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Dash Board of 2015 Pharmaceutical & Biologic Regulatory
Science’s Review
Obaid Ali & Roohi B. Obaid, Pharmaceutical & Biological Regulatory Sciences Forum 26 Dec 2015, Karachi
Dash Board of 2015 Pharmaceutical Regulatory Science’s Review
Learn, De-learn & Re-learn
Not the view of DRAP
Current judgment of speaker
No obligation on DRAP
Regulatory experience
It has nothing to do with any specific
commercial product
It is just a knowledge sharing
exercise nothing more than that
DISCLAIMER
Background Review of Regulatory Sciences
Changes & Emerging shape of Regulatory Sciences
Discussion, Case Studies & Explanation
Relative Scale of Concerns
N
G
B
S E Q
S E Q
QES
Pre-Market Compliance Post-Market
G
B
N
SafetyEfficacyQuality
Background Review of Regulatory Sciences
Changes & Emerging shape of Regulatory Sciences
Discussion, Case Studies & Explanation
New
Too
ls
Approaches
Stan
dard
sE
Q
P
S
REGULATORY
SCIENCE
Globalization
Harmonization
ICH
International Generic Drugs Regulator Pilot
Collaboration Convergence Regulatory Mandate
Increased work load Globalization Scientific
complexity
Mutual Reliance
Work sharing
Efficient use of
Resource
Faster review
Greater availability Generics
EU
Australia Canada
Chinese Taipei
Switz
erla
nd
First Phase
Brazil
China
Japan
Korea
Mexico New Zealand
Russia Singapore
South Africa
Second Phase
Background Review of Regulatory Sciences
Changes & Emerging shape of Regulatory Sciences
Discussion, Case Studies & Explanation
Qua
lity
Integrity
Shor
tage
Supply chain
Integrity
Regulatory violations
Contamination Particles
Good Manufacturing Practices & Products
Culture of Quality Drug Shortage
Program
Quality Pharmaco
Chemo Econo
Metrics
UBER?
Connecting the Dots
Connecting the Dots
People
Regulation Science
Quality Metrics (Russell Wesdyk, Acting Director for the Office of Surveillance, OPQ, CDER, FDA
How is industry performing?
Who & what is out there?
Do we understand our industry?
What should Regulatory Authority do when they show up at the site?
Can we sum up what we have with data & transfer that data into knowledge?
Quality Metrics (Russell Wesdyk, Acting Director for the Office of Surveillance, OPQ, CDER, FDA
More information is better than less information
Business Model Shifting(Monika Cahilli, Green Mountain Quality Assurance)
Increased Outsourcing
Paper Tiger does not always work
Management needs to be fully engaged in Quality Agreements
Feedback mechanism for Control Strategy
Continuous review of electronic data
How many data points are involved to support the release of one product?
Learn to embrace in perfection in order to accept residual risk
Business Model Shifting(Monika Cahilli, Green Mountain Quality Assurance)
Data Integrity(Douglas Starn, Director Enforcement & Import Operations, FDA)
Integrity & Fraud are mostly close
Lack of integrity at one area raise question about others
Ability to assure safety & efficacy is doubtful
Data accountability is the only tool
Data integrity issues are not always easy to see and thus difficult to remediate
It is better to be safe than sorry…proper control can prevent and limit data integrity
issues
Data Integrity(Douglas Starn, Director Enforcement & Import Operations, FDA)
Quality & Innovations are linked(Lisa Zboril, Vice President Regulatory Affairs, Pfizer)
Product lifecycle … what occurs in manufacturing & how reflected in submission
Quality submission is planning, control & continuous improvement
Early planning to target product profile and label requirement
Regular communication of uncertainties
Continuous improvements include regulatory intelligence, deficiency tracking,
lessons learned & scientific rigor of data
In generic world, the key to success is being efficient, timely and accurate
Quality & Innovations are linked(Lisa Zboril, Vice President Regulatory Affairs, Pfizer)
Make the reviewer excited that they are getting an application from you
Quality & Innovations are linked(Ted Sherwood, Acting Director, Office of Regulatory Operations, FDA)
Background Review of Regulatory Sciences
Changes & Emerging shape of Regulatory Sciences
Discussion, Case Studies & Explanation
Proposed Product Manufacturing Classification System
Right particle
Best process
Difficult API
Good API
Ref: Lilly, GSK ……….
Highly Soluble & Highly Permeable
Highly Soluble & Less Permeable
Low Soluble & Highly Permeable
Less Soluble & Less Permeable
BCS
Direct Compression Dry Granulation
Wet Granulation Other Technologies
MCS
Direct Compression
Grind drug Intra-granular excipients Compression
Direct Compression
Grind drugIntra-
granular excipients
Roller compaction
Extra-granular excipient
Compression
Direct Compression
Grind drugIntra-
granular excipients
Granulation Wet Screen
DryingDry ScreenExtra-
granular excipient
Compression
Evolving shape of Biopharmaceuticals
Regulatory
PoliticalLegislative
Science of
Risk
Regulatory Oversight
Production Quality Reducing shortage
Facilitating development
Price, Value, Innovation
BreakthroughLife saving therapy is being coming
Hepatitis C
Cholesterol lowering agents
Cancer
drugs
Rare disease therapies
2014
41 new drugs
10 biologics
2015
1st Bio-similar approval in US
Zarxio from SandozOver 50 applications are in pipeline
Quick response on EbolaA beautiful collaborative demonstration of different organizations & countries to combat deadly virus
Quality remains a Challenge
Predictable & timely approval
Reduced inspection burden
Quality Metrics on way
Smart & Progressive
vision
Able to detect quality
problems before they
occur
Changes Evolved
• CMC from pre-clinical/clinical through review to postapproval changes & generic drug developmentChanges in Review
• Continue to oversee innovators and biosimilarsBiotechnological Products
• Quality aspect during development & approvalNew drug product
• Post-marketing changes & generic drug developmentLifecycle
• Manufacturing operation, microbiology review & preapproval inspection Collaborative Oversight
Adoption of a Risk based Model
Target oversight where quality
failures are most likely to harm
patients
Product
Facilities
Process
Footprints of knowledge is in your backyard to navigate you …
Example Elemental impurities
Ref: Pharmaceutical Technology, March 2015, Andrew Teasdale et al.
Drug Product
DS
Excipients
Equipment Utilities
Container Closure
Footprints of knowledge is in your backyard to navigate you …
Drug Substance
Inorganic reagents
Organic material
Processing aids
Equipment Metal catalysts
Water & Solvents
Container Closure
Footprints of knowledge is in your backyard to navigate you …
Excipients
1. Mind (Talc)
2. Metal catalysts (Mannitol)
3. Plant origin (cellulose)
4. Animal origin (lactulose)
5. Without metal catalysts (colloidal
SiO2)
Footprints of knowledge is in your backyard to navigate you …
Limited solubility in DP & limited interaction but
High metal content in packaging
Highest risk (high conc. of metal in packaging; high degree of interaction b/w
packaging & DP)
Lowest risk (low conc. of metal in packaging;
limited interaction b/w packaging & DP)
Good solubility in DP, intimate contact, but low
metal content in packaging
From Packaging
Met
al C
onte
nt in
Pac
kagi
ng
Metal solubility in product
RISK
IN
PACKAGING
Footprints of knowledge is in your backyard to navigate you …
Security of internal supply chain
Control of vendor elemental impurity specifications & elemental impurity reporting on ingredient COA
Security of external supply chain + a quality history for each vendor
Audit history Level of complaints Recall etc.
PRIOR KNOWLEDGE IS THE WAY TO MOVE FORWARD
Footprints of knowledge is in your backyard to navigate you …
PDE Calculation
Residual active substance
Toxicology
Pharmacology
Industry & Regulatory Agencies on Global Watch
Lifecycle data management & Quality System
Innovative strategies to meet
timeframes
Global framework & collaborations to secure supply chain
Drug development & Drug Pricing
battle
Controversy on strategies &
Science Scale
Modernization in Manufacturing & Quality Initiatives
Efficient generic drug review regulatory framework
Policies to enhance drug safety &
security
ReferenceJill Wechsler, 2015
Lifecycle data management & Quality System
Alteration in System,
Formulation & Test Method
Variation submission
Costly & time consuming
Regulatory & Post approval
changes
Developing International
Quality StandardsIntegrations
Review, Inspection & Surveillance
Innovative strategies to meet timeframes
Expedite development &
approval of innovative drug
Quick results of reviews
Innovative risk mitigation strategies
Less stability data at submission
Accepting amendment during the review process
Increased post-marketing
commitmentEarly decision for
dosage form
Early decision for method validation strategies before
time
Global Framework & Collaborations to secure supply
Storm of counterfeit & adulterated drugs
Over 2000 incidences of pharmaceutical
crime reported in 2014
Theft, counterfeiting, diversions, illegal drug
websitesAggressive &
collaborative actions
June 2015 operation Pangea VIII by
InterpolePoor quality medicines
SSFFC (Substandard, Spurious, Falsely
Labeled, Falsified & Counterfeit)
Drug Development & Drug Pricing battle
Costing Therapeutic value
Free economy Innovation
Fee Liability Profit
Controversy on Strategies & Science Scale
Quality Metrics Overworking Increased burden
Reduced inspection
Reduced regulatory burden on post approval
Slow move
Modernization in Manufacturing & Quality Initiatives
More powers of inspection Recall power New Inspection
approach
Unannounced inspection
Tougher inspections
Disregarding the delaying, denying, limiting or refusing
of inspections
Efficient Generic Drug Review Regulatory Framework
API focus Inspections Quality & Complaints
Policies to enhance Drug Safety & Security
Meningitis outbreak
IV Compounding Contamination
Microbial Penicillin Standardization
Prospective data can
sometime bring irreversible
tragedy
Aseptic processing proven safe but not sterile
Incr
ease
d se
para
tion
of P
erso
nnel
Increased confidence in Sterility Assurance
Manual aseptic fill
Conventional aseptic fill
Barrier System
Open RABS
Closed RABS
Open Gloved Isolator
Closed Glove Isolator
Glove-less Isolator
Warm up
Inhalation of a non-sterile product (Ribavirin powder for solution) with microbial contamination ….
What is harm?
Inhalation of a non-sterile product (Ribavirin powder for solution) with microbial contamination ….
What is harm?
Increase risk of respiratory infection Patients are usually immuno-compromised and more
susceptible to infection
Inhalation of a non-sterile product (Ribavirin powder for solution) with microbial contamination ….
What is harm?
Increase risk of respiratory infection Patients are usually immuno-compromised and more
susceptible to infection
RECALL (Virazole Expiry date: Oct 2018)Valeant Pharmaceuticals, USA
If you want to go fast, go aloneIf you want to go far, go together
Thanks