1 Challenge: Make High Quality Medicines...

Ajaz S. Hussain, Ph.D.

Ajaz S. Hussain, Ph.D., Chief Scientific Officer

Challenge: Make High Quality Medicines Affordable

4/10/2013

1

Fort Aguada; 16th-century Portuguese fort


My personal point of view

4/10/2013

2

B.Pharm.

CSO VP Biopharmaceuticals CSO

Deputy Director Office of Pharmaceutical Science

Associate Professor of Pharmaceutics (tenured)

Assistant Professor of Pharmacy

Ph.D. Interdisciplinary


Returning to Pharma, added appreciation for…

4/10/2013

3

After several years of thinking about how to achieve tobacco harm

reduction

Predictors of human behavior? Decision-

making in the presence of risk?

Behavioral economics

Ajaz S. Hussain. SWISS PHARMA 34 (2012) Nr. 6. The notion ‘by design’, in the phrase ‘Quality by Design’, conveys an intention to deliver a product or service with a pre-defined ‘quality’ so as to satisfy intended customers.

Why econometrics?


Outline

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4

• Reflecting back to articulation of ‘Vision 2020’ >>> ICH Desired State • Focus was on chemometrics and pharmacometrics Background

• Manufacturer “acceptability” increasingly an important driver • Making quality affordable

Topics selected for discussion & why?

• Maintain high quality - At high rate of capacity utilization • QbD for complex products - Under high level of uncertainty

A high level over view of my learning: How to …

• Comparable quality (pharmacovigilance) and • Metrics to measure performance of an organization What should we measure?

• And closing thoughts Summary


In 2000 @ FDA – anticipation of changes needed by 2020

4/10/2013

5

www.fda.gov/ohrms/dockets/ac/01/slides/3804s1_02_hussain.ppt

PAT Initiative è Pharmaceutical Quality for 21st Centuryè ICH Initiative

Real-time and remote inspection was deemed “too radical” (in 2000)


A simple idea - improved understanding is needed for risk management

4/10/2013

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“I can see clearly now” - Vision 2020

¤ Perspectives on Regulation: Law,

Discretion, and Bureaucratic Behavior (Kagan and Scholz, May 1980)

n ‘Good citizens’ Vs. {‘political citizens, ‘incompetent’, and/or ‘amoral’}

¨ For FDA to be risk-based it needs scientific data & information, capability, ..

CORRELATIVE KNOWLEDGE What Is Correlated to What?

“CAUSAL" KNOWLEDGE What “Causes” What?

MECHANISTIC KNOWLEDGE

How?

DESCRIPTIVE KNOWLEDGE: What?

Nee

d fo

r reg

ulat

ory

over

sight

Know

ledge based decisions

Desired State

Current State

First Principles Why?

http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4052B1_09_Hussain-Arden-UK-Presentation.ppt


21st Century Opportunities

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¨ “Pharmaceutical (development and) manufacturing is evolving from an art form to one that is now science and engineering based”.

¨ “Effectively using this knowledge in regulatory decisions in establishing specifications and evaluating manufacturing processes can substantially improve the efficiency of both manufacturing and regulatory processes.”

www.fda.gov/ohrms/dockets/ac/04/.../2004-4052S1_01_Hussain.ppt


Two topics, established fundamentals, a way forward…let me know if you agree, if not, why?

4/10/2013

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Manufacturer “acceptability” increasingly an important driver • Who makes the medicines I take?

Pride of workmanship is key to delivering manufacturers’ acceptability • I make the medicines you take

Making quality affordable • A system which encourages design thinking and continually

reduces process entropy


Example: Pride of workmanship

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Disc

iplin

e an

d Ti

me

Man

agem

ent: • “These disciplined

workers work perpetually and effectively in a city that movement is difficult due to the extremely high number of residents. They have received World record in best time management.”

Mot

ivat

ion:

• “The dabbawalas are highly motivated individuals. Their job is very important. It is a very big deal in India if a customer does not receive his box on time or even receives a wrong box.”

Inte

rdep

ende

nce

and

trus

t: • “There are many small groups and each group has to be responsible for itself and for every other group. So there is a high interdependence. If one team is not working well then the whole procedure is at risk.”

http://www.strategicmanagement-sixsigma.com/2011/06/mumbai-dabbawalas.html


Example: Pride of workmanship (cont.)

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Clo

se to

the

cust

omer

• “They are very close to the customer. They try to satisfy the need of every customer by taking and delivering on time with no mistake.”

Trai

ning

tim

e • “Three months is the training time and a practice test in order somebody to be a dabbawala. In contrast big companies like Mc Donald’s spend less than one day to train their employees.”

Smal

l Gro

up F

orm

atio

n • “A group consists of few people with a supervisor. The team members share the revenue. Trust and respect are the raw materials that describe a group.”

http://www.strategicmanagement-sixsigma.com/2011/06/mumbai-dabbawalas.html


Why is this talk relevant to IPA members?

4/10/2013

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Increasing generic competition has been an

important policy consideration for several

years

Beyond the traditional oral dosage forms the generic drug approval

model faces many challenges

Global consensus - the generic model is not

applicable for biotechnology products

Beyond the current ‘patent cliff’ generic

companies are looking towards complex

generics, biosimilars and NCE products


Manufacturer “acceptability” increasingly an important driver

Who makes the medicines I take?

4/10/2013

12


Today’s challenges

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Increasing complexity and uncertainty • Complex products (e.g., MDI/DPIs, biosimilars) • Evolving regulatory pathways; hence uncertainty • Local to global markets; reducing variability

Erosion of public trust • Shortage of injectable products • Falsified and substandard drugs • Other factors


Public trust is the bed-rock of our industry

4/10/2013

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¨ Perceptions do matter!

JAMA, March 5, 2008—Vol 299, No. 9

http://management.fortune.cnn.com/tag/generic-drugs/


Continual effort needed to counteract forces that erode public trust

4/10/2013

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Shortage of injectable products in the US

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• “Cancer drug shortages cause treatment, research problems” (http://www.oncologynurseadvisor.com/cancer-drug-shortages-cause-treatment-research-problems/article/287359/)

• “Drug shortages spur debate over role of compounding pharmacies” (https://home.modernhealthcare.com)

Previous week news

• “Drug shortages at all-time high” (CNN; June 2011)

• “New effort to reduce drug shortages a small step” (Business Week; October 2011)

News in 2011


Today’s challenges.. Not different from challenge a decade ago.... Different companies

4/10/2013

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¨ Reflecting back to 2000 ¤ How is the situation

different today? n Then few generic injectable drugs;

current injectable shortage predominantly generic manufacturers

¨ Reflecting back to early 1990’s ¤ We were getting beyond

the ‘generic drug scandal’


Several efforts to understand & correct….

• “The rapid increase in volume

and scope … high rate of capacity utilization in the [generic] industry. At these high levels … difficult to maintain manufacturing quality levels and any disruptions to supply – through, for example, quality problems …..– can lead to cascading and persistent shortages.” [emphasis added]

Economic analysis of the causes of drug

shortages (ASPE Issue

Briefing October 2011)

• “Drug shortages in the

US point to a need to differentiate manufacturers by reliability.”

• “FDA could support the buyers and payers in their purchase and reimbursement decisions by providing them with meaningful manufacturing quality metrics.”

Economic and

technological drivers of

generic sterile

injectable drug

shortages (J. Woodcock and

M. Wosinska (2013))

4/10/2013

18

http://aspe.hhs.gov/sp/reports/2011/drugshortages/ib.shtml http://www.nature.com/clpt/journal/v93/n2/abs/clpt2012220a.html


Global product safety and quality

4/10/2013

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http://www.fda.gov/downloads/aboutfda/centersoffices/oc/globalproductpathway/ucm259845.pdf

“…prepared for a regulatory environment in which product safety and quality know no borders”


Asian middle class: A dominant market by 2020

4/10/2013

20

http://www.jana.com/blog/the-battle-for-the-emerging-middle-class/

Indian Pharma

Growth drivers

• 55 billion USD by 2020 (base case)

• Acceptability • Accessibility • Affordability • Epidemiological

factors

http://online.wsj.com/public/resources/documents/McKinseyPharma2020ExecutiveSummary.pdf


Manufacturer “acceptability”…..

4/10/2013

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Historically, in the Asian context – “Traditional vs.

Western” medicine

“Patients are not consumers” – but this distinction is

eroding

Increasingly a concern – “not

manufactured here”

(The Asian middle class) more

conscious on where a product is

manufactured


Key points: Established and emerging need to..

4/10/2013

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• Maintain high quality • At high rate of capacity utilization

• QbD for complex products • Under high level of uncertainty

Build/maintain public trust

• Product safety and quality know no borders • Utilize meaningful manufacturing quality metrics

Differentiate manufactures by

reliability


Maintain high quality

At high rate of capacity utilization

4/10/2013

23


Top FDA 483 citations in 2012 (Drugs)… no significant change in this list since…

4/10/2013

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The responsibilities and procedures applicable to the quality control unit are not [in writing] [fully followed]. 169 There is a failure to thoroughly review [any unexplained discrepancy] [the failure of a batch or any of its components to meet any of its specifications] whether or not the batch has been already distributed.

119

There are no written procedures for production and process controls designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess.

116

Laboratory controls do not include the establishment of scientifically sound and appropriate [specifications] [standards] [sampling plans] [test procedures] designed to assure that [components] [drug product containers] [closures] [in-process materials] [labeling] [drug products] conform to appropriate standards of identity, strength, quality and purity.

115

Control procedures are not established which [monitor the output] [validate the performance] of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product.

89

Written procedures are not [established] [followed] for the cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing or holding of a drug product.

73

Routine [calibration] [inspection] [checking] of [automatic] [mechanical] [electronic] equipment is not performed according to a written program designed to assure proper performance.

69

Employees are not given training in [the particular operations they perform as part of their function] [current good manufacturing practices] [written procedures required by current good manufacturing practice regulations].

65

http://www.fda.gov/ICECI/EnforcementActions/ucm250729.htm


Econometrics: Important questions

4/10/2013

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• How widespread are deviations from SOP? • What factors impact process entropy? • How effective are FDA inspections to decrease process entropy? • Does offshore production pose an added quality risk relative to

domestic production? If so, what factors influence the quality risk?

• To what extent regulators utilize previously secured information in guiding regulatory (inspection) decisions?

• What is the impact of regulator experience and training (along with a host of other controls) on regulatory outcomes?

For example: Modeling of the relationship

between regulators and the firms they regulate


Relevant econometric analyses

4/10/2013

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Decay, Shock, and Renewal: Operational Routines and Process Entropy in the Pharmaceutical Industry

Gopesh Anand, John Gray, and Enno Siemsen. Organization

Science. Vol. 23, No. 6,

November–December 2012, pp. 1700–1716

Quality risk in offshore manufacturing: Evidence from the pharmaceutical industry

John Gray, Aleda Roth, and Michael Leiblein. Journal of Operations

Management 29 (2011) 737–752

Regulator heterogeneity and endogenous efforts to close the information asymmetry gap: evidence from FDA regulation

Jeffrey Macher, John Mayo, and Jack Nickerson. Journal of Law and Economics. Vol. 54, No. 1 (February 2011), pp. 25-54


Achieve QbD for complex products

Under high level of uncertainty

4/10/2013

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A key difference between FDA & EMA

4/10/2013

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Complex generics and biosimilars

4/10/2013

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Manufacturing FDA cGMP Inspections

Development Review NDA, BLA, or ANDA

Complexity Increases system wide Considered high risk –

team inspections

QbD approach to development of

analytics, product and process

Multi-disciplinary; ensure appropriate

weighting of evidence

Uncertainty Validation, state of control & rate of

entropy

483-to-WL-to-Enforcemnt

Evidence of pharmaceutical

equivalence, similarity, and interchangeability

Review evaluation criteria evolving

Variability More critical to control quality of materials

used and final product

Frequency of inspections & focus

areas

Controlled within lot-lot variability of RLD

Expected - different review disciplines &

culture


Woodcock: ‘Paradigm Shift’ in Reviews

4/10/2013

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“…companies intending to market Biosimilars must come

to FDA with an extensive characterization package, comparing theirs with the

reference product.”

“..the amount of clinical evidence required by FDA

will be related to the amount and the quality of analytical and functional information that is available on any biosimilar product…”

DIA/FDA Biosimilars Conference 12 September 2012


Quality of development and regulatory communication

Design

Product & process

Specifications & controls

Product use information

Understanding

Acceptable variability

Causal links

Failure modes & likelihood

Continuous – real time

People, materials,

machines and environment

Monitoring & control system

Process capability

Recognize knowledge

Prior knowledge –

similar products

Link between quality, safety

& efficacy

Intended use

Level of understanding

Experimental evidence in

development reports

Material attributes critical to quality

Failure modes & likelihood

Risk-based

QMS track record

Acceptable variability

Process capability

4/10/2013

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Indu

stry

Regu

lato

rs


‘Transdisciplinary’ & ‘Design Thinking’

‘Package Insert’ &

marketing messages

‘Interchange-able’

designation

Analytics, mechanisms and clinical indications ‘Quality

by Design’

Target Product Profile and

QTPP

Ability to measure

and explain

Multi-functional

review and

challenge

Not a Thing,

But a Way (MIT Sloan

Management Review, July

2, 2009)

4/10/2013

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Transdiciplianry Design Thinking


QbD Approach: Targeted development

4/10/2013

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Sandoz: Thomas Stangler | EAPB SIG Regulatory Aspects for Biopharmaceuticals | October 4th, 2010


Organizing for success

• Inadequate focus on TPP, QTPP (analytics) & market research

• Functional check-box • Cut-paste approach

to clinical trials • Rush to clinical

Common pitfalls

and symptoms

Early investment in analytics and understanding variability in RLD

TPP & QTPP in the context of residual uncertainty

Review/challenge culture and decision ‘gates’

Design of clinical trials to address scientific and clinical (market) uncertainty

4/10/2013

34


Product safety and quality know no borders Utilize meaningful manufacturing quality metrics

Differentiate manufactures by reliability

4/10/2013

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Product safety and quality know no borders

4/10/2013

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¨ Quality system that can convincingly demonstrate delivery of comparable quality & pharmacovigilance

QUALITY

TIME

COST

Select 2? Optimize

three?

1

2

3

4

TIME COST

QUALITY RISK

Scientific evidence for risk-based

quality


Cost, Quality & Risk: Unproductive time

4/10/2013

37

COS Product & process quality Regulatory compliance

Activity - Costs Risk Activity - Cost Risk

External failure Complaint investigations, impact and RC-investigations, CAPA

To patient, reputation and business

483s, WL, seizure,. ….. Recall activities

To patients, reputation and business

Internal failure Down-time, impact & RC-investigations, CAPA

To business and quality system

OOS investigation report, change - regulatory supplements for review

Inability to improve or risk to patients?

Prevention Improve design of product and/or process; Quality System, Training,…

“Corrective actions” not continual improvement

Change control and regulatory supplements Validation & batch records SOP development/training

CQAs? controls?, representative batches? Focus on documentation & inadequate system understanding

Appraisal Testing and inspection for incoming materials and products

CQAs?, representative samples?,….

Batch records, review QC release. Document review , audits


Making high quality affordable

4/10/2013

38

Optimal “driver

behaviors”? Drivers Manufactures

Consumers, prescribers and payers

Access to products and information

Market access

Time to market

ROI

Right First Time

Reputation Reliability


Making high quality affordable

4/10/2013

39

Purpose Process People

Consumers Confidence & satisfaction

Regulators Optimal [Benefit/Risk] Evidence Rp Professional satisfaction

& financial security

Manufacturers Deliver products & generate profit Mp Professional satisfaction

& financial rewards

Right first time and on-time (identify and eliminate regulatory disharmony in multiple regions that hinders this goal)


If you don’t measure something, you can’t understand it

4/10/2013

40

“Measurement is the first step that leads to control and eventually to improvement.

If you can’t measure something, you can’t understand it. If you can’t understand it, you

can’t control it.

If you can’t control it, you can’t improve it.” ― H. James Harrington


High reliability organization – per Deming

4/10/2013

41

Appreciation for a system

Knowledge about

variation

Theory of Knowledge

Psychology of people

Reduce variability; statistical process control

Mgmt. ‘culture’

influence the system and

outcome

Theory, predict,

feedback – a way to

learn

Org. is a system that interacts

with environment


What to measure?

4/10/2013

42

• The Malcom Baldrige National Quality Award (USA)

• Deming Prize (Japan)

There are major awards such as

• Alignment and/or relevance to regulatory ‘right first time and on-time’ (review and inspection) need to be factored in

Which provide relevant metrics


Summary

4/10/2013

43

• Manufacturer “acceptability” increasingly an important driver • Making quality affordable

Topics selected for discussion & why?

• Maintain high quality - At high rate of capacity utilization • QbD for complex products - Under high level of uncertainty

A high level over view of my learning: How

to …

• Ability to provide evidence of comparable global quality (pharmacovigilance) and

• Performance metrics per recognized awards – linked to ‘right first time and on time’ (for a high regulatory standard; review & inspection)

What should we measure?


“The essence of communication is intention” Werner Erhard

4/10/2013

44

¨ The notion ‘by design’, in

the phrase ‘Quality by Design’, conveys an intention to deliver a product or service with a pre-defined ‘quality’ so as to satisfy intended customers. ¤ Ajaz S. Hussain. SWISS PHARMA 34 (2012) Nr. 6

http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4052B1_09_Hussain-Arden-UK-Presentation.ppt


A quality revolution in India…..

4/10/2013

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Deming Prize winners •Since 2000, organizations based in India have received 19 prizes while organizations based in all other countries combined have received 21 (Thailand 10, Japan 7, USA 1, Singapore 1, China 1 and Taiwan 1)

Deming Grand Prize (previously Japan Quality Medal): 2012 •Tata Steel Limited (India) •Rane (Madras) Ltd. (India) •Lucas-TV Ltd. (India)

What steps a Pharma company take to achieve this by 2020?

http://blog.deming.org/2012/10/2012-deming-prize-winners/

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