the impact of quality by design on modern manufacturing · 2012. 7. 4. · –the pipeline has been...

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


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


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


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 …


….. to 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 .

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


Gerry Migliaccio, 2011



KQA = key quality attribute


Quality by Design results in a robust

process and enables rapid

improvements in process capability


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 !


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.


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 ??


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


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

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