Considerations for Commercialization of a Microneedle Product.€¦ · 3M MTS –Established...

© 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



Key Considerations for Microneedle Drug Delivery

Dissolvable

Solid Coated Hollow

+

Poke ‘n Patch

Materials

Quality and Manufacturing

Regulatory




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 Drug Delivery Systemss

Materials Needle and Array Design ResilienceCompatible for Skin & Formulation




5

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




6

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




7

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




8

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




Quality and Manufacturing

Commercial Scale GMP

Meaningful Specifications




10

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




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




12

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




13

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




14

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




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




Regulatory -Human Factors & Iterative Design

Applicable Guidances




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




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




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)




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




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




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




Acknowledgements• Ann Purrington

• Mark Tomai

• Michele Gehrt

• Allan Bohlke

• Kris Hansen

• Dave Wirtanen

• Ron Krienke

• Dan Dohmeier

• Vinh Hua

• Jerry Gysbers


Considerations for Commercialization of a Microneedle Product.€¦ · 3M MTS –Established...

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