Working Group for BME
Education in Innovation, Design
and Entrepreneurship
Advisory Board Member
Perspective
Art Coury
Genzyme Corporation
Nashville, TN
10/01/03
Advisory Board Memberships





Boston University- BME Industrial Advisory
Board
Case-Western Reserve University-BME Industrial
Advisory Board
Duke University- BME Industrial Advisory Board
Harvard/MIT- HST Graduate Committee
UMASS Boston- Industrial Scientific Advisory
Board
Contributions of Industrial
Advisory Boards







Advice on Curriculum
Advice on New Programs, e.g., Masters Degrees
Advice on Approaches to Fund Raising
Interactions with Professors and Students (Board
Meetings, Collaboration Opportunities, Internships, Coops)
Recruiting Advantages
Teaching (Courses, Seminars, Tours)
Program Support (Donations, ABET Reaccreditation)
Medical Device Development: Quality
Systems, Standards, Design and
Process Control
Arthur J. Coury
Genzyme Corporation
Cambridge, MA
Senior Projects in Biomedical Engineering
Boston University
Biodegradation/Biostability
of Biomaterials
Biomaterials and Medical
Devices:
Status and Outlook
Arthur J. Coury
Genzyme Corporation
Cambridge, Massachusetts
BU 9//24//03
Overview of Biomaterials:
Past, Present and Future
Arthur J. Coury
Genzyme Corporation
Cambridge, Massachusetts
Quality Systems


In order to gain approval to market regulated
medical devices, manufacturers must conform to
the requirements of quality systems as mandated
by regulatory agencies worldwide.
Regulatory agencies worldwide are collaborating
for the systematic harmonization of medical
device regulations under the umbrella of the
International Organization for Standardization
(ISO).
FDA 21 CFR 820,30
ISO Quality Systems

The US Food and Drug Administration (FDA) which
regulates medical devices has adopted major elements of
the ISO quality standards:
– ISO 9001: 1994; Quality Systems Model for Quality
Assurance in Design, Development, Production, Installation
and Servicing
– ISO/DIS 13485: Quality Systems Medical Devices Particular
Requirements for the Application of ISO 9001 (April, 1996)
FDA 21 CFR 820.30
Design and Development Planning




Regulated device development requires a plan
which describes activities and responsibilities of
individuals and groups.
The plan establishes tasks, timetables,
resources, personnel, responsibilities,
prerequisite information, interrelationships among
tasks, deliverables and constraints.
The plan provides for reviews to update and
modify the schedule.
Management support and oversight is required
and helps ensure an effective planning process.
FDA 21CFR 820.30
Definitions




QUALITY- The totality of features and characteristics that
bear on the ability of a device to satisfy fitness-for-use
including safety and performance.
QUALITY SYSTEM - The organizational structure,
responsibilities, procedures, processes and resources for
implementing quality management.
DESIGN CONTROL - Element of quality system that
provides the process to assure that devices meet user
needs, intended uses and specified requirements.
PRODUCTION/PROCESS CONTROL - Control of the
manufacturing process so that devices consistently meet
specifications.
FDA 21 CFR 820,30
Definitions



SPECIFICATION - Any requirement with which a
product, process, service or other activity must conform.
VERIFICATION - Confirmation by examination and
provision of objective evidence that specified requirements
have been fulfilled (Performance Specifications).
VALIDATION - Confirmation by examination and provision
of objective evidence that the particular requirements for a
specific intended use can be consistently fulfilled
(Functional Specifications).
FDA 21 CFR 820,30
Definitions




PERFORMANCE SPECIFICATIONS - Specify how much or
how well the device must perform in quantitative terms (Basis for
verification).
FUNCTIONAL SPECIFICATIONS - Specify how the device
meets user requirements in qualitative terms (Basis for
validation).
INTERFACE SPECIFICATIONS - Specify characteristics of the
device critical to compatibility with external systems - ie user
and/or patient interface and possibly other interfaces (Validated
by clinical studies).
PRODUCTION SPECIFICATIONS - Drawings and documents
used to procure components, fabricate, test, inspect, install,
maintain and service the device.
FDA 21 CFR 820,30
Device Classes
Class I - General Controls
General Controls: Requirements
 Company registration with FDA
 Medical device listing
 Good manufacturing practice conformance*
 Submission of premarket notification (510K)*
* Many Class I devices exempted
Examples:
Elastic bandages, examination gloves, hand-held
surgical instruments
www.fda.gov/cdrh/devadvice/3132.html
Device Classes
Class II - Special Controls
Special Controls: Requirements
 Apply general controls
 Special labeling
 Mandatory performance standards
 Postmarket surveillance
 Etc.
Examples:
Powered wheelchairs, infusion pumps, surgical
drapes
www.fda.gov/cdrh/devadvice/3132.html
Device Classes
Class III - Premarket Approval (PMA)
Support or sustain life, substantially prevent
impairment of health or present a potential,
unreasonable risk of illness or injury
 Require scientific review to ensure safety and
effectiveness
 Can gain approval through premarket notification
(510K) if substantially equivalent to devices marketed
before May 28, 1976
Examples:
PMA - Silicone-filled breast implants, prosthetic heart
valves, implanted brain stimulators
510K - Implantable heart pacemakers, certain
vascular grafts, endosseous implants

www.fda.gov/cdrh/devadvice/3132.html
Design Control Regulations
All Class II, III devices require design control.
Most Class I devices are exempt except
“software automated” devices, surgeon’s gloves,
protective restraints, tracheobronchial suction
catheters, radionuclide applicators and sources.
www.fda.gov/cdrh/devadvice/3132.html
DESIGN INPUT - The physical and
performance requirements of a device
that are used as a basis for device
design.



Requirements include functional, performance
and interface specifications.
Design inputs should be comprehensive,
unambiguous, self-consistent, realistic and
appropriate.
Design inputs are subject to modification during
the development process.
FDA 21 CFR 820,30
DESIGN OUTPUT - The results of a
design effort at each design phase and at
the end of the total design effort.



Includes results of verification tests and
conclusions regarding validation requirements.
Total finished design output consists of the
device, its packaging and labeling and the device
master record.
Device master record holds documents the
device, packaging and labeling.
FDA 21 CFR 820,30
Medical Device Development Protocol
User Need
Proof of Concept
Medical Device Concept
Preliminary Research (Discovery)
Development Project Initiation Under Design and Documentation Control
Design and Development Planning
Design Review
Design Input
Design Output
Design Changes
Design Verification
Design Validation
Production Control
Design Transfer
Product Marketing
Product Servicing
Project Description
(A) Title: (Project #)
(B) Project: Coordinator(s)
• Technical
• Administrative
(C) Objective: 1 or 2 Sentences
(D) Rationale:
• User Need
• Business Opportunity
• Improvements Over Competition
• Technical Feasibility
(E) Approach:
• Technical
(F) Functional Specs:
• General Goals of Project
(How user needs are met I.e. validated)
(G) Performance Specs:
• Quantitative Requirements
(Verified to fall within stated range)
(H) Status:
• As of Current Date
(I) Issues:
• Technical Barriers
• Competition
• Alternatives
• Logistics
• etc.
(J) Resources:
• Internal Staff (FTE’s, Names, Function)
• Collaborators (Institution, Relationship)
• Major Space (Preclinical, Lab, etc.)
• Major Equipment
(K) Tasks:
• Details of Science, Preclinical,
Clin/Reg.
(L) Cost Estimates:
• Project Initiation to Product
Introduction
(M) Schedule:
• Gantt Chart (Project Initiation to
Product Introduction)
Case Study
Development of a sealant for use in
lung surgery
Project Description
Title
Development of a Lung Sealant
Project Coordinators
Technical - Leonardo DaVinci
Administrative - Julius Caesar
Objective
To develop a sealant for sites on a lung undergoing
resection which demonstrate intraoperative leakage
or are at risk of post-surgical leakage.
Project Description
Rationale





Lung resection surgery produces intra-operative air leaks in the
majority of cases using standard techniques of closure such as
staples and sutures.
Lung air leaks often require extended use of percutaneous chest
drainage, tubes and hospital stays until adequate healing
occurs.
Tumor resection and lung reduction surgery occurs at the rate of
400,000 worldwide, annually, and almost every patient would be
a candidate for a treatment to assure pneumostasis intra or
post-operatively.
There is currently no intra-operative therapy for sealing or
preventing leaks.
We hypothesize that the use of a resorbable sealant applied
intra-operatively will be technically feasible and reduce the time,
pain, and costs associated with extended lung air leaks.
Project Description
Approach
Technical:
An adherent, bioresorbable hydrogel results from
the use of a tissue primer and sealant topcoat
which convert from fluid to solid form by a
photopolymerization process. The resultant
coating provides a barrier to prevent leakage
while tissue healing occurs underneath. The
composition resorbs by dissolution and clearance
through normal metabolic pathways after
appropriate healing assures a leak-free lung.
Photocurable
Hydrogels
“Macromer”
Based
Vision for Interventional Therapeutics
Macromer Structure
A: Water Soluble/Biocompatible Core
B: Biodegradable Moieties
C: Photopolymerizable End Caps
Formation and Degradation of Hydrogel
Micelles of
Macromer
in Solution
Acrylate
Lactate
Illumination
Crosslinked
Hydrogel
Hydrolysis
Hydrolytic
Dissolution
of Hydrogel
PEG
Visible Light Initiating System
COO
Br
Br
514 nm
O
O
[Eosin Y]*
+
:N(CH2CH2OH)3
O
Na
Br
Br
Eosin Y
POLYMERIZATION
Macromer
:N(CH2CH2OH)2
CH2CH2OH
+
COO
COO
Br
Br
HO
O
OH
Na
Br
Br
Br
Br
O
O
O
Na
Br
Br
Na
Hydrogel Sealant Application
Brush on
Primer
Brush on
Sealant
Drip
Illuminate
FocalGelTM: Customized Properties
• Adherence to Tissue
Low
High
• Degradation Time
Days
Months (Years)
• Drug Loading
Low
High
• Stiffness
- Macromer Formulation
- Hydrogel Formulation
• Fatigue Resistance
• Thickness
• Cellular Attachment
• Cross-linking Rate
Liquid
Paste
Soft
Hard
Low
High
Microns
Non-Adherent
Seconds
Centimeters
Adherent
Minutes
Tissues to Which Strong or Moderate
Acute Bonding of Hydrogels was
Achieved In-Vivo
• Lung Parenchyma
• Parietal Pleura
• Visceral Pleura
• Blood Vessels
- Media
- Endothelium-Denuded Intima
• Nerves
• Liver Capsule
• Liver
• Dura Mater
• Cortical Bone
• Mouth Floor
• Mucogingival Flap
• Ear Cartilage
• Articular Cartilage
• Epicardium
• Small Intestine
• Urinary Bladder
• Spleen
• Pelvic Sidewall
• Uterine Horn
• Kidney
• Pancreas
• Esophageal Muscularis
Characteristics of Focal Hydrogels
Formation
• In Situ Curable
• Can form in bulk or interfacially
• Can fill void or coat surfaces
• Conformal
Biocompatibility
• Blood compatible
• Tissue compatible
Physical Properties
• 95% water at equilibrium
• Transparent
• Adherent to moist tissue
• Drug loadable
Degradation
• Degrades by dissolution,
not fragmentation
• Moderate molecular weight,
soluble products
• Bioresorbable
Project Description
Functional Specifications
(Provide Validation of Conformance to User Needs)








The sealant shall arrest or prevent leaks under the sites to
which it is applied.
The sealant shall allow healing to occur to the attached tissue
so that subsequent leaks do not occur.
The sealant shall not interfere with the normal function of the
lung to which it is attached.
The sealant shall be resorbed innocuously after performing it’s
function.
The sealant shall be biocompatible for its lifetime in the body.
The sealant shall be easy to prepare and apply by practitioners
functioning normally in the lung/surgery suite.
The sealant shall be readily producible, storable and
transportable under conditions available at source and
destination.
The sealant shall be cost effective to supplier and user.
Preclinical Verification/Validation
Examples:

The sealant shall arrest or prevent leaks under the sites to which it is
applied (validation).
1. The sealant shall perform leak-free in the excised pig lung in vitro
model for 18 hr, maintaining an adherence score of at least 3 out
of 4 (verification).
2. The sealant shall seal the leaks produced from an imperfect
staple line in the dog lung wedge resection model evaluated after
2 weeks duration (verification).
3. The sealant shall act as the sole sealing mechanism for a wound
produced by resecting a lobe of a dog lung evaluated after 2
weeks duration. (verification).
4. The sealant shall effectively eliminate intra-operative leaks in
human subjects where applied and shall, on average, reduce the
time of post-operative chest drainage by 25% relative to controls.
5. Etc.
Pre-Clinical Testing
BURST STRENGTH
- Rat peritoneal tissue
FocalSeal® Sealant
Fibrin Glues
377.53 + 98.26 mmHg
23.79 + 17.07 mmHg
Pre-Clinical Testing
TISSUE ADHERENCE
- Porcine lung tissue
FocalSeal® Sealant
4.0
Fibrin Glues
1.0
Scoring System
0
1
2
3
4
Gel falls off when touched
Entire gel can be removed by lifting one edge
Peeling motion required to remove gel
Scraping required to remove gel
Vigorous scraping required to remove gel
Control, 5 months Dog
Lung Lobectomy
FocalSealR L,
5 months Dog
Lung Lobectomy
Preclinical Verification/Validation
Examples:
 The sealant shall not interfere with the normal function of the lung to
which it is attached (validation).
1. The sealant shall be designed to have a Young’s
modulus less than that of the expanding human lung
(<100KPa), and demonstrate an elongation in excess of
the fully expanded human lung (>300%) (verification).
2. Etc.
 The sealant shall be biocompatible for its lifetime.
1. The sealant shall pass the ISO10993 test protocol for long term
implants.
2. The sealant shall display, by histological examination, normal,
viable tissue with only mild inflammation under the hydrogel and
a thin or absent fibrous capsule around the hydrogel
(verification).
Comparison of Macromer-Based
Hydrogels
Macromer Type
8,000 MW PEG
27,000 MW PEG
Viscosity
Fluid
Thick
Stiffness (vs Pig Lung)
3X
1X
Elongation
100%
500%
Lung Adherence
1
4
(18 hours fatigue test, 0-4)
Tensile Behavior of FocalSeal™
200
Stress (Kpa)
Young’s Modulus
150
Stress = 151.1 + 59.80 kPa
Strain = 768.5% + 255.2% mm/mm
100
Modulus = 29.4 kPa
50
0
200
400
600
800
% Strain (mm/mm)
Histology of FocalSeal® Treated
Dog Lung (14 Days)
Definition
Investigational Device Exemption (IDE):
An IDE allows the performance of a clinical study with an
investigational device in order to collect safety and effectiveness
to support a PMA or a [510K] submission. It requires: Approval
by an institutional review board (IRB); informed consent of all
patients; labeling “for investigational use only”; monitoring of the
study; required records and reports.
www.fda.gov/cdrh/deadvice/ide/print/index.htm
Risk Management:
The systematic application of management policies, procedures
and practices to identifying analyzing, controlling and monitoring
risk. Methodologies include: Preliminary hazard analysis
(PHA); failure mode and effects analysis (FMEA); failure mode,
effects and criticality analysis (FMECA); fault tree analysis
(FTA); hazard analysis and critical control points (HACCP).
www.devicelink.com/mddi/archive/98/10/011.html
Definition
Failure Modes and Effects Analysis:
A method of determining, before a product is introduced, potential
failure modes, and their consequences. A typical approach involves
weighting the failure modes according to the following equation:
Risk Priority =
Number (RPN)
Severity Occurrence Detectability
Rating X Frequency X Rating
Number Rating
Number
(1-10)
(1-10)
(1-10)
Maximum Effect = 1000
Minimum Effect = 1
Modes are prioritized in decreasing number order.
Thresholds of concern are low for critical systems, higher for general
systems.
www.mines.edu/academic/courses/eng/EGGN491/lecture
Project Description
Status
The program has received management approval
to initiate design control after preliminary proofof-principle research has shown promise.
Preliminary research results have been
documented in technical reports. Technical and
business program managers and members of the
multi-disciplinary program team have been
appointed. A project initiation meeting has been
scheduled where signoff by management, the
program managers and leaders of each discipline
will take place. The design and development
plan will then be formulated for approval.
Project Description
Issues
Technical Barriers:
The hydrogel coating must be shown to adhere and stop leaks for the
projected two week healing time. Adhesion durability has not yet been
achieved with known tissue coatings and adhesives. In order to be fully
functional for two weeks, a degradation profile of months results. Long
lasting devices require more extensive testing than subchronic devices.
Competition:
Recently-approved fibrinogen/thrombin based products (“fibrin glues”) are
being used as lung sealants. They are two-part liquids that solidify when
mixed. While they do not perform well (the lung is fibrinolytic; the product is
stiff and does not adhere well), they have the feature of not requiring light to
effect crosslinking. There are rumors that other companies are in earlystage development of sealants that do not require light to polymerize.
Project Description
Issues
Alternatives:
Alternatives to sealants for pneumostasis have included staples,
sutures, talcum powder (causes adhesions of lung to thoracic
sidewall) and chest tube drainage. Each has significant drawbacks in
terms of healing, pain and hospital time
Logistics:
We manufacture the polymerizable “macromer” in-house, but clinical
studies require that the “fill and finish” process for the formulation be
performed by a contractor. Scheduling and cost considerations will be
important during advanced stages of development.
Other Issues:
If the hydrogel barrier is not substantially resorbed within 30 days, it is
considered a chronic device. Preclinical, clinical and regulatory
strategies require more complex and extended testing.
Project Description Resources
Internal Staff
Technical Coordinator:
Leonardo D. Vinci, Biomaterials Dept.
Administrative Coordinator:
Julius Caesar, Business Development
Polymer Synthesis Rep:
Pierre Curie, Process Development
Analytical Rep:
Marie Curie, Analytical
Regulatory Rep:
Alex Hamilton, Regulatory
Clinical Rep:
Alex Carrell, Clinical
Intellectual Property:
Clarence Darrow, Legal
Project Description
Resources
Collaborators:
Preclinical Studies - Professor Harry Houdini will collaborate on the
use of his porcine lung resection model to establish pre-clinical safety
and efficacy.
Clinical Studies - The Universities of Peoria and Kalamazoo have
been qualified by a team from clinical, QC, and regulatory departments
to run the first pilot clinical trial.
Major Space:
Section B of the chemical labs and section C of the analytical labs will
be dedicated to this project. A 2000 square foot production facility will
be needed to service advanced clinical studies and worldwide
marketing. Cell culture and small animal facilities will be used as
needed.
Major Equipment:
For preclinical studies, polymer synthesis will take place in 20 liter scale
glass reactors. The manufacturing plant will have, as its base reactor,
a 100 gallon glass-lined steel system with full accessories and safety
equipment. A dedicated HPLC and GC will be required for all stages.
Tasks (2002-2003)
Completion
Initiate design control
Develop work plans
Synthesize polymer candidates
Screen polymers/formulations in vitro
Perform preclinical verification
Recruit clinical centers, patients
File IDE for pilot clinical trial
Perform pilot clinical trial
File IDE for pivotal clinical trial
* General tasks - more details in sub-categories
February, 2002
March, 2002
June, 2002
Sept. 2002
March, 2003
March, 2003
March, 2003
December, 2003
December, 2003
Cost Estimates - Project Initiation to
Product Introduction
Project #: 10051
Project Title: Lung Sealant Development
Project Duration: Feb., 2002 - May, 2006
Projected Costs:
Year
2002
2003
Quarter
1
2
3
4
1
2
3
2004
4
1
2
2005
3
4
1
2
2006
3
4
1
2
3
4
FTE*
R&D
Clin.
Reg.
Mfg.
Other
8
0.5
0.5
0.5
1
8
0.5
0.5
0.5
1
8
0.5
0.5
0.5
1
8
0.5
0.5
0.5
1
Total
10.5
10.5
10.5
50
50
50
50
50
50
Outside
Expense
(000)
Special
Proj.
Costs
(000)
Capital
(000)
FTE*
(000)
Total
Cost
(000)
4
1
2
1
1
3
5
2
1
1
3
5
1
1
1
3
5
1
1
1
2
6
1
2
1
2
6
1
2
1
2
6
1
4
1
2
6
1
4
1
1
6
1
4
1
1
6
1
4
1
1
2
3
4
1
1
2
3
4
1
1
1
3
4
1
1
1
3
4
1
1
4
3
4
1
10.5
9.0
12.0
11.0
11.0
12.0
12.0
14.0
14.0
13.0
13.0
11,0
11.0
10.0
10.0
13.0
13.0
50
100
100
50
75
300
300
300
300
300
300
150
150
150
150
200
200
50
50
75
75
50
60
150
150
150
150
150
150
75
75
75
75
100
50
50
50
60
60
60
60
100
100
500
500
150
50
50
50
50
50
50
2100
2100
2100
2100
1800
2400
2200
2200
2400
2400
2800
2800
2400
2600
2200
2200
2000
2000
2600
2600
2250
2250
2250
2250
2035
2635
2360
2395
2950
2950
3800
3750
3000
3100
2475
2475
2275
2275
2950
2950
Grand Total = $53,375,000
*Costed at $200,000/Year
1
4
3
4
1
100
50
Senior Projects in Biomedical Engineering, Boston University
“Biomaterials and Tissue Engineering”
“Development, Manufacturing, Standards and Quality Systems”
Problem:
A cardiac pacemaker system consists of a pulse generator (power source, circuitry, container, connector) and pacing leads (Figure 1). This very complex
electronic device senses the electrical activity of the heart and responds, when appropriate, by delivering pulsed shocks to the heart to restore rhythm.
Some pacemakers respond to body motion to modulate pulsed stimulation rate.
The endocardial leads are critically important because they contact the heart (Figure 1 illustrates an atrial “J” lead and a ventricular lead) and deliver the
sensing signal to the pulse generator and the stimulation pulse from the pulse generator. The lead consists, minimally, of a conductor coil, distal
electrode, proximal electrode with connector, insulation tubing and a mechanism to fix the distal electrode in the heart (e.g., a tine).
(Figure 2). So that fibrous capsule formation around the distal electrode does not raise the stimulation or sensing threshold too high, some electrode
designs contain an anti-inflammatory steroid reservoir for diffusion of drug to surrounding tissue (Figure 3) and some leads contain a “suture sleeve” for
holding the lead to tissue (Figure 2).
The lifetime of a pulse generator is usually defined by the battery it contains and may now reach 5-10 years. Pacing leads, ideally, would function for
several pulse generator lifetimes since they “fibrose” into the vein and heart chamber in which they reside and are hard to remove.
Materials of construction of the pacing leads shown consist of a platinum distal electrode (hollow or porous for drug delivery), a stainless steel
crimp to hold the distal electrode to the “MP35N”, Co-Cr-Mo alloy conductor (lengthwise coiled wire), a proximal, crimped electrode with silicone connector
for inserting into the pacemaker connector, a polyurethane fixation tine (distal), polyurethane insulation tubing and a thermoplastic polyethylene suture
sleeve (Figure 2).
Questions:
1.
2.
3.
4.
5.
For the pacing leads of the device shown, describe six functional specifications.
For each functional specification, describe at least one performance specification. Pick a functional specification out of the six in which you describe three
performance specifications. (Note: the actual values you choose are not critical, although they should be reasonable. Understanding the concepts is most
important.
Complete the analogy: (Performance specs): (Verification) = (Functional Specs): (?)
Perform an FMEA on the pacemaker lead for 5 modes according to the handout. Refer to Art Coury’s earlier handouts on polyurethane degradation to
describe at least one mode (see note above).
What class device is a heart pacemaker (I, II, III)? What regulatory pathway would be required to gain approval to sell a new pacemaker in the US? It is
likely that some clinical trials will be necessary to show safety and efficacy of the leads. What is the name of the process leading to approval to run clinical
trials?
Figure 1
Figure 2
Bipolar Pacemaker System
Endocardial Pacing Lead
Figure 3
Steroid Eluting Pacing Lead
(porous tip, steroid plug, tine)