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Novel Drug Delivery Systems & Implantable Medical Devices:
Current Landscape Related to E&L - the Issues, Challenges, & Path forward
1Proprietary & Confidential. © 2016 Albany Molecular Research Inc.
John IannoneDirector of Extractrables/Leachables & ImpuritiesAlbany Molecular Research, Inc. (AMRI)
Overview
•Novel Drug Delivery Systems and Implantable Devices
•Regulatory Testing Differences
•The Power of E&L
–it’s current downfall…
–It’s bright future!
•Conclusion
2 Proprietary & Confidential. © 2016 Albany Molecular Research Inc.
3 Proprietary & Confidential. © 2016 Albany Molecular Research Inc.
● A system which utilizes a unique approach, formulation, technology, etc that aids in
delivering a drug in a safe manner that achieves desired therapeutic effects.
● May include site specific delivery or unique pharmacokinetics
● Typically manages the issues of how much, for how long, and sometimes, to where
Delivery Systems using Implantable technology may include:
● Device Coatings
● Polymeric reservoirs
● Mixed extrusions
● Polymer conjugates (excipients)
● Active Agents
– Nanoparticles, stimulus sensitive, microspheres, microcapsules, etc.
What is a Novel Drug Delivery Systems?
4 Proprietary & Confidential. © 2016 Albany Molecular Research Inc.
● Standard Drug Delivery by typical dosage forms cause fluctuations in drug levels
● As we develop more advanced drugs, we need more advance drug delivery systems
● Right dose at the right time and right location!
– Efficient use of drugs & excipients reduction in production cost
– Better therapy, decreased side effects improved patient experiences/ outcomes
● It is critical to maintain drug concentrations within the effective therapeutic window
Why Novel Drug Delivery Systems?
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Why Novel Drug Delivery Systems?
Typically classified as a combo product Materials utilized are NOVEL Brand New!
6 Proprietary & Confidential. © 2016 Albany Molecular Research Inc.
• Need Unique Evaluation Plan
– Satisfy Drug requirements:
Quality, Efficacy, Toxicology, etc.
– Satisfy Medical Device Requirements:
Control, Functionality, Biocompatibility, etc.
– Address Concerns due to Drug-Device
o Novel = Brand Spanking New!
– Innovative materials
May allow for extended release,
controlled release rate, etc.
– Unique applications
May allow for local drug delivery to target
site not possible under typical drug
dosing
What’s so unique about Novel Drug Delivery Systems?
What does this mean in terms of E&L?
Toxicology Focus
Extractables & Leachables
Recognize the Requirements of the Toxicologist to conduct a suitable
Toxicology Risk Assessment (evaluate biocompatiblity)
Meet criteria set forth in ICH/ USP/ ISO/ PQRI/ etc.
Theme: Understand what is Delivered to Patient SAFETY
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1. Model Interactions and Behavior of the System of
Interest - Material/ Component/ Device
2. Comprehensive Identification of those Compounds
that leach from the System
3. Adequately Quantify those Compounds Detected
4. Correlate the E&L data to the Actual Patient Exposure
Material Considerations - Safety
Source: USP Workshop on <87> , <88> , & <661>
Class Testing per USP <88>
● Extraction durations: 1 hr, 24 hrs, 72 hrs, 120 hrs
● Extraction Temperatures: 121⁰C, 70⁰C, 50⁰C, or 37⁰C
● Material Exposure: Cut & Cover
Ratio – 6 cm2/ml or 3 cm2/ml
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NaCl CSO EtOH PEG NaCl CSO EtOH PEG
I X X
II X X X X
III X X X X X X
IV X X X X X X X
V X X X X X X X X
VI X X X X X X X X X
Systemic Toxicity Intracutaneous ReactivityClass Implant
Drug Company’s Impression of Bicompatibility (Material Safety)
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Contact duration Cyto
toxic
ity
Sen
sit
ivit
y/S
en
sit
izati
on
Irri
tati
on
/In
tracu
tan
eo
us
Reacti
vit
y
Syste
mic
To
xic
ity
(Acu
te)
Pyro
gen
icit
y
Su
b a
cu
te a
nd
/or
Su
b
ch
ron
ic t
oxic
ity
Gen
eti
c
To
xic
ity/G
en
oto
xic
ity
Imp
lan
tati
on
Hem
oco
mp
ati
bil
ity
Ch
ron
ic T
oxic
ity
Carc
ino
gen
icit
y
Rep
rod
ucti
ve/
Develo
pm
en
tal
Bio
deg
rad
ati
on
/
Bio
deg
rad
ab
le
Category Contact
less than 24 hours
24 hours to 30 days
more than a 30 days
less than 24 hours
24 hours to 30 days
more than a 30 days
less than 24 hours
24 hours to 30 days
more than a 30 days
less than 24 hours
24 hours to 30 days
more than a 30 days
less than 24 hours
24 hours to 30 days
more than a 30 days
less than 24 hours
24 hours to 30 days
more than a 30 days
less than 24 hours
24 hours to 30 days
more than a 30 days
less than 24 hours
24 hours to 30 days
more than a 30 days
= Evaluation required by ISO, FDA and MHLW
= Evaluation required by ISO and FDA
=Evaluation required by FDA
=Evaluation required by ISO
Circulating Blood
Initial Evaluation Supplemental
Body Contact
Tissue/Bone/Dentin
Device Categories
Tissue/Bone
Blood
Skin
Mucous/Mucosal
Membrane
Breached/Compromised
Surface
Blood Vessels/Blood Path
Indirect
Body Surface
Contact
Device/Surface
Device
Devices
connecting the
internal to the
external/External
communicating
device
Internally
implanted
devices/Implant
device
The Reality of Bicompatibility... Sort of
Over simplified view on Toxicity Testing of a Compound
TOXICOLOGY TESTING FOR DRUG PRODUCTS
OECD 401 – Acute Oral Toxicity Test
OECD 407 – Repeated Dose 28-Day Oral Toxicity Study in Rodents
OECD 408 – Repeated Dose 90-Day Oral Toxicity Study in Rodents
OECD 409 – Repeated Dose 90-Day Oral Toxicity Study in Non-Rodents
OECD 471 – Ames Reverse Mutation Assay
OECD 473 – Mammalian Chromosomal Aberration Test
OECD 474 – Rodent Bone Marrow Micronucleus Test
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MATERIAL SAFETY / BIOCOMPATIBILITY
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Contact duration Cyto
toxic
ity
Sen
sit
ivit
y/S
en
sit
izati
on
Irri
tati
on
/In
tracu
tan
eo
us
Reacti
vit
y
Syste
mic
To
xic
ity
(Acu
te)
Pyro
gen
icit
y
Su
b a
cu
te a
nd
/or
Su
b
ch
ron
ic t
oxic
ity
Gen
eti
c
To
xic
ity/G
en
oto
xic
ity
Imp
lan
tati
on
Hem
oco
mp
ati
bil
ity
Ch
ron
ic T
oxic
ity
Carc
ino
gen
icit
y
Rep
rod
ucti
ve/
Develo
pm
en
tal
Bio
deg
rad
ati
on
/
Bio
deg
rad
ab
le
Category Contact
less than 24 hours
24 hours to 30 days
more than a 30 days
less than 24 hours
24 hours to 30 days
more than a 30 days
less than 24 hours
24 hours to 30 days
more than a 30 days
less than 24 hours
24 hours to 30 days
more than a 30 days
less than 24 hours
24 hours to 30 days
more than a 30 days
less than 24 hours
24 hours to 30 days
more than a 30 days
less than 24 hours
24 hours to 30 days
more than a 30 days
less than 24 hours
24 hours to 30 days
more than a 30 days
= Evaluation required by ISO, FDA and MHLW
= Evaluation required by ISO and FDA
=Evaluation required by FDA
=Evaluation required by ISO
Circulating Blood
Initial Evaluation Supplemental
Body Contact
Tissue/Bone/Dentin
Device Categories
Tissue/Bone
Blood
Skin
Mucous/Mucosal
Membrane
Breached/Compromised
Surface
Blood Vessels/Blood Path
Indirect
Body Surface
Contact
Device/Surface
Device
Devices
connecting the
internal to the
external/External
communicating
device
Internally
implanted
devices/Implant
device
» Biocompatibility per ISO 10993-1 or USP
– Assess Specific Mechanisms for Biological Reactivity
– Material Focused
– Typically polymeric devices are extracted in assay
» Toxicology per OECD, ISO etc.
– Toxicological effects of the drug/biologic are known or determined
– Evaluation of product use in combination product must demonstrate maintenance of safety
Chemical Interactions & Safety Profile
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» Extractables/Leachables
– Determine changes in leachates after interactions between material, drug/biologic, & intended environment
– Characterize potential changes in safety
– Assessed for Toxicological Impact by Risk Assessment
CONFIDENTIAL
Leachate Migration/ Extraction
Polymer
Migration
Extraction Solution
Environment of Concern
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Analytical Chemistry in Safety Testing
Through technological advancements, refinement & necessity, Analytical
Chemistry has become a critical aspect in many Safety Evaluations:
Noted by regulators and industry as necessary for Adequate Evaluation of
Drug Delivery Systems & Implantable Devices
1. Evaluate parameters Acheive Desired Effects (tweak product development)
2. Understand why something unexpected has occured(failure analysis)
3. Key to Risk Mitigation through:• Assessment
• Resolution
• Control
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So what’s the problem?
16 Proprietary & Confidential. © 2016 Albany Molecular Research Inc.
More than one way to get to your final destination in E&L!
EXTRACTABLES & LEACHABLES RELATIONSHIP
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Controlled Extraction relevance to clinical application
Overlap is based on how well Controlled Extraction study
models Clinically Relevant condition
EXTRACTABLES & LEACHABLES RELATIONSHIP
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Controlled Extraction relevance to clinical application
Overlap is based on how well Controlled Extraction study
models Clinically Relevant condition
Considerations in Chemical Characterization
•Extraction Ratios– Sensitive enough to evaluate relevant exposure
• ISO 10993-12
• Lifetime exposure
• AET???
•Extraction Solutions– Consider the environment of concern
• Equivalence in biocompatibility: ISO 10993-12: polar & nonpolar
• Body Contact: tissue, blood, etc.
• Drug formulation
• Reprocessing
» Extraction Temperature, Duration & Technique– Consider body contact, storage, & any reprocessing conditions
• Leachables: Simulated
• Extractables: Exhaustive, Aggressive, or Exaggerated
•Adequate & Sufficiently Comprehensive19
REMINDER: SOURCES OF POTENTIAL LEACHATES (Extractables)
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REMINDER: SOURCES OF POTENTIAL LEACHATES (Extractables)
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Potential
Inorganic
Compounds
of concerns
Metals
Example Analytical Methods
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Where is it toxicologically relevant?
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What about
Biological Reactivity
Assay Sensitivity?
ISO 10993:
Biological Evaluation of Medical DevicesEvaluation Strategy
ISO 10993–1:2009 Biological Evaluation of Medical Devices: Part 1: Evaluation & testing within a risk management process.
Test Methods
Part 5: Cytotoxicity
Part 10: Irritation & hypersensitivity
Part 11: Systemic toxicity
Part 3: Genotoxicity, carcinogenicity and reproductive toxicity
Part 6: Implantation and local effects
Part 4: Blood compatibility
Part 16: Toxicokinetic study design for leachables and degradation
products
Part 20: Principles and methods for immunotoxicology testing
Reference Materials
Part 8: Selection of reference materials
Part 12: Sample preparation and reference materials
Animal Welfare
Part 2: Animal welfare requirements
Sterilization Residuals
Part 7: Ethylene oxide sterilization residuals
Degradation Products
Part 9: Framework for Identification and quantification of degradation
products
Part 13: Identification and quantification of polymeric degradation products
Part 14: Identification and quantification of ceramic degradation products
Part 15: Identification and quantification of metallic degradation products
Materials Characterization
Part 18: Chemical characterization of materials
Part 19: Physico-chemical, morphological and topographical characterization
Risk Assessment
Part 17: Establishment of allowable limits for leachables
Source: USP Workshop on <87> , <88> , & <661>
Biocompatibility
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Biocompatibility Decision Tree
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No
Start: Establish Patient Contact (6.2.1)
Assess Patient Contact
Is there direct or indirect contact between device
& user? (6.2.2)
Establish the Device’s Worst Possible Behavior via Compositional Profiling
Yes
Does Worst Possible Behavior Exceed
the Safety Threshold for any Chemical Component?
(6.6.2)
Assess the Device’s Likely Behavior
(Extractables Profile). Does toxicological safety assessment conclude that the adverse user health
effect of the extractables is negligible?
(6.8.2)
No
Model the Device’s likely behavior via its Extractables profile Perform a
toxicological safety assessment of all
reported extractables.
Yes
Determine the Device’s Actual Behavior via its Leachables Profile
End; Chemical Characterization CompleteFrom a Chemical perspective, the device
has been established to present a negligible adverse health risk to its user.
Evaluate safety further using non-chemical approaches as appropriate
(6.11.1)
No
Yes
CH EMICAL C HARAC TERIZATION
Phase I
Phase II
Phase III
Future of ISO 10993-18
Extraction Duration as a function of solvent
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Possible Future of ISO 10993-18: SOLVENTS
Conclusion
Materials that are used in Drug Delivery/Implantable Devices are being utilized in more
sensitive and unique configurations
•Understanding materials through the development process can improve design efficacy while minimizing
unforeseen circumstances
•Combining two or more existing technologies allows for improved care while mitigating other issues
Extractables/Leachables provides Key Information
•Required to better design complicated/integrated systems
•Understand how various interactions will ultimately affect the patient
Proper Alignment is a goal, but not yet achieved, for the proper evaluation of these
multifaceted & regulated technologies
Need to maintain a balance in guidance and mandating.
•E/L is too complex to manage with only 1 approach.
•Education of critical parameters & what they mean is necessary
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