Making High Quality Affordable

Fort Aguada; 16th-century Portuguese fort

1 Challenge: Make High Quality Medicines Affordable

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

Ajaz S. Hussain, Ph.D. 4/10/2013

My personal point of view
2

Assistant Professor Associate Professor Deputy Director
B.Pharm. Ph.D. Interdisciplinary
of Pharmacy of Pharmaceutics (tenured) Office of Pharmaceutical Science

CSO CSO VP Biopharmaceuticals


Returning to Pharma, added appreciation for…
3

After several years of
thinking about how to
achieve tobacco harm
reduction

Predictors of human
behavior? Decision- Ajaz S. Hussain. SWISS PHARMA 34 (2012) Nr. 6.
making in the presence The notion ‘by design’, in the phrase ‘Quality by
of risk? Design’, conveys an intention to deliver a product
or service with a pre-defined ‘quality’ so as to
satisfy intended customers.
Behavioral economics
Why econometrics?


Outline
4

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

Topics selected for • Manufacturer “acceptability” increasingly an important driver
discussion & why? • Making quality affordable

A high level over view of • Maintain high quality - At high rate of capacity utilization
my learning: How to … • QbD for complex products - Under high level of uncertainty

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

Summary • And closing thoughts


In 2000 @ FDA – anticipation of changes
needed by 2020
5

PAT Initiative è
Pharmaceutical Quality for
21st Centuryè ICH Initiative
Real-time and remote inspection was
deemed “too radical” (in 2000)
www.fda.gov/ohrms/dockets/ac/01/slides/3804s1_02_hussain.ppt


A simple idea - improved understanding is
needed for risk management
6

“I can see clearly now” - First
Principles
Vision 2020

Knowledge based decisions
Why?

Perspectives on Regulation: Law, MECHANISTIC Desired State

Need for regulatory oversight
¤ KNOWLEDGE
Discretion, and Bureaucratic How?

Behavior (Kagan and Scholz, May 1980)
“CAUSAL" KNOWLEDGE
n ‘Good citizens’ Vs. {‘political What “Causes” What?
citizens, ‘incompetent’, and/or
‘amoral’} CORRELATIVE KNOWLEDGE Current State
What Is Correlated to What?
¨ For FDA to be risk-based it needs
scientific data & information, DESCRIPTIVE KNOWLEDGE:
capability, .. What?

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

21st Century Opportunities
7

¨ “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?
8

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
9

• “These disciplined • “The dabbawalas are • “There are many small

Interdependence and trust:
Management:

Motivation:
Discipline and Time

workers work highly motivated groups and each
perpetually and individuals. Their job is group has to be
effectively in a city very important. It is a responsible for itself
that movement is very big deal in India and for every other
difficult due to the if a customer does not group. So there is a
extremely high number receive his box on time high interdependence.
of residents. They have or even receives a If one team is not
received World record wrong box.” working well then the
in best time whole procedure is at
management.” risk.”

Ajaz S. Hussain, Ph.D. http://www.strategicmanagement-sixsigma.com/2011/06/mumbai- 4/10/2013
dabbawalas.html

Example: Pride of workmanship (cont.)
10

• “They are very close to • “Three months is the • “A group consists of
Close to the customer

Small Group Formation
Training time
the customer. They try training time and a few people with a
to satisfy the need of practice test in order supervisor. The team
every customer by somebody to be a members share the
taking and delivering dabbawala. In revenue. Trust and
on time with no contrast big companies respect are the raw
mistake.” like Mc Donald’s spend materials that describe
less than one day to a group.”
train their employees.”

http://www.strategicmanagement-sixsigma.com/2011/06/mumbai-
Ajaz S. Hussain, Ph.D. dabbawalas.html 4/10/2013

Why is this talk relevant to IPA members?
11

Increasing generic Beyond the traditional Beyond the current
competition has been an oral dosage forms the Global consensus - the ‘patent cliff’ generic
important policy generic drug approval generic model is not companies are looking
consideration for several model faces many applicable for towards complex
years challenges biotechnology products generics, biosimilars and
NCE products


12
Who makes the medicines I take?
Manufacturer “acceptability” increasingly an important driver


Today’s challenges
13

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
14

¨ 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
15


Shortage of injectable products in the US
16

• “Cancer drug shortages cause treatment, research
Previous week problems” (http://www.oncologynurseadvisor.com/cancer-drug-shortages-cause-
treatment-research-problems/article/287359/)
news • “Drug shortages spur debate over role of compounding
pharmacies” (https://home.modernhealthcare.com)

• “Drug shortages at all-time high” (CNN; June
2011)
News in 2011 • “New effort to reduce drug shortages a small
step” (Business Week; October 2011)


Today’s challenges.. Not different from challenge
a decade ago.... Different companies
17

¨ 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….
18

Economic
• “The rapid increase in volume and • “Drug shortages in the
technologic US point to a need to
Economic and scope … high rate of differentiate
analysis of capacity utilization in the al drivers of manufacturers by
[generic] industry. At these generic
the causes high levels … difficult to
reliability.”
of drug maintain manufacturing quality sterile • “FDA could support the
levels and any disruptions to injectable buyers and payers in their
shortages purchase and
(ASPE Issue supply – through, for example, drug
Briefing October quality problems …..– can reimbursement decisions
2011) lead to cascading and shortages by providing them with
persistent shortages.” (J. Woodcock and
meaningful
[emphasis added] M. Wosinska manufacturing quality
(2013)) metrics.”
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
19

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

http://www.fda.gov/downloads/
aboutfda/centersoffices/oc/glob
alproductpathway/ucm259845.p
df


Asian middle class: A dominant market by 2020
20

Indian • 55 billion USD
by 2020 (base
Pharma case)

• Acceptability
Growth • Accessibility
• Affordability
drivers • Epidemiological
factors

http://online.wsj.com/public/resources/documents/McKinseyPharma
http://www.jana.com/blog/the-battle-for-the-emerging-middle-class/ 2020ExecutiveSummary.pdf


Manufacturer “acceptability”…..
21

Historically, in the “Patients are not (The Asian middle
Asian context – consumers” – but Increasingly a class) more
“Traditional vs. this distinction is concern – “not conscious on where
Western” medicine eroding manufactured here” a product is
manufactured


Key points: Established and emerging need to..
22

• Maintain high quality
Build/maintain • At high rate of capacity utilization
public trust • QbD for complex products
• Under high level of uncertainty

Differentiate
• Product safety and quality know no borders
manufactures by • Utilize meaningful manufacturing quality metrics
reliability

23
At high rate of capacity utilization
Maintain high quality


Top FDA 483 citations in 2012 (Drugs)… no
significant change in this list since…
24

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 119
meet any of its specifications] whether or not the batch has been already distributed.
There are no written procedures for production and process controls designed to assure that the drug products have the 116
identity, strength, quality, and purity they purport or are represented to possess.
Laboratory controls do not include the establishment of scientifically sound and appropriate [specifications] [standards] 115
[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.
Control procedures are not established which [monitor the output] [validate the performance] of those manufacturing 89
processes that may be responsible for causing variability in the characteristics of in-process material and the drug product.
Written procedures are not [established] [followed] for the cleaning and maintenance of equipment, including utensils, used 73
in the manufacture, processing, packing or holding of a drug product.
Routine [calibration] [inspection] [checking] of [automatic] [mechanical] [electronic] equipment is not performed according to 69
a written program designed to assure proper performance.
Employees are not given training in [the particular operations they perform as part of their function] [current good 65
manufacturing practices] [written procedures required by current good manufacturing practice regulations].
http://www.fda.gov/ICECI/EnforcementActions/ucm250729.htm

Econometrics: Important questions
25

• How widespread are deviations from SOP?
• What factors impact process entropy?
• How effective are FDA inspections to decrease process entropy?
For example: Modeling • Does offshore production pose an added quality risk relative to
of the relationship domestic production? If so, what factors influence the quality
between regulators and risk?
the firms they regulate • 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?


Relevant econometric analyses
26

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

Quality risk in offshore manufacturing: Evidence from the
Gopesh Anand, pharmaceutical industry
John Gray, and
Enno Siemsen.
Organization
John Gray, Aleda
Regulator heterogeneity and endogenous efforts to close the
Science. Vol. 23, information asymmetry gap: evidence from FDA regulation
No. 6, Roth, and Michael
November– Leiblein. Journal
December 2012, of Operations
Management 29 Jeffrey Macher, John Mayo, and Jack Nickerson. Journal of Law and
pp. 1700–1716 Economics. Vol. 54, No. 1 (February 2011), pp. 25-54
(2011) 737–752


27
Under high level of uncertainty
Achieve QbD for complex products


A key difference between FDA & EMA
28


Complex generics and biosimilars
29

FDA cGMP Review NDA,
Manufacturing Development
Inspections BLA, or ANDA
QbD approach to
Multi-disciplinary;
Considered high risk – development of
Complexity Increases system wide
team inspections analytics, product and
ensure appropriate
weighting of evidence
process
Evidence of
Validation, state of
483-to-WL-to- pharmaceutical Review evaluation
Uncertainty control & rate of
Enforcemnt equivalence, similarity, criteria evolving
entropy
and interchangeability
More critical to control Frequency of Expected - different
Controlled within lot-lot
Variability quality of materials inspections & focus
variability of RLD
review disciplines &
used and final product areas culture


Woodcock: ‘Paradigm Shift’ in Reviews
30

“…companies intending to “..the amount of clinical
market Biosimilars must come evidence required by FDA
to FDA with an extensive will be related to the amount
characterization package, and the quality of analytical
comparing theirs with the and functional information
reference product.” that is available on any
biosimilar product…”

Ajaz S. Hussain, Ph.D. DIA/FDA Biosimilars Conference 12 September 2012 4/10/2013

Quality of development and regulatory
communication
31

Regulators
Industry

Design Understanding Continuous – Recognize Level of Risk-based
real time knowledge understanding

People, Prior Experimental
Product & Acceptable materials, knowledge – evidence in QMS track
process variability machines and similar products development record
environment reports

Link between Material
Specifications & Causal links Monitoring & quality, safety attributes Acceptable
controls control system & efficacy critical to variability
quality

Product use Failure modes Process Intended use Failure modes Process
information & likelihood capability & likelihood capability


‘Transdisciplinary’ & ‘Design Thinking’
32

Transdiciplianry Design Thinking

Analytics,
mechanisms Not
and clinical Target Ability to Multi- a Thing,
indications ‘Quality Product measure functional But
‘Interchange- by Profile and review a Way
able’ Design’ and explain and (MIT Sloan
Management
designation QTPP challenge Review, July
2, 2009)
‘Package
Insert’ &
marketing
messages


QbD Approach: Targeted development
33

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


Organizing for success
34

Early investment in analytics and
understanding variability in RLD
• Inadequate focus on
TPP, QTPP (analytics)
Common & market research
TPP & QTPP in the context of residual
pitfalls • Functional check-box uncertainty
and • Cut-paste approach Review/challenge culture and decision
symptoms to clinical trials ‘gates’
• Rush to clinical Design of clinical trials to address scientific
and clinical (market) uncertainty


35
Differentiate manufactures by reliability
Product safety and quality know no borders
Utilize meaningful manufacturing quality metrics


Product safety and quality know no borders
36

¨ Quality system that can convincingly demonstrate delivery of
comparable quality & pharmacovigilance
TIME
TIME
2 COST
1
Scientific
evidence for
Select 2? risk-based
Optimize quality
three? 3
RISK 4
COST QUALITY
QUALITY

Cost, Quality & Risk: Unproductive time
37

Product & process quality Regulatory compliance
COS
Activity - Costs Risk Activity - Cost Risk
External failure Complaint investigations, To patient, 483s, WL, seizure,. ….. To patients,
impact and RC-investigations, reputation and Recall activities reputation and
CAPA business business
Internal failure Down-time, impact & RC- To business and OOS investigation report, change - Inability to improve
investigations, CAPA quality system regulatory supplements for review or risk to patients?
Prevention Improve design of product “Corrective Change control and regulatory CQAs? controls?,
and/or process; Quality System, actions” not supplements representative
Training,… continual Validation & batch records batches?
improvement SOP development/training Focus on
documentation &
Appraisal Testing and inspection for CQAs?, Batch records, review
inadequate system
incoming materials and products representative QC release. Document review , audits
understanding
samples?,….


Making high quality affordable
38

Consumers, Optimal
prescribers Manufactures Drivers “driver
and payers behaviors”?

Time to market
Market access
ROI
Access to
products and Right First Time
information

Reputation Reliability


Making high quality affordable
39

Purpose Process People
Consumers Confidence & satisfaction

Regulators Optimal [Benefit/Risk] Professional satisfaction
Evidence Rp & financial security
Manufacturers Deliver products & Professional satisfaction
generate profit Mp & 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
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
41

Org. is a Reduce
system that Knowledge variability;
interacts Appreciation about statistical
with for a system variation process
environment control

Theory, Mgmt.
predict, Theory of Psychology ‘culture’
feedback – Knowledge of people influence the
a way to system and
learn outcome


What to measure?
42

• The Malcom Baldrige National Quality
There are major Award (USA)
awards such as • Deming Prize (Japan)

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


Summary
43

Topics selected for • Manufacturer “acceptability” increasingly an important driver
discussion & why? • Making quality affordable

A high level over view
• Maintain high quality - At high rate of capacity utilization
of my learning: How • QbD for complex products - Under high level of uncertainty
to …
• Ability to provide evidence of comparable global quality
What should we (pharmacovigilance) and
measure? • Performance metrics per recognized awards – linked to ‘right first time and
on time’ (for a high regulatory standard; review & inspection)


“The essence of communication is intention”
Werner Erhard
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…..
45

Deming Prize winners Deming Grand Prize (previously
•Since 2000, organizations based in India Japan Quality Medal): 2012
have received 19 prizes while •Tata Steel Limited (India) What steps a Pharma company
organizations based in all other countries •Rane (Madras) Ltd. (India) take to achieve this by 2020?
combined have received 21 (Thailand 10,
Japan 7, USA 1, Singapore 1, China 1 and •Lucas-TV Ltd. (India)
Taiwan 1)

Ajaz S. Hussain, Ph.D. http://blog.deming.org/2012/10/2012-deming-prize-winners/ 4/10/2013

Making High Quality Affordable

Recomendados

Recomendados

Mais conteúdo relacionado

Destaque

Destaque (18)

Semelhante a Making High Quality Affordable

Semelhante a Making High Quality Affordable (20)

Mais de Ajaz Hussain

Mais de Ajaz Hussain (20)

Último

Último (20)

Making High Quality Affordable