Scientific Considerations for Microneedle Drug Products: Product Development, Manufacturing, and Quality Control

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Caroline Strasinger, PhD Office of New Drug Products (ONDP) Chair of the FDA Transdermal Working Group

James J. Norman, PhD Office of Process and Facilities (OPF)

Disclaimers The contents of this presentation are ours and do not necessarily reflect the view and/or policies of the United States Food and Drug Administration or its staff. The United States Food and Drug Administration will not be bound by any comments or information contained in this presentation. Use of Images Our use of images as examples does not represent FDA preference for specific products, processes, or manufacturers. None of the images were taken from FDA submissions. Conflict of Interest Statement James is a co-author on patent applications related to microneedles. He has waived his rights to any royalties from these patent applications.

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Poking its way into the Regulated Industry?

Build

Innovate

3 Communicate

Resources for Communicating with FDA • IND Guidance Documents

– Formal meetings between the FDA and Sponsors or Applicants – IND Meetings for human drugs and biologics – Exploratory IND studies – INDs for Phase 2 and Phase 3 Studies:

Chemistry, Manufacturing, and Controls Information – Best Practices for Communication Between IND Sponsors and FDA

During Drug Development • Request for Designation:

http://www.fda.gov/CombinationProducts/RFDProcess/ • Emerging Technology Team: Draft guidance • OPQ Inbox: CDER-OPQ-Inquiries@fda.hhs.gov

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Outline •Considerations for a QTPP

• Strength • Purity • Drug release • Intended use • Sterility • Container Closure

•Considerations for Robust Manufacturing

• Coatings • Micromolding

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Outline

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•Considerations for a QTPP • Strength • Purity • Drug release • Intended use • Sterility • Container Closure

•Considerations for Robust Manufacturing

• Coatings • Micromolding

Using ICH Q8 to Generate a QTPP

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QTPP: Microneedle Design

• Density, distribution, and dimensions • Changes in microneedle design during development can impact other quality

attributes and interfere with process development • Consider finalizing the microneedle design early in development

QTPP: Dosage Strength

• Identity

• Average Assay

• Content Uniformity – Between products – Between individual needles – Within individual needles

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QTPP: Purity

• Drug substance degradants • Leachables

– From metal or plastic surfaces – From the manufacturing equipment – From the container closure system

• Particulates Endotoxins Excipient impurities / residual impurities

– Solvents, monomers, initiator impurities, excipient degradants

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QTPP: Drug Release In Vitro Release Testing

Crystallinity

Swelling Ratio Particle Size, Polymorphic Form

• Establishment of at least three sampling times covering initial, middle and terminal phases of the elution profile

• Acceptance criteria set in a way to ensure consistent performance from lot to lot

• Chosen method should be discriminating and sensitive enough to reject lots that would have less than acceptable clinical performance

Residual Drug Analysis Refer to the 2011 guidance: Residual Drug in Transdermal and Related Drug Delivery Systems 11

Control over Related Attributes

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QTPP: Intended Use • Mechanical Characterization

– Tip sharpness – Static loading, linear buckling analysis – Shear representative of patient use – Coating delamination and friability

• Interaction with Tissue – Insertion depth and tissue recovery – Adhesion – Presence of sharps after use – Impact of humidity, temperature

• Applicator testing – Safety, efficacy, repeatability, robustness, durability

• Functionality testing of hollow microneedles

Human factors are reviewed by multiple offices in multiple centers

QTPP: Sterility / Bioburden Control • Do microneedles need to be sterile?

– Target tissue and depth of penetration – Duration of application – Intended patient population (immunocompromised, young, elderly)

• Approaches to sterile manufacturing – Aseptic manufacturing: combination of previously sterilized components – Terminal sterilization – novel approaches can be validated

• Justifying a non-sterile product – Scientific rationale for why the product does not increase infection risk – Examples: clinical trial experience, animal data, in vitro experiments

• Manufacturing limitations – If sterile manufacturing is not possible, low bioburden manufacturing with

documented controls and release criteria may be acceptable – The need for a sterile product should be evaluated early in development

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QTPP: Container Closure and Stability

• Container Closure Considerations – Simulated shipping studies – Pouch/clamshell integrity on stability

• Considerations for Stability Testing

– Formulation migration – consider the worst-case product orientation – Continued testing of mechanical attributes – Desiccant performance

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Process Reliability and Robustness

Example Microneedle Processes

Pre-Filling Hollow Microneedle Devices

“Poke and Patch” Topical Formulations

Extrusion for Solid Dose Injection

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Example Microneedle Processes

Dip Coating Spray Coating

Drawing Lithography

Micromolding

Gas-Jet Drying

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Hot Melt

Dip Coating Processes

Potential High Risk Quality Attributes

Example Dip-Coating Processes Micro-Reservoir

Rolling Drum

• Content uniformity • Sterility, if applicable • Mechanical attributes

Wider in every dimension? (x +∆x)3 relationship?

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Dip Coating – Control Strategies • Raw Material Controls

– Rheological properties – Surface tension of the

formulation – Needle orientation and

array flatness – Needle roughness and

surface energy

• Environmental Conditions – Humidity and temperature – Air flow

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• Process Parameters – Relative needle velocity – Coating depth

• Vision Systems and Other Process Analytical Technology (PAT) – Acceptance Criteria – Method Validation – Refer to 2004 Guidance on Process

Analytical Technology (PAT)

Other Coating Processes

Example Considerations • Distinguishing drug on the base from the “deliverable dose” during development • Demonstrating robustness against air and surface contamination in critical areas • Conducting worst-case process simulations/media fills (required for aseptic processes)

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Micromolding – Example Processes

• Solution casting – Convection/vacuum drying

– UV curing

– Microwave curing

• Melt casting – Vacuum filling

– Microparticle melting

• Other – Ultrasonic welding

Considerations for Silicone Micromolds •Mold Creation

– Establishing a type of silicone and curing system – Master structures: maintenance and qualification – Laser ablation: parameter justification, cleaning – Leachables assessment – Mold qualification: Durometer and geometry post-sterilization

•Mold Cleaning – Cleaning validation – Consider permeability of silicones to cleaning solvents (ex: isopropanol)

•Mold Replacement – Silicones are subject to both physical and chemical degradation – Assessment of mold lifetime

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Concluding Remarks • Early communication with OPQ is recommended to create a more

fluid and predictable review process.

• Expectations for microneedle quality scale with the phase of development.

• ICH guidelines provide a framework for adopting a Quality by Design (QbD) approach for designing and manufacturing microneedles.

• Microneedle manufacturing has unique control strategy considerations. 23

Acknowledgements

• CDER • CBER • CDRH

Transdermal Working Group

• Jessica Cole, Microbiology • Tapash Ghosh, Biopharmaceutics OPQ Colleagues

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References – Organized by Slide Number 8. http://medcitynews.com/2013/05/its-smaller-than-a-fingernai l-but-this-needle-free-nanopatch-could-be-the-future-of-

vaccines/ http://drugdelivery.chbe.gatech.edu/Images/Image_gallery/Full/metal_out_of_plane.jpg

9. http://www.sciencedirect.com/science/article/pii/S0378517315304452 10. http://drugdelivery.chbe.gatech.edu/gallery_microneedles.html 11. http://www.ncbi.nlm.nih.gov/pubmed/22361098

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3627464/figure/fig05/ http://onlinelibrary.wiley.com/doi/10.1002/adma.201001525/abstract

12. http://connection.ebscohost.com/c/articles/66347534/enhanced-delivery-topically-applied-formulations-following-skin-pre-treatment-hand-applied-plastic-microneedle-array http://drug-dev.com/Main/Back-Issues/SPECIAL-FEATURE-Transdermal-Topical-Subcutaneous-D-607.aspx

14. http://solutions.3m.com/wps/portal/3M/en_US/CNDDSD/Home/technology-solutions/transdermal-technologies/microstructured-transdermal-systems/

15. http://www.medicaldevice-network.com/contractors/packaging/gallery.html 16. http://www.businesswire.com/news/home/20150128005967/en/Microneedles-Breakthrough-Brings-3M-Step-Closer-

Introducing http://www.tandfonline.com/doi/full/10.1517/17425247.2014.938635 http://www.ondrugdelivery.com/publications/Transdermal_Microneedles_NFI_March_2013/Glide.pdf

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References – Organized by Slide Number

17. http://onlinelibrary.wiley.com/doi/10.1002/adma.200902418/full http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390019/ http://www.sciencedirect.com/science/article/pii/S0022354915316993

18. US patent 8771781 http://www.ncbi.nlm.nih.gov/pubmed/25213295 http://link.springer.com/article/10.1007%2Fs11095-009-0019-8

20. http://www.mdpi.com/1999-4923/7/4/486/htm 21. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2293299/figure/F1/

http://www.coriumgroup.com/Publication_TransdermalDeliveryofMacromolecules062010.html https://openi.nlm.nih.gov/detailedresult.php?img=PMC3310406_ijn-7-1415f1&req=4 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917494/ http://onlinelibrary.wiley.com/doi/10.1002/mame.201500016/full http://mems.seas.upenn.edu/publications/2005/Biodegradeable%20polymer%20microneedles-%20fabrication.pdf http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3595545/ http://mems.seas.upenn.edu/publications/2007/Polymer%20particle-based%20micromolding%20to%20fabricate%20novel%20microstructures.pdf

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