1 Challenge: Make High Quality Medicines...
Transcript of 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
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Fort Aguada; 16th-century Portuguese fort
Ajaz S. Hussain, Ph.D.
My personal point of view
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B.Pharm.
CSO VP Biopharmaceuticals CSO
Deputy Director Office of Pharmaceutical Science
Associate Professor of Pharmaceutics (tenured)
Assistant Professor of Pharmacy
Ph.D. Interdisciplinary
Ajaz S. Hussain, Ph.D.
Returning to Pharma, added appreciation for…
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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?
Ajaz S. Hussain, Ph.D.
Outline
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• 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
Ajaz S. Hussain, Ph.D.
In 2000 @ FDA – anticipation of changes needed by 2020
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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)
Ajaz S. Hussain, Ph.D.
A simple idea - improved understanding is needed for risk management
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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
Ajaz S. Hussain, Ph.D.
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
Ajaz S. Hussain, Ph.D.
Two topics, established fundamentals, a way forward…let me know if you agree, if not, why?
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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
Ajaz S. Hussain, Ph.D.
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
Ajaz S. Hussain, Ph.D.
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
Ajaz S. Hussain, Ph.D.
Why is this talk relevant to IPA members?
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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
Ajaz S. Hussain, Ph.D.
Manufacturer “acceptability” increasingly an important driver
Who makes the medicines I take?
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Ajaz S. Hussain, Ph.D.
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
Ajaz S. Hussain, Ph.D.
Public trust is the bed-rock of our industry
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¨ Perceptions do matter!
JAMA, March 5, 2008—Vol 299, No. 9
http://management.fortune.cnn.com/tag/generic-drugs/
Ajaz S. Hussain, Ph.D.
Continual effort needed to counteract forces that erode public trust
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Ajaz S. Hussain, Ph.D.
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
Ajaz S. Hussain, Ph.D.
Today’s challenges.. Not different from challenge a decade ago.... Different companies
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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’
Ajaz S. Hussain, Ph.D.
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))
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http://aspe.hhs.gov/sp/reports/2011/drugshortages/ib.shtml http://www.nature.com/clpt/journal/v93/n2/abs/clpt2012220a.html
Ajaz S. Hussain, Ph.D.
Global product safety and quality
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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”
Ajaz S. Hussain, Ph.D.
Asian middle class: A dominant market by 2020
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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
Ajaz S. Hussain, Ph.D.
Manufacturer “acceptability”…..
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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
Ajaz S. Hussain, Ph.D.
Key points: Established and emerging need to..
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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
Ajaz S. Hussain, Ph.D.
Maintain high quality
At high rate of capacity utilization
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Ajaz S. Hussain, Ph.D.
Top FDA 483 citations in 2012 (Drugs)… no significant change in this list since…
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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
Ajaz S. Hussain, Ph.D.
Econometrics: Important questions
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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
Ajaz S. Hussain, Ph.D.
Relevant econometric analyses
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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
Ajaz S. Hussain, Ph.D.
Achieve QbD for complex products
Under high level of uncertainty
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Ajaz S. Hussain, Ph.D.
A key difference between FDA & EMA
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Ajaz S. Hussain, Ph.D.
Complex generics and biosimilars
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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
Ajaz S. Hussain, Ph.D.
Woodcock: ‘Paradigm Shift’ in Reviews
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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
Ajaz S. Hussain, Ph.D.
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
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Indu
stry
Regu
lato
rs
Ajaz S. Hussain, Ph.D.
‘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)
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Transdiciplianry Design Thinking
Ajaz S. Hussain, Ph.D.
QbD Approach: Targeted development
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Sandoz: Thomas Stangler | EAPB SIG Regulatory Aspects for Biopharmaceuticals | October 4th, 2010
Ajaz S. Hussain, Ph.D.
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
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Ajaz S. Hussain, Ph.D.
Product safety and quality know no borders Utilize meaningful manufacturing quality metrics
Differentiate manufactures by reliability
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Ajaz S. Hussain, Ph.D.
Product safety and quality know no borders
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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
Ajaz S. Hussain, Ph.D.
Cost, Quality & Risk: Unproductive time
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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
Ajaz S. Hussain, Ph.D.
Making high quality affordable
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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
Ajaz S. Hussain, Ph.D.
Making high quality affordable
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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)
Ajaz S. Hussain, Ph.D.
If you don’t measure something, you can’t understand it
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“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
Ajaz S. Hussain, Ph.D.
High reliability organization – per Deming
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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
Ajaz S. Hussain, Ph.D.
What to measure?
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• 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
Ajaz S. Hussain, Ph.D.
Summary
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• 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?
Ajaz S. Hussain, Ph.D.
“The essence of communication is intention” Werner Erhard
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¨ 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
Ajaz S. Hussain, Ph.D.
A quality revolution in India…..
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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/