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© 3M 2015. All Rights Reserved. 3M Confidential
3M Drug Delivery Systems
Considerations for Commercialization of a Microneedle Product.
Lisa Dick, Ph.D.
Microneedles 2016 – Lisa Dick – 3M Company
© 3M 2015. All Rights Reserved. 3M Confidential
3M Drug Delivery Systems
Key Considerations for Microneedle Drug Delivery
Dissolvable
Solid Coated Hollow
+
Poke ‘n Patch
Materials
Quality and Manufacturing
Regulatory
Microneedles 2016 – Lisa Dick – 3M Company
© 3M 2015. All Rights Reserved. 3M Confidential
3M Drug Delivery Systems
Key Considerations for Microneedle Drug Delivery
3M Solid Microstructured Transdermal System
(sMTS)
• Coated microneedles for systemic delivery
of
small molecules, biologics and vaccines
• Formulation development expertise to
design
API-coated microneedle patches
• Manufacturing capability to meet pre-clinical
and clinical study needs
• Clinical studies completed in US and
Western Europe
3M Hollow Microstructured Transdermal System
(hMTS)
• Hollow microneedles for systemic delivery of
biologics, vaccines, monoclonal antibodies and
small molecules in liquid volumes from 0.5 mL to
2 mL
• Phase I studies and Human Factors studies
completed in US
• hMTS kits available for human factors and pre-
clinical studies
• Clinical-ready devices (for use in conjunction
with a partner’s IND)Microneedles 2016 – Lisa Dick – 3M Company
© 3M 2015. All Rights Reserved. 3M Confidential
3M Drug Delivery Systemss
Materials Needle and Array Design ResilienceCompatible for Skin & Formulation
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Material – Needle and Array Design
Hollow Microneedle & Array Example Development
Array Type Tyche 4.4 Saber 3.2 Saber 3.4 Saber 3.5
Number of Microneedles 18 12 12 12
Needle Height (µm) medium long long mediumAverage Overall DOP
(µm)486 787 791 655
Microneedles 2016 – Lisa Dick – 3M Company
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3M Drug Delivery Systems
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Material – Resilience
Photo shows deformation of LCP microneedles after applying ~250 N of static force to the array surface for approximately 10 seconds.
Type Skin Accumulation Needle Integrity
Dissolvable Maybe FormulationDependent?
Silicon No Bend or Fracture?
Metal No Bend or Fracture?
Plastic No Bend or Fracture?
Resilience
Microneedles 2016 – Lisa Dick – 3M Company
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3M Drug Delivery Systems
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Materials: Compatible with Formulation
0
200
400
600
800
1000
1200
1400
1600
1800
2000
0 kGy 34 kGy 0 kGy 34 kGy
Probe Tack
Force (g)
Gamma Irradiation Dose (kGy)
Adhesive Probe Tack Following Gamma Irradiation
0 kGy
0 kGy
Adhesive “A”
Adhesive “B”
Patch Adhesive Stable to Sterilization
3 years of storage at room temperatureCoating didn’t shift, migrate, fracture, etc.
Drug Product Physically & Chemically Stablewith Microneedles and Primary Packaging
Microneedles 2016 – Lisa Dick – 3M Company
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3M Drug Delivery Systems
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Material - Compatible with Skin & Depth of Penetration
Histology method
DOP
Rhodamine B dye wipe-off methodBIOCOMPATIBILITY DEMONSTRATED
APPLICATION TO SKIN
By HandPossibly simple housing/device Less expensivePerson to person variabilityBest for shallow penetration
By ApplicatorDeviceExpenseLower variability person to personAble to penetrate deeper
Microneedles 2016 – Lisa Dick – 3M Company
© 3M 2015. All Rights Reserved. 3M Confidential
3M Drug Delivery Systemss
Quality and Manufacturing
Commercial Scale GMP
Meaningful Specifications
Microneedles 2016 – Lisa Dick – 3M Company
© 3M 2015. All Rights Reserved. 3M Confidential
3M Drug Delivery Systems
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Lab Scale
~500/day
GMP Pilot Scale
~5-10,000/day
Full Scale
as needed
3M MTS – Established Manufacturing Capabilities
• Microneedle arrays
manufactured using 3M
molding expertise
• Solid MTS Arrays coated
and packaged aseptically
or terminally sterilized
• Experience with Preclinical
through GMP Phase II
Clinical
• Full commercial scale array
manufacturing has been
achieved solid MTS arrays
Increasing automation
Increasing capacity
Increasing control
Non-GMP Preclincal, Tox,
or Clinical
Toxicology or Clinical
Clinical or Commercial:
GMP sites
Microneedles 2016 – Lisa Dick – 3M Company
© 3M 2015. All Rights Reserved. 3M Confidential
3M Drug Delivery Systems
Consideration: Quality on Commercial Scale
Specification – Critical Quality Attribute examples
Length
Strength
Dosage Uniformity
Impurities
Microbials and Sterility
Delivery System
Feasibility Width
Specification Width
Suppliers, Raw Materials, In-Process, and Finished Products
TargetCommercialWidth
Microneedles 2016 – Lisa Dick – 3M Company
© 3M 2015. All Rights Reserved. 3M Confidential
3M Drug Delivery Systems
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Reproducible Solid Microneedle AppearanceManufacturing hasn’t always been perfectDevelopment of microneedle manufacture from small to large sale
Variation Issues Resolved Through
Materials of ConstructionCritical Material AttributesCritical Process Parameters
Microneedles 2016 – Lisa Dick – 3M Company
© 3M 2015. All Rights Reserved. 3M Confidential
3M Drug Delivery Systems
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GMP Array Manufacturing Pilot FacilityClass 100,000
RSD <1%
Average Needle Height / Array~ 500 micron height
140 arrays sampled from 40,000 units
Ave
rag
e H
eig
ht
(µm
)
Sample Number
3M solid microneedles,
50 x magnification
3M solid microneedle array, size = ~ 1 cm2
Reproducible Solid Microneedle LengthsMTS Array Molding at Pilot Facility
Microneedles 2016 – Lisa Dick – 3M Company
© 3M 2015. All Rights Reserved. 3M Confidential
3M Drug Delivery Systems
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Microneedle API Coating GMP Pilot Facility Class 100
Drug Content UniformityThrough Batch Manufacturing
Dosage Uniformity sMTS Array Coating Process –GMP Pilot Facility
Content = 99.5% of TargetRSD = 5.5%Run Length ~ 1300 sMTS patches
+ 15%
- 15%
+ 5%
- 5%
On TargetNo TrendingReproducible
Microneedles 2016 – Lisa Dick – 3M Company
© 3M 2015. All Rights Reserved. 3M Confidential
3M Drug Delivery Systems
Delivery System - Reproducible Intradermal Delivery StudyResearch tool used during development of array and hMTS Injector
In the beginning, ~50% success rate
Improvements to adhesives and
springs
58 hMTS Injector deliveries to
Swine
(n=10, range of time & weights)
Criteria for Success:
95-100% of 1mL placebo volume
delivered in < 10 minutes
Outcome:
98% success rate, 57/58 deliveries
1 delivery incomplete at 10 minutes,
took longer to complete
Swine ID
Swine Wt (kg)
4S50
4S49
4S48
4S47
4S35
4S30
4S29
4S28
4S21
4S13
32.5
26.8
31.0
27.8
31.4
34.3
30.4
31.1
35.0
40.1
32.1
33.9
34.5
100
80
60
40
20
0
% o
f In
fusio
n
Successful Infusion> 95%
% Infusion on Swine- Zone 11
Microneedles 2016 – Lisa Dick – 3M Company
© 3M 2015. All Rights Reserved. 3M Confidential
3M Drug Delivery Systemss
Regulatory -Human Factors & Iterative Design
Applicable Guidances
Microneedles 2016 – Lisa Dick – 3M Company
© 3M 2015. All Rights Reserved. 3M Confidential
3M Drug Delivery Systems
Consideration: Iterative Product & Device DesignExample of current status and future approach
Basic Array/Device
Human Factors (HF) Formative
Formulation Development & PreClinical
Testing
Improved Design
Voice of Customer / Marketing
General Microneedle
Applicator Device Design
Design Work
HF Formative, Patient Population
& Indication
Formulation Development & PreClinical
Testing
Microneedle Applicator/
Injector
Voice of Customer / Marketing
Additional Microneedle
Applicator Device Design –
API-specific defined Opportunity
Clinical Study
Summative HF
Microneedles 2016 – Lisa Dick – 3M Company
© 3M 2015. All Rights Reserved. 3M Confidential
3M Drug Delivery Systems
Device Design Elements Gleaned from Formative HF Trials
Rheumatoid Arthritis Focus
Place & Actuate easily, Medication window, Successful Injection, Easy to Grip, Visible Dose
Confirmation
Audible start, Minimal skin irritation, <15 minute delivery, Hands-free
Audible end, Low horizontal profile,
Patient Dosing Convenience
Seconds fordelivery
CRITICAL, “MUST” HAVE
LESS CRITICAL, “NICE” TO
HAVE
“That’s a loud click, I like that!” - female
“I don’t have to pinch my fat… all I have to do is lay [the device] down…” - female
Microneedles 2016 – Lisa Dick – 3M Company
© 3M 2015. All Rights Reserved. 3M Confidential
3M Drug Delivery Systems
Key Considerations- Regulatory - DevicesDevice aspect Applicable Standard
Materials of construction
USP Class VI for plastics that have patient / product contact.
Biocompatibility – ISO 10993 (ISO, 2009)
Human Factors Draft Guidance for Industry and FDA Staff: Applying Human Factors and Usability Engineering to Optimize Medical Device Design (Food and Drug Administration, 2011)
IEC 62366 (IEC, 2015)
Applicator packaging ASTM D4169: Standard Practice for Performance Testing of Shipping Containers and Systems (ASTM, 2014)
Sterility & Sterile Barrier (as applicable)
ISO 11137: Sterilization of Health Care Products – Radiation (ISO, 2006-2013)
ISO 11607: Packaging for Terminally Sterilized Medical Devices (ISO, 2006-2014)
Device Performance ISO 11608: Needle Based Injection Systems for Medical Use (ISO, 2014)
Microneedles 2016 – Lisa Dick – 3M Company
© 3M 2015. All Rights Reserved. 3M Confidential
3M Drug Delivery Systems
Key Considerations- ICH Quality Guidance - RegulatoryTitle of Guidance(s) Scope of guideline Relevance to
microneedle productsQ1 Stability Testing:
A(R2):
New Drug Substances and Products
Recommendations on stability testing protocols including temperature, humidity and trial duration
Basis for combination products’ stability protocol design for determination of expiry
B: Photostability of New Drug Substances and Products
Annex to main stability guideline; evaluation protocol for light sensitivity
Applicability is product specific
C: New Dosage Forms Annex to main stability guideline; new dosage form stability requirements when same API is in a different product type
Potential for reduced stability database at submission time if API used in previous dosage form
D: Bracketing and Matrixing Designs
General principles for reduced stability testing, bracketing & matrixing designs
If multiple strengths of products, pull point matrices may reduce testing, can add risk to expiry prediction
E: Evaluation of Stability Data Statistical methodology for stability data analysis and expiry prediction
Guideline is applicable
Worldwide Parity for Pharma Dosage
Forms
Microneedles 2016 – Lisa Dick – 3M Company
© 3M 2015. All Rights Reserved. 3M Confidential
3M Drug Delivery Systems
Key Considerations- ICH Quality Guidance -Regulatory Title of Guidance(s) Scope of guideline Relevance to microneedle products
ICH Q3 Impurities:
A: New Drug Substances Thresholds for reporting, identification and qualification
Same base requirements as other dosage forms
B: New Drug Products Degradation products arising from interactions
Analogous to other dosage forms for interactions of drug substance, excipients and components of primary packaging materials
C: Guideline for Residual Solvents Sets pharmaceutical limits for residual solvents in drug products
Analogous to other dosage forms, high dependency on API and excipients.
D: Guideline for Elemental Impurities Global policy for limiting metal impurities in drug products and ingredients
ICH Q6 Specifications: Test Procedures and Acceptance Criteria:
A: New Drug Substances and New Drug Products: Chemical Substances
Process of selecting tests / methods and setting specifications
General guidance offered for specification setting for tests, as applicable
B: Biotechnological / Biological Products
Justifying and setting of specifications for proteins and polypeptides
Specifications as a component of the product’s control strategy
ICH Q8 Pharmaceutical Development Guidance on contents of Module 3.2.P.2 Pharmaceutical Development and Quality by Design (QbD) approaches
Analogous to other dosage forms, opportunity to uniquely define quality target product profile (QTPP) and critical quality attributes (CQAs) for microneedle products
Microneedles 2016 – Lisa Dick – 3M Company
© 3M 2015. All Rights Reserved. 3M Confidential
3M Drug Delivery Systems
22
MaterialsQuality & Manufacturing
Regulatory
Innovative microneedle technologies from 3M
3M Solid Microstructured Transdermal System (sMTS)
• Coated microneedles for systemic delivery of
small molecules, biologics and vaccines
• Formulation development expertise to design
API-coated microneedle patches
• Manufacturing capability to meet pre-clinical and
clinical study needs
• Clinical studies completed in US and Western Europe
3M Hollow Microstructured Transdermal System (hMTS)
• Hollow microneedles for systemic delivery of
biologics, vaccines, monoclonal antibodies and small
molecules in liquid volumes from 0.5 mL to 2 mL
• Phase I studies and Human Factors studies completed in US
• hMTS kits available for human factors and pre-clinical
studies
• Clinical-ready devices (for use in conjunction with a
partner’s IND)
Conclusions
Microneedles 2016 – Lisa Dick – 3M Company
© 3M 2015. All Rights Reserved. 3M Confidential
3M Drug Delivery Systemss
Acknowledgements• Ann Purrington
• Mark Tomai
• Michele Gehrt
• Allan Bohlke
• Kris Hansen
• Dave Wirtanen
• Ron Krienke
• Dan Dohmeier
• Vinh Hua
• Jerry Gysbers
Microneedles 2016 – Lisa Dick – 3M Company