jwdorpema, leiden, 10-11-20101 gmp for the 21 st century: gmp

jwdorpema, leiden, 10-11-2010 1

GMP for the 21st Century: GMP


QbD positioned

• QbD concerns the making of medicines• QbD is:

– The new (bio)pharmaceutical quality system– Replaces current GMP rules

– Not longer based on the trial error approach of drug substance and drug product development & production

– Instead it is a systemic, knowlegde and risk based quality methodology

– Complies with the general purpose of product quality: suited for use – Puts the patient in focus

– A quality system customized for (bio)pharmaceutics

QbD: GMP for the 21st Century


QbD workshop program

• Origin of QbD: why, where, what– Introduction – A-MAB case study– LSH-Biofarmind pilot

• How to apply QbD on biopharmaceutics: – 2 Presentations on the new quality system: how it is implemented– Replaces old GMP rules

• Regulatory consequences– 2 Presentations on regulatory impact– Requirements and demand, communication – Panel discussion: regulatory relief or extra burden– Take home messages


Time to market is long (> 12J) conservative (blockbuster) strategy

Expensive originator products substitution US 2009 = 66 % generics

Low consumer orientation see next slide

Moderate quality see next slide

Patent cliff pipeline gap

Moderate safety & efficacy phase IV and PMS imposed

Governmental control by GMP and market authorization

deterioration into paper quality terror and technical bureaucracy

Marketing and sales practices transparency lack

3 Crises (2009)

Economic

Microbiologic

Pharmaceutic

QbD: why?


%Anti depressiva 38Asthma 40Diabetes 43Arthritis 50Alzheimer 70Cancer 75

Avarage % of patients for which a group of drugs is ineffective Cancer: MAB with billions sales/y performs

clinical 5-10% above placebo and show a QOL of 0.5 y.

Note: this is not an exemption, rather common rule

Low consumer directed

Moderate quality

Sigma ppm Defects Yield (%) Cost of Quality (%)2σ 308.537 69,2 25-353σ 66.806 99,3 20-254σ 6210 99,4 12-185σ 233 99,98 4-86σ 3,4 9.999.966 1-3

Pharma scores high % defects (rejections, recalls): 2-3 sigma. ICT , medical devices and automotive score 6 sigma.

Pharma performance: moderate?

jwdorpema, leiden, 10-11-2010

Message: time to change

Political issued Late senator Kennedy

Health care inspired FDA initiative (ICH inspired)

Marketing and sales decided Health care directed marketing policies

Financial controlled Profitability risk management

Technical executed Quality by Design (QbD)

Clinical fuelled Translational Medicine Research (TMR) = input

Patient directed Personalized medicine

Science guided Molecular & system biology and nanotechnology innovations to change the making of (bio)pharmaceuticals

Process driven New business model centred around the redesign of the making of (bio)pharmaceutics i.e. QbD

Result: “the faster, cheaper and safer mandate”

6


Faster, cheaper and safer mandate

• Western world wages: • the costs in the EU to employ someone are $ 300.000. • In China $ 100.000 ( source: US multinational)

• How to compete than?– Create trade barriers – Change business model: options

– Innovate, perform better and stay ahead (previous slides)– License in R&D– Outsource – Market access strategies– Join them– Become virtual


Business Life Cycle

Time

Pow

er

Life cycle

START GROWTH MATURE DECAY

© JWD/2004

PHASES


Business Competences

Time

Pow

er

Life cycle


© JWD/2004

SCIENCE TECHNOLOGY & MARKETING

MARKETING & FINANCAL

LEGAL

PHASES

Business Expertise


Business Dynamics

Time

Pow

er

Life cycle


© JWD/2004



LEGAL

PHASES

Business Expertise

R

5% Cost

Activity

10 -15 %

Dev. Manuf.

15 -20 %

M & F

60 %


Business Dynamics

Time

Pow

er

Life cycle


© JWD/2004



LEGAL

PHASES

Business Expertise

R

5% Cost

Activity

10 -15 %

Dev. Manuf.

15 -20 %

M & F

60 %

EntitiesUn SME Multinationals


Business Model

• Business model has become uniform & universal: also for sectors such as ict, nanotechnology & mechatronics, automotive ect.

• Features• Like all multinational controlled business the financial strategy is dominant• Earlier vertical integration replaces by horizontal integration• QbD alone is not enough to make the change

• R= 5%• D = max 15%

• Affects the whole (bio)pharma business• Does also affect the biogeneric business• Based on the principle: only profitable business sustains• Dominating issues:

o How to stay in the business of ever growing health care cost?o Comply with the fcs mandate


QbD position in business model

• Without R&D no innovative products• Do we really need QbD?: the conservative criticism

• “All the billions of dollars poured into research and development in the U.S. wont mean a thing”

• “We must streamline and strengthen the regulatory science” • Areas cited where this is being accomplished include FDA’s

partnership with ICH around Quality by Design (QbD)

New FDA commissioner Margaret Hamburg’s keynote address at Regulatory Affairs Professionals Society annual conference in Philadelphia, September 2009

Conclusion: QbD is the method to innovate (bio)pharma industry


• DOE (1920s: factorial designs in agriculture)• FMEA (US Military development; combined software available)• Launched through FDA report: “Pharmaceutical cGMPs for the 21st Century (August

2002)”• ICH spin off: perception of reality (“ time to change”)• Implies a strategic change towards the presentation of more scientific knowledge in

submissions• Shortly afterwards FDA issued the guidance document “PAT – a framework for

Innovative Pharmaceutical Development, Manufacturing and Quality Assurance (Pat doc. discusses many principles of QbD); finalized in 2004

• PAT plays a pivotal role in the QbD process

Message: systemic product and process development replaces current trial & error approach

QbD origine


QbD frame (in ICH docs)

Definition QDb: a systemic approach to pharmaceutical development that begins with predefined objectives and emphasizes product and process understanding based on sound science and quality risk management

1. The QbD frame contains concepts and tools - e.g. design space - to practice QbD in a submission file (design space approval)

2. The selection of QbD implies the use of Quality Risk Management (ref.: ICH 9, Quality Risk Management)

3. The connection to a suitable (bio)pharmaceutical quality system offers opportunities to enhance science ad risk based submissions approaches

Ref: Q8 Annex

Message: QbD considers pharmaceutical development


Pharmaceutical Development

Purpose:

• “to design a quality product such, that the manufacturing of it continuously delivers a drug product suited for is purpose”

Ref: Q8 (R1) June 2009, p2


Quality by Design (QbD)

Basics: • a systemic (multivariate statistics) development and manufacturing by use

of prior knowledge,• risk assessment guided design and process control,• combined molecular and system biology based diagnostics - therapy

solutions for disease treatment,• through the total life cycle of a product (continuous improvement).

Implications:• Quality back to the roots: product suited for its purpose• Quality is dynamic: continuous improvement• Quality must be build in• Quality means first time right

Message: CONSUMER = PATIENT directed


QbD: away from the specifications trap

Patient Idea Design Space Control Strategy Risk Assessment Product Life Cycle

Idea Development Preclinical & Licensing Manufacturing M&S Clinical testing

Traditional

QdB

Patient first: the chain is reversed


QbD: what are the issues?

• Quality itself is not the issue, but pharmaceutical development and manufacturing has to be improved

• Improve how: we need to get it right first time and then continue to improve )

• The problem is (uncontrolled) variability • Varibility is reduced by obtaining increased process and product

understanding leading to first time right performance

• Paradigm change: from regulatory compliance to enhanced product and process understanding


PWC view: the supply & availability of medicines

Today

2020

Patho-Physiology

Molecule Submission In-Life Development Testing

Development of a molecule only when the company is confident that the mechanism of action works

CIM

CIM

CIS

CIS

Launch

CIM = Confidence in Mechanism (half way Ph II)

CIS = Confidence in Safety (end Ph II)

Ref.: PWC Pharma 2020: The vision, Which path will you take?

Discovery Lead Pre-Clinical Phase I, II Phase III Submission Phase

& Screening Development Evaluation IIIb/IV

Launch


PWC view & QbD

Approach & Tools

2020

Patho-Physiology

Molecule Submission In-Life Development Testing

Development of a molecule only when the company is confident that the mechanism of action works

CIM

CIS

CIM = Confidence in Mechanism (half way Ph II)CIS = Confidence in Safety (end Ph II)

Ref.: PWC Pharma 2020: The vision

First Time Right

&

Continuous improvement

Develop enabling capabilities

Implementation phase

< 10.209

Ontwikkeling

Onderzoek

Productie

KontroleVerpakking/distributie

Toelating

Vermarkting

Patient

Quality by Design

Translational medicine

Eerste keer meteen goed &

Continue verbetering

Lean en sigma

In life testing

Ontwikkeling en maken van een geneesmiddel: nieuw


Develop enabling capabilities

Implementation phase

< 10.209Packaging/distribution

Market Authorization

Market Acessand Sales

Patient Research

Development

Production

ControlQuality by Design

Translational Medicine Research

First time right

&

Continuous improvement

Lean &

6 sigma

In life testing

Development & production of biopharmaceutics: new


QbD: implementation

• Adoption by industry goes slow: why?

• Business must be clear• Planning of the implementation in a way that takes near and long

term returns in account• Quality needs planning (Juran 1992): companies generate much

quality-related waste by redoing work already done

• QbD: an opportunity that brings business benefits for the entire organization

• Basic message is: Control the design and you control the lifecycle


QbD: what does it bring?

• Time to market reductions: from 12 to 6 years realized by amongst others

• First time right: lean assets management

• Continuous improvement over the total product life cycle (i.e. controlled, patient guided variability)

• Absence of design freeze (no variation issues)

• Less validation burden

• Real time controls (less batch controls)

• Increased price control

• Realistic risk perceptions

• Contributes substantially to realize the better, cheaper and safer mandate

jwdorpema, leiden, 10-11-20101 gmp for the 21 st century: gmp

Documents

gmp slide

business dynamics slide

slide moderate quality

biopharmaceutics qbd

qbd process

business model business

century slide

qbd result