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, Co-ops)

Recruiting Advantages Teaching (Courses, Seminars, Tours) Program Support (Donations, ABET Reaccreditation)

Medical Device Development: Quality Systems, Standards, Design and

Process Control

Arthur J. CouryGenzyme Corporation

Cambridge, MA

Senior Projects in Biomedical EngineeringBoston University

Biodegradation/BiostabilityBiodegradation/Biostability of Biomaterialsof Biomaterials

Biomaterials and Medical Devices:

Status and Outlook

Arthur J. CouryGenzyme Corporation

Cambridge, Massachusetts

BU 9//24//03

Overview of Biomaterials:Past, Present and Future

Arthur J. CouryGenzyme 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

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

ISO Quality Systems

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 ClassesClass 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 ClassesClass 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 ClassesClass 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 Medical Device Concept

Proof of Concept Preliminary Research (Discovery)

Development Project Initiation Under Design and Documentation Control

Design and Development Planning Design Input

Design Review Design Output

Design Changes

Design Verification Design Validation

Production Control Design Transfer

Product Marketing Product Servicing

(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)

(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)

Project Description

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

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.

Approach

Photocurable Hydrogels

“Macromer” Based

Vision for Interventional Therapeutics

Macromer Structure

A: Water Soluble/Biocompatible Core B: Biodegradable Moieties C: Photopolymerizable End Caps

Hydrolytic Dissolution of Hydrogel

Crosslinked Hydrogel

Micelles of Macromer in Solution

Illumination

Hydrolysis

Acrylate

Lactate

PEG

Formation and Degradation of Hydrogel

Visible Light Initiating System

O

COO

Br

O

BrBr

Br

O

O

COO

Br

OH

BrBr

Br

HOO

COO

Br

O

BrBr

Br

ONa

Na

Na

:N(CH2CH2OH)2

CH2CH2OH

:N(CH2CH2OH)3

Na

514 nm [Eosin Y]*

POLYMERIZATION

+

+

Eosin Y

Macromer

Hydrogel Sealant Application

Brush on Primer

Drip IlluminateBrush onSealant

FocalGelTM: Customized Properties

• Adherence to Tissue

• Degradation Time

• Drug Loading

• Stiffness

- Macromer Formulation

- Hydrogel Formulation

• Fatigue Resistance

• Thickness

• Cellular Attachment

• Cross-linking Rate

Low

Days

Low

Liquid

Soft

Low

Microns

Non-Adherent

Seconds

High

Months (Years)

High

Paste

Hard

High

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

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.

Functional Specifications(Provide Validation of Conformance to User Needs)

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 TestingBURST STRENGTH - Rat peritoneal tissue

FocalSeal® Sealant

377.53 + 98.26 mmHg

Fibrin Glues

23.79 + 17.07 mmHg

Pre-Clinical TestingTISSUE ADHERENCE- Porcine lung tissue

Scoring System

0 Gel falls off when touched1 Entire gel can be removed by lifting one edge2 Peeling motion required to remove gel3 Scraping required to remove gel4 Vigorous scraping required to remove gel

FocalSeal® Sealant4.0

Fibrin Glues1.0

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

Viscosity

Stiffness (vs Pig Lung)

Elongation

Lung Adherence (18 hours fatigue test, 0-4)

Macromer Type

Fluid

3X

100%

1

Thick

1X

500%

4

8,000 MW PEG 27,000 MW PEG

Tensile Behavior of FocalSeal™

200

150

100

50

0200 400 600 800

Stress = 151.1 + 59.80 kPa

Strain = 768.5% + 255.2% mm/mm

Modulus = 29.4 kPa

Young’s Modulus

Str

es

s (K

pa

)

% 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

DefinitionFailure 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 = Severity Occurrence Detectability

Number (RPN) 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

The program has received management approval to initiate design control after preliminary proof-of-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.

Status

Project Description

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 early-stage development of sealants that do not require light to polymerize.

Issues

Project Description

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.

Issues

Project Description

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

Resources

Internal Staff

Project Description

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.

Resources

Tasks (2002-2003)

Completion

Initiate design control February, 2002

Develop work plans March, 2002

Synthesize polymer candidates June, 2002

Screen polymers/formulations in vitro Sept. 2002

Perform preclinical verification March, 2003

Recruit clinical centers, patients March, 2003

File IDE for pilot clinical trial March, 2003

Perform pilot clinical trial December, 2003

File IDE for pivotal clinical trial December, 2003

* General tasks - more details in sub-categories

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 2004 2005 2006Quarter 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4

FTE*

R&D 8 8 8 8 4 3 3 3 2 2 2 2 1 1 1 1 1 1 1 1

Clin. 0.5 0.5 0.5 0.5 1 5 5 5 6 6 6 6 6 6 2 2 1 1 4 4

Reg. 0.5 0.5 0.5 0.5 2 2 1 1 1 1 1 1 1 1 3 3 3 3 3 3

Mfg. 0.5 0.5 0.5 0.5 1 1 1 1 2 2 4 4 4 4 4 4 4 4 4 4

Other 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

Total 10.5 10.5 10.5 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

OutsideExpense(000)

50 50 50 50 100 100 50 75 300 300 300 300 300 300 150 150 150 150 200 200

SpecialProj.Costs(000)

50 50 50 50 75 75 50 60 150 150 150 150 150 150 75 75 75 75 100 100

Capital(000)

50 50 50 50 60 60 60 60 100 100 500 500 150 50 50 50 50 50 50 50

FTE*(000)

2100 2100 2100 2100 1800 2400 2200 2200 2400 2400 2800 2800 2400 2600 2200 2200 2000 2000 2600 2600

TotalCost(000)

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

Senior Projects in Biomedical Engineering, Boston University

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. For the pacing leads of the device shown, describe six functional specifications.

2. 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.

3. Complete the analogy: (Performance specs): (Verification) = (Functional Specs): (?)

4. 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).

5. 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?

“Biomaterials and Tissue Engineering”

“Development, Manufacturing, Standards and Quality Systems”

Figure 1 Figure 2

Figure 3

Bipolar Pacemaker System Endocardial Pacing Lead

Steroid Eluting Pacing Lead(porous tip, steroid plug, tine)