kns-ef17 april 25, hall a key note am #1, agmed zidan, fda … · 2017-05-10 · different 3d...

Keynote Speaker

Before you Click “Print”: Regulatory Considerations for 3D Printed Oral Drug Products

Ahmed ZidanU.S. Food and Drug Administration

Before You Click “Print”: Regulatory Considerations for 3D Printed Oral Drug products

ExcipientFest Americas 2017 :

April 25th, 2017

Ahmed Zidan, Ph.D. Staff FellowCDER/OPQ/OTR/DPQRU.S. Food and Drug Administration

www.fda.gov 2

Disclaimer

The views expressed in this presentation do not reflect the official policies of the FDA, or the Department of Health and Human Services; nor does any mention of trade names, commercial practices, or organization imply endorsement by the United States Government.

www.fda.gov 3

Outline

• Introduction

• Different 3D printing techniques

• Typical 3DP manufacturing of oral tablets

• Case studies: Increased product complexity

• Risks and process control consideration

• 3DP current status of drug products, device & biologics

• Regulatory challenges: present & future

• FDA’s Initiative on 3DP

• Summary

www.fda.gov 4

Outline

Introduction








• Summary

www.fda.gov 5

Introduction

• Evolution of pill: 140 BC to 1887 and so on…

• How 3D printing came into pharmaceuticals?

– 1984: First 3D Printed object made by Chuck Hill

– Use of 3DP in medical device & human organ in past decade

– 1996: First reported 3D pill

– 2015: FDA approved first 3D printed orodispersible tablet, Spritam®

(levetiracetam)

• Why 3D printing? What is the motivation?

– Product complexity

– Personalized use

– Compounding and low cost

www.fda.gov 6

Introduction

• Three-dimensional (3D) printing is a form of additive manufacturing, wherein a structure is built by depositing or binding materials in successive layers to produce a 3D object.

• Potential benefits of 3D additive manufacturing techniques in dosage form design:

1. Accurate control the spatial distribution of an active pharmaceutical ingredient (API) within a dosage form.

2. Production of complex geometries.

3. Depositing very small amounts of API.

4. Reduction of production waste.

5. Preparation of individualized dose strengths (i.e. varying dose strengths) without the need for a high volume manufacture.

6. Avoiding the traditionally complex, slow and expensive supply chains.

www.fda.gov 7

Adopted from Mol Pharm 12 (2015) 4077‐4084

Introduction


• PEDIATRICS Children are not committed to take tablets e.g. (swallow issues, taste)

Medicine related toxicity (e.g. physiological differences)Gastric emptying, pH, GI permeability, surface area of absorption, biliary excretion and renal clearance

Off label and unlicensed use

Oral solid formulation →multi-particulate oral formulations with greater dose flexibilityNeonates + Cancerdosage forms desirable in liquids or foods. Fixed dose formulations for chronic diseases like HIV and TB.

www.fda.gov 8

Adopted from https://3dprint.com/73807/3d‐printed‐medication‐shapes/

Introduction


• Personalized Medicine (individual based therapy)

www.fda.gov 9

Adopted from Int J Pharm. 2015 Oct 30;494(2):578‐84. doi: 10.1016/j.ijpharm.2015.02.032. Epub 2015 Feb 13.

Outline

• Introduction

Different 3D printing techniques







• Summary

www.fda.gov 10


1. Stereolithography

2. Digital light processing

3. Selective laser sintering

4. Powder inkjet printing

5. Extrusion/Fused deposition modelling

6. Micro-extrusion/Bioprinting

www.fda.gov 11


1. Stereolithography

• The first 3D printing process.• The laser reacts (in X-Y axes) with photopolymer resins to cure it into a solid layer.

The platform within the vat drops down by a fraction (in the Z axis) and the subsequent layer is traced out by the laser.

• It requires support structures for some parts, specifically those with overhangs or undercuts.

• Limiting factors include the post-processing steps required and the stability of the materials over time, which can become more brittle.

www.fda.gov 12

Adopted from https://3dprintingindustry.com/3d‐printing‐basics‐free‐beginners‐guide/processes/International Journal of Pharmaceutics, Volume 503, Issues 1–2, 30 April 2016, Pages 207–212


2. Digital light processing

• Similar process to stereolithography in employing photopolymers but faster. • It uses a more conventional light source, such as an arc lamp, with a liquid crystal

display panel or a deformable mirror device (DMD), which is applied to the entire surface of the vat of photopolymer resin in a single pass.

• It produces highly accurate parts with excellent resolution. • It requires shallow vat of resin to facilitate the process, which generally results in

less waste and lower running costs.

www.fda.gov 13

Adopted from https://3dprintingindustry.com/3d‐printing‐basics‐free‐beginners‐guide/processes/https://3dprint.com/163042/ackuretta‐launches‐ackuray‐a135/


3. Selective laser sintering (melting)

• Substrate is powder, a laser draws the shape of the object printed and fuse it afterwards.

• Layer are build after a new layer of powder has been laid down on the object.• The build chamber is completely sealed to maintain the melting temperature of the

powdered material of choice.• Creation of drugs, metal, plastic and ceramic objects.

www.fda.gov 14

Adopted from https://3dprintingindustry.com/3d‐printing‐basics‐free‐beginners‐guide/processes/


4. Powder inkjet printing

• Inkjet printer sprays the ink onto a powder foundation using thermal, electromagnetic or piezoelectric technology

• Contact between ink and powder creates a solid dosage form layer by layer.• Flexibility of using API, binders and other in-active ingredients in the ink• Limitless dosage forms (Aprecia: up to 1000 mg)• The need for supports is negated because the powder bed itself provides it.

www.fda.gov 15

Adopted from https://3dprintingindustry.com/3d‐printing‐basics‐free‐beginners‐guide/processes/https://phys.org/news/2015‐05‐inkjet‐kesterite‐solar‐cells.html


5. Extrusion/Fused deposition modelling

• Printhead is similar to inkjet printer• Beads/filaments are released from print head• Melting polymers (printing of filaments) is headed as it is extruded, it fuses or bonds• Layers (multiple print heads possible)• Suitable for 3D printing of oral dosage forms• Requires support structures for any applications with overhanging geometries

www.fda.gov 16

Adopted from Acosta‐Vélez GF, Wu BM. 3D Pharming: Direct Printing of Personalized Pharmaceutical Tablets. Polym Sci. 2016, 1:2.http://www.3ders.org/articles/20150510‐pharmaceutical‐researchers‐create‐new‐shapes‐for‐medicine‐tablets‐using‐3d‐printing.html


6. Micro-extrusion/Bioprinting

• Similar to Fused Deposition Modelling• Printing semisolids are released from print head under pneumatic pressure• Material can be preheated to produce the desired viscosity for extrusion.• Layers (multiple print heads possible) fuse or bond followed by curing or drying• Powder loaded semisolids pastes can be used for printing oral drug products. • For oral tablets, powder loading percentage, composition, viscosity, cohesion,

drying, geometric design resolution, etc. should be optimized.

www.fda.gov 17

Adopted from Visscher, Dafydd O. et al., Advances in Bioprinting Technologies for Craniofacial Reconstruction. Trends in Biotechnology , Volume 34 , Issue 9 , 700 ‐ 710Biomaterials. 2014 Oct;35(31):8810‐9. doi: 10.1016/j.biomaterials.2014.07.002. Epub 2014 Jul 19.

Outline

• Introduction


Typical 3DP manufacturing of oral tablets






• Summary

www.fda.gov 18

Typical 3DP manufacturing of oral tablets

• Computer design of the product

• Software workflow to print head (slicing parameters)

• Build cycle (Material and in-process controls)

• Post Processing (curing, rigidization, drying, etc.)

• Packaging (CCS)

• Finished product testing

www.fda.gov 19

Adopted from International Journal of Pharmaceutics, Volume 494, Issue 2, 30 October 2015, Pages 657–663

Outline

• Introduction



Case studies: Increased product complexity





• Summary

www.fda.gov 20

Case study 1: Multicompartmental tablets

A bilayer multicompartmental fixed dose combination products of captopril, nifedipine and glipizide sustained release tablet.

Bi-modal release mechanism in built: osmotic pressure controlled and diffusion controlled

www.fda.gov 21

Adopted from Clive Roberts et al., 3D printing of tablets containing multiple drugs with defined release profiles, Intl Journal of Pharmaceutics., Vol 494, Oct’ 2015.

Case study 2 : Gradient arranged matrix tabletsDigitally controlling arrangement of matters:

(a) barrier layer;

(b) drug‐containing region;

(c) gradients of release‐retardation material

(d) Photographs of tablets at different time points

(e) Release profiles from tablets with different material gradients

www.fda.gov 22

Adopted from Deng Guang Yu et al., Tablets With Material Gradients Fabricated by Three‐Dimensional Printing, Journal of Pharmaceutical Sciences, Volume 96, Issue 9, 2007

Case study 3: Doughnut-shaped tablet Doughnut-shaped tablet by FDM for zero-order release:

Top and bottom layers comprised impermeable ethylcellulose (EC)

Inner core of acetaminophen (APAP) with 2% EC.

Infill percentage with FDM of tablets Budmen et al.:

0% infill would result in a hollow shell

100% infill would lead to a completely solid geometry,

The tablets showed a slower release (ER profile) with increase in infill percentage.

www.fda.gov 23

Adopted from Yu D‐G, Branford‐White C, Ma Z‐H, et al. Novel drug delivery devices for providing linear release profiles fabricated by 3DP. Int J Pharm 2009;370:160–6.Budmen I. Understanding shells, layer height and infill. 2013. Available from: http://blog.teambudmen.com/2013/09/understanding‐ shells‐layer‐height‐

and.html.

Case study 4: 3D inkjet printing

Continuous jet (CJ) and drop on demand (DOD) printing principle

3D inkjet printing can be separated into three parts:

(1) Droplet formation,

(2) Droplet impact and spreading,

(3) Drying or solidification.

www.fda.gov 24

Adopted from Drug Development and Industrial Pharmacy, 2016, VOL. 42, NO. 7, 1019–1031. http://dx.doi.org/10.3109/03639045.2015.1120743

Droplet formation is influenced by fluid viscosity (η), density (ρ) and surface tension (ν), area (a), etc. Many dimensionless values have been developed to predict fluid behavior:

Reynolds (Re) number

Weber (We) number

Ohnesorge (Oh) number

We-number was used to determine areas where energy was sufficient to eject a drop from the nozzle.

Z-number is the inverse of the Oh number and is used to define areas for stable drop generation.

Z values of 1–10 are classified as printable fluids.



www.fda.gov 25

Adopted from Mckinley GH, Renardy M. Wolfgang von Ohnesorge. Phys Fluids (1994–Present) 2011;23:127101‐1–6.Jang D, Kim D, Moon J. Influence of fluid physical properties on ink‐jet printability. Langmuir 2009;25:2629–35.

Proper droplet formation

Stable drop generation as a function of Re, We and Oh numbers.

Improper droplet formation resulting in satellite droplets



• When using a suspension as the binder liquid, particle size, suspension stability and effect on fluid rheology must beconsidered to prevent clogging of the nozzle.

• The distance from nozzle to substrate is known as the “standoff distance”. This distance is usually minimized to decrease the effects of environmental airflow on droplet trajectory.

• Droplet spreading is primarily a function of droplet volume, substrate porosity, substrate surface smoothness, fluid infiltration and equilibrium contact angle.

• The drying or solidification process is a function of the solvent system selected. The formation of amorphous solid dispersions and recrystallization of API may evolve to affect the stability and mechanical properties of the dosage form.

www.fda.gov 26

Adopted from Drug Development and Industrial Pharmacy, 2016, VOL. 42, NO. 7, 1019–1031. http://dx.doi.org/10.3109/03639045.2015.1120743

Outline

• Introduction




Risks and process control consideration




• Summary

www.fda.gov 27

Control Strategy Consideration

Raw material control

1. Powder characteristics:

• Physicochemical properties such as particle size, shape, porosity, solid state form, water content, viscoelastic property, density, flow and uniformity of mixed material

2. Print fluid characteristics:

• Print fluids can be liquids, suspensions, hot melts,

• It may contain API, polymers, etc.

• Rheological/Viscoelastic properties and surface tension

• Thermal/Isothermal properties: Thermal conductivity, specific heat capacity, Tg, etc.

3. Printability of API, excipients

4. Appropriate formulation selection and stability

www.fda.gov 28

Control Strategy Consideration

Printing Process

• Variable layer thickness

• Inaccurate position during printing

• Print head clogging

• Inconsistent binding between layers

• Inconsistent extrusion patterns

• Friable tablets

• Inefficient drying

• Software control

• Real‐time layer thickness monitoring

• PAT tools

www.fda.gov 29

• Raw material control

• In process tests

• Post processing

• Real‐time monitoring of inkjet flow

• Powder deposition rate

• Roll speed

• Nozzle diameter

• Droplet spacing

• Print head speed

• Droplet frequency and velocity,

Outline

• Introduction





3DP current status of drug products, device & biologics



• Summary

www.fda.gov 30

3DP current status of drug products, device & biologics

• The journey started with genomic revolution in early1990s with a concept of a possible platform for personalized medicine

• First 3D printed pill, Spritam® (levetiracetam) approved by FDA in August 2015

• FDA’s Center for Device and Radiological Health (CDRH) has reviewed and cleared 3DP medical devices for over 10 years

• More than 85 3D‐printed medical devices cleared via FDA’s 510 (k) regulatory pathway

• OsteoFab® Patient‐Specific Facial Device, an orthopedic implant used in facial reconstruction surgery (First 3DP facial implant)

• No biological products manufactured by additive manufacturing yet for FDA approval

• US Government has launched the National Advanced Manufacturing portal with multiple linked Manufacturing Innovation Institutes in August 2012, in an effort to foster collaboration and provide support for 3D printing technologies and products.

Source: http://www.manufacturing.gov/nnmi_pilot_institute.html

www.fda.gov 31

Outline

• Introduction






Regulatory challenges: present & future


• Summary

www.fda.gov 32

Regulatory challenges: present & future

• What should be the dosage form nomenclature for the 3D printed drug product?

• Can 3D Printing be used for compounding and at Pharmacy?

How should 3D print cartridges loaded with drugs be regulated?

Should FDA regulate 3D printers?

Regulated body ‐ industry vs. pharmacy or compounding facility.

• The regulatory challenges could include defining a new dosage form, and identifying labeling claims for the product.

• Print equipment: robustness against shipping and changing environmental conditions, or the potential for cross‐contamination.

• Early interaction with FDA on 3D printed dosage forms, particularly via ETT for drugs

www.fda.gov 33

Outline

• Introduction


• Typical 3DP manufacturing





FDA’s Initiative on 3DP

• Summary

www.fda.gov 34

FDA’s Initiative for 3DP Technology

• CDER’s Emerging Technology Team

• Draft Guidance on “Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base”.

• Draft Guidance on “Technical Considerations for Additive Manufactured Device” (CDRH)” –May, 2016

• Public workshop “Additive Manufacturing of Medical Devices: An Interactive Discussion on the Technical Considerations of 3D Printing” , October 2014

www.fda.gov 35

Summary

• 3DP technology has proven commercial feasibility through the FDA approval of a 3D product in August of 2015, and through medical device approvals

• It is continually evolving in pharmaceuticals for complex formulation and for better safety & efficacy

• Potential use in personalized pharmaceutical products manufacturing and compounding

www.fda.gov 36

Acknowledgements

U.S. Food & Drug Administration

• Celia N Cruz, Ph.D.

• Muhammad Ashraf, Ph.D.

• Alaadin Alayoubi, Ph.D.

• James Coburn, Ph.D.

• AKM Khairuzzaman, Ph.D.

• CDER/OPQ 3D printing scientists

• CDRH 3D printing scientists

www.fda.gov 37

www.fda.gov 38

kns-ef17 april 25, hall a key note am #1, agmed zidan, fda … · 2017-05-10 · different 3d...

Documents