generated !
• Provides for control closer to the source of variability in the process.
• Allows for Real Time Release Testing of the batch.
• Regulators have already demonstrated their willingness to review and approve RTRT submissions. Gerry Migliaccio, 2011
GE Analytical Instruments
The RTRT Value Proposition
• Reduced Quality Control Lab costs
– Reduced throughput time
– Reduced inventory
• Experience to date indicates
pay‐back time of 12 months
– Dependent on product volume
– Dependent on required upfront investment
– Dependent on inventory value
Gerry Migliaccio, 2011
Industrial
Pharmaceutical
Innovation
1. Incremental Innovation: new dosage forms, new formulations, new packaging. Supply chain with increased safety of distribution, etc.
2. Stepwise Innovation: different molecules of one chemical family offering meaningful differences in properties, such as indications, side effects, and drug metabolism. Replacing batchwise production by continuous manufacturing rendering the product much more affordable, a paradigm shift such as Quality by Design; etc.
3. Breakthrough Innovation: a genuine new approach to a disease, or a New Chemical Entity (NCE); nanotechnology, etc.
Technological
Innovation
Innovation
Quality by Design – macro perspective
QbD principles also hold
• for the regulatory system itself. If you want to have the system to have a certain quality this should be built into the system and into the processes; it cannot be added as an afterthought
• not only for the products to be developed, but also for registration files to be reviewed and industries to be audited.
Quality by Design – macro perspective
• What do we want the regulatory system to be? - easily maintainable: good change system - policies based on sound science - considering the needs of all stakeholders (HAs, companies, society) - efficient and effective - predictable and reliable - stimulating rather than blocking innovation
• A big step forward is to work in a harmonized environment, applying scientific and risk based decision making.
• Harmonized environment
– ICH
– PIC/S
– EDQM / EP
• Science and risk based
If you want to go fast, go alone.
If you want to go far, go together.
African Proverb
Acknowledgement
• Charles Cooney, MIT
• Gerry Migliaccio, Pfizer
• Stephan Roenninger, Roche
• Gert Thurau, Merck