3P10 Contemporary Issues in ManufacturingMedical Devices and Biomaterials

Definitions and Descriptions“A medical device is any instrument or apparatus for the cure, treatment or

prevention of diseases and conditions”

ClassificationsThe medical device classification system allows for a pragmatic approach

to be taken to the inspection, manufacturing, regulation and auditing of medical devices, the system used in the EU is detailed below. By classifying devices by the level of potential risk they pose to the patient, regulators and manufacturers can invest more time and attention on higher risk devices. This ensures that the costs for lower risk devices are not made higher by unnecessary precautions being taken.Material Uses Advantages ChallengesPolymers Contact

lenses, joint implants. Controlled degradation useful in drug delivery

Strong Light Good optical

properties Low Cost Easy to

manufacture Good control over

properties

Can be subject to high wear and degradation

All residue is resealed inside the patient

Do not perform well in high fluid environments due to solvent damage

Metals Hip replacements, oral implants

Good fatigue strength

Low ductility Easy to machine to

shape Good control over

properties

Corrosion Some specialist

alloys have high cost Do not integrate well

with bone

Ceramics Internal parts to join replacements

No ductility Resists corrosion Superior wear and

lubrication characteristics

Brittle (No ductility) Poor tensile strength Biocompatibility of

some carbon based ceramics is uncertain

Composites

Bone fracture repair

Can be used on a cellular level

Lightweight High strength

Poor shear strength Debris can be

harmful

BiomaterialsPolymers, metals, ceramics and composites are all commonly used in

medical devices to be implanted in to the body, they possess manufacturing and design challenges specific to each material which limit their range of use:Bio-compatibility: The ability of a material to perform with an appropriate host

response in a specific application.Biomaterials come in 3 categories:

Bio-inert – no cells or living components Hybrid – cellular and material elements Biological – transplants

Market and RegulationsMarkets

The global market for Medical Devices is valued at $381 billion with a growth rate of 4.4%. The three highest growth areas are In-Vitro diagnostics, cardiology and ophthalmics. There are around 25,000 medical technology companies in Europe, within the UK there are about 3000 and the market is valued at £6.3bn with a 7% growth rate.Market Trends: Decisions are now taken as a business rather than by doctors

Networks of hospitals are working together to increase market power

Price pressureComplex regulatory environmentCommoditisation of some devices

Top 5 Growth Sectors: Structural heartRobotic assistanceInfection control toolsHome-careNeurological devices and implants

Technology Trends: InteroperabilityMulti-functionalityBig dataLow cost alternativesNano-technology

Class I

Non-serile dressingsCorrective glassesStethoscopesWalking aids

Class IIa

Anti-static TubingArterial blood filterHearing aidsDevices to manage the micro-environment of wounds

Class IIb

Dialysis machinesInsulin penTrachael cannula

Class III

Vascular stentCathetersTotal knee replacementTotal hip replacement

Bio-ethicsTo protect patients and guide doctors three ethical principles have been

established around medical devices:1. Consent of the human subject is essential2. Must bring an overall positive impact on the patient3. Must consider the device’s safety throughout its life

Regulatory AffairsAll new devices must go through a rigorous regulatory process. The steps

to the compliance and acceptance of a new biomedical device are:1. Identify the appropriate regulation2. Determine the classification (I, Ila, IIb, III)3. Implement a quality management system at the manufacturer4. Submit a technical report to the EU5. Audit by a notified body6. Register with competent authority7. Prepare declaration of conformity8. Compliance, followed by subsequent annual audit

The Technical Report: Must include clinical dataNotified Bodies: Like PwC, Deloitte etc. but for medical devices, they are

licensed and managed by the EUCE Mark: Proof that the product conforms with the European

regulations

Manufacturing ChallengesSterilising Medical DevicesIn order to make devices safe to use they must undergo a sterilisation process that kills all living organisms. The sterilisation of the device should be considered from the early stages of the design, the device must remain sterile after manufacturing until it is used. Some important considerations include:

Compliance with safety standards All processes must be safe for staff Process should have a rapid cycle time to save cost and increase

throughput The process should be effective against the whole range of possible

microbes.The common processes are:

Process

Details Advantages Disadvantages/Challenges

Steam 15 – 30 minutes in high temperature steam

Cheap.Easy to control.No toxic residue.Fast.

Distortion.May lead to contaminants.Moisture absorption.Limits range of packaging materials.

Radiation

Exposure to gamma radiation

Complete penetration.Process in packaging.No residue.Reliable and controlled.

Dangerous to staff.Damages some products.Large capital outlay.Can have ozone build up.

Ethylene Oxide

Bathe in chemical to kill microbes

Good efficacy.Process in packaging.Good compatibility.

Requires quarantine.Leaves harmful residue.Many process variables.

Sterilisation MetrologyAn exam question may ask you to calculate the amount of time required

to bring a product down to a certain sterilisation assurance level (SAL) based on a sample from a test, the process for this question is:

Establish the bioburden on the product Identify the SAL (usually around 10-6) Carry out a test run Plot log10(number of spores) against time Find the time taken for the number of spores to equal the

required SALBiocompatibility

A biocompatible medical device can do the intended job without harming the host or evoking a negative immune reaction. If the material in question hasn’t previously been used in the same application and the provider can’t confirm biocompatibility, then it must be tested.

Cytotoxicity: Toxic to cells in one of four categories:1. Cell death2. Cell damage3. Cell growth slowed4. Cell metabolism altered

Cytotoxicity can be tested by exposing cells to the material for 3 days.

Future Trends in BioengineeringTissue Engineering

Tissue engineering is a set of methods that can replace or repair damaged or diseased tissues with natural, synthetic, or semisynthetic tissue mimics.

Tissue: Tissue is a combination of cell with an extra-cellular matrix (ECM) to perform a specific function in the body. There are 4 types of tissue:

1. Epithelial2. Muscle3. Nervous4. Connective

Tissue engineering requires the artificial growth of cells, outside of the human body:

Autologous Cells: Cells from yourself. This means there are fewer ethical issues and a lower of cells being rejected, but the production scales must be very small which makes processes inefficient and expensive. Transporting cells can lead to damage if the final use cannot take place at the site where they were cultured.

Allogenic Cells: Cells from someone else. This allows for larger scales of production with a standardised and repeatable process, however, regulations are now more complex because of the potential safety/ethical issues associated with implanting cells from another person. Rejection is also a possibility and issues surround transport are reduced, but not removed by the potential for centralisation of use and culturing.

Tissue Engineering in PracticeCarticel: Autologous cell transplantation for cartilage repair in sports injuriesApligraf: Bilayer skin substitute: epidermal layer formed by human keratinocytes

Drug DeliveryTechnologies that allow a targeted and controlled release of a drug in the

body. It has the advantages of maintaining high drug levels for a longer period of time whilst smoothing the extremely high and low levels associated with current drug delivery techniques.

Bulk Erosion: The entire polymer erodes at the same rate, leading to fast diffusion, requires a polymer that water can diffuse in quickly and easily.

Surface Erosion: Polymer erodes from the outside in, leads to faster hydrolysis.

Isolated Cells Biodegradable Polymer Scaffold Bioreactor

Cell Tissue Ready for

Transplant

Drug Delivery System Types:

Type 1: Diffusions controlled delivery, governed by Fick’s second law

Type 2: Swelling controlled delivery, drug in a polymer vs. drug in water. A useful approach if the drug cannot diffuse in the polymer.

Type 3: Erosion controlled system.

Personalised MedicineThe systematic use of information about each individual patient to select

or optimise the patient’s preventative and therapeutic care. It is generally associated with genome sequencing and genome based targeted treatments. One example might be the use of in-vitro diagnostics to identify the presence of biomarkers for a specific disease and predict the response of the patient to targeted therapy.

Micro and Nano Manufacturing

Microfluidics: Completing tests and analysis using very small volumes of fluid

MEMS: Micro-electromechanical systems

Advantages of micro and Nano manufacturing Small size Large volume of production High sensitivity Less chemical waste Fast response time Low blood volume needed for testing

Scale Up

Overview and IntroductionDefining scale up:

“The translation of an innovation into the market”

“A 20% annual growth rate in revenue or employees”

Types of Scale Up

Sub-Optimal Capabilities to Mature Value ChainScaling up production requires scaling up value chain activities such a supply, technical services, logistics and business functions.

Value Chain Scale Up

Small Business to Large BusinessGrowing firms must quickly expand their technical and operational capabilities.Firms must develop a mature organisational structure.

Business Scale Up

Pilot to Mass ProductionRequires demonstration that the process is applicable, functional and cost-effect at realistic production volumes.

Process/Production Scale Up

Technology development brings significant uncertainties:Taking a technology from lab prototype to productDevelopment of the fundamental technologyIntegration of new and old technology

Technology Development Scale Up

Frameworks for Scale UpCritical Path Dimensions

Regulation focused framework for the development of medical devices:

Each attribute of the product will follow its own critical path, e.g. Safety, medical utility etc.

Innovation 4 JourneysA framework focused on gaining investment and developing and

identifying markets for the innovation, the four journeys are:1. Technology Journey – From basic research, to demonstration and

product launch2. Company Journey – from 1 or 2 individuals, gaining the first

outsider (e.g. VC investors and then developing to 30+ employees

3. Market Journey – Enter the market, find early adopters and then exploit the full market

4. Regulation Journey – Meeting relevant regulation

Aligned InnovationA framework for the funding of a scale-up, transitioning from public to

private financing:

Barriers and EnablersShows how a technology has developed over a timeline, split into categories:

Market Policy Application

Technology Enablers (Science, research or other technologies)

It shows the key innovations, and the key barriers that must be overcome to scale up.Technological and Manufacturing DevelopmentThe Phase-Gate Model

Possible outcomes from the Phase-Gate model:Go: Commit to continuingKill: One or more criteria not fulfilled, stop projectHold: The need has gone away, e.g. lack of market demandRecycle: More work needed to accomplish goalsTechnology Readiness

Technology readiness levels define the amount of risk involved with using a technology and they are used to compare the maturity of developing technologies. Developed by NASA for mission critical systems. A series of metrics is used to put a technology into a certain level. Funding is linked to TRL and there is a Valley of Death between early stage proof of concept and private sector funding of a fully commercialised product.

The private sector requires documented evidence that a technology can work, can be manufactured and will be a commercial success.

Manufacturing ReadinessHaving a technology that is ready to go is not enough, it must also be capable of being produced on the scale required to make it a commercial success, for this we also define manufacturing readiness levels. The goal of a scale-up should be to develop the manufacturing capability and the fundamental technology together to avoid failure on either side.

Manufacturing readiness is very important to private investors as it dictates the ability of the company to commercialise the product. The valley of death is widening at the moment as businesses become more concerned about risk.

Innovation, Research and Development

The Black Box View of Innovation“Just developing stuff and deploying it when ready”

Types of Technology

Generic Technologies: Have the potential to be applied to a variety of applications, as such it is seen as a “platform”. The researchers must choose which application to pursue when commercialising the technology.

Infra-Technologies: An engineering toolkit that can help with scale up. Examples include: scientific or engineering databases, analysis techniques and measurement methodologies.

Innovation InfrastructureWhat Should a Scale Up Support Centre Do?

1. Finance2. Management and business skills training3. Links with industry4. Links with regulators5. Laboratories6. Small scale manufacturing facilities7. Access to Infra-technologies

Industrial Sustainability Going GreenThe Sustainable Business Model archetypes provide a template for companies wishing to go green and can be applied to a variety of case study situations:

1. Maximise material and energy efficiencya. Do more with less resources, generating less waste, emissions and

pollution2. Create value from waste

a. Turn waste into feedstocks for other products and processes3. Use renewable resources

a. For both materials and energy4. Deliver functionality, rather than ownership

a. Offer customers product-service systems that satisfy the users need without owning a physical product

5. Encourage sufficiencya. Actively seek to reduce consumption and production

6. Adopt a stewardship rolea. Stakeholder capitalism rather than shareholder capitalism

7. Re-Purpose the business for society/environmenta. Deliver social and environment benefits, consider the triple bottom

line8. Integrate the business more fully with other stakeholders

a. Community, employees and partners9. Develop scale-up solutions

a. Deliver sustainable solutions at the largest possible scaleMany companies are already taking significant steps towards going green, below are some examples of steps taken by companies to reduce their impact on the environment:

1. Educating customers to use products more efficiently – Toyotaa. If the most significant eco-impact of a product comes in the use

phase then, by helping customers to understand how to best use the product, the impact on the environment is reduced.

2. Reducing unnecessary energy usage – The Onion Factorya. Visibly label light switches and use automatic sensors where

possible. Make use of natural light as much as possible during daylight hours. Re-use waste heat and steam from production to heat the factory

3. Moving to a new, state-of-the-art production facility – Adnamsa. Environmentally friendly built using sustainable materials in a

former gravel pit. Moving out of town made distribution easier and had a social impact. Use of solar panels for water heating, recycling of rain water.

4. Closed loop system – Kalundborga. Bring all the industries in the municipality together to re-use the by-

products of each other, it means no waste leaves the system. Requires very complicated coordination.

The Big PictureThe Eco-Impact of Industrial Activity

Humans clearly cause global warming, we must adopt mitigation measures and change current practices to avoid disaster. CO2 is the least potent of a large number of greenhouse gases, one of the most over-looked is water vapour which has a large contribution to global warming. Global warming is causing changes in weather patterns and ocean currents, sea levels are rising as sea ice melts.Energy and Resource Usage

Industry (35%), Transport (32%) and Homes and Facilities (29%) are the largest consumers of power. The energy usage in industry is dominated by the production of 5 materials:

Iron and Steel 25%Cement 19%Plastics 5%Paper 4%Aluminium 3%

Industry has set a target for a 50% reduction in energy use by 2050. This will require a significant reduction is material lost as waste and a change in production methods that reduces energy consumption.

Resource SecurityAs resources become scarcer globally, prices will rise, increasing the

incentives for new methods of resource extraction and more prospecting.

The Triple Bottom LineA sustainable, modern company should:

1. Make enough profit for the company to survive2. Keep a happy, fulfilled and empowered workforce3. Minimise its impact on the environment

ECONOMIC SOCIALENVIRONMENTAL

The firm should account for all of its costs. By offering cheap, low quality products the firm may make a profit but the products will not survive as long and thus generate more waste.

Supply Chain Waste

Supply chains generate waste, the more complex a supply chain is the more wasteful it will be because there will be more stages at which waste can be generated. Examples of waste within the supply chain include:

Off-Spec goods Transport Packaging Inefficient of inaccurate processes Materials wastage

The Detailed PictureMeasurement and Legislation

In order to be able to control the eco-impact of a firm we must be able to measure it, once we understand the sources we can then regulate them. Examples of legislation include:

ISO 14001: Requires organisations to have an environmental policy in place, good for PR and relations with business partners and customers.

WEEE: Encourages better performance in the manufacture, supply, use and recycling of equipment.

REACH: EU legislation to protect human health and the environment from hazardous chemicals, the list is updated annually.

How Do We Change Attitudes?

Fiscal Incentives: Rewards good behaviour and punishes bad but may not lead to permanent change

Direct Regulation: Command and control

Taxation: Revenues should be used for environmental protection by the government

Moral Suasion: Public campaigns to promote change

Life Cycle AnalysisAssesses the environment impact of everything that goes into and comes out of products, which allows us to understand the environmental footprint. The main sources of impact are:

Waste Energy Resources

To make the biggest different to the impact of a product target the phase of its lifecycle

where it has it largest impact, for example with cars this is during the usage phase.

Mitigation Measures

Improving Eco-EfficiencyWhat can we do to reduce waste? Reduce, Re-use or Recycle. Reducing

usage of unnecessary products is the best way to reduce waste, followed by re-using wherever possible. Recycling still results in some waste and uses energy so should only be considered as a last resort. Reducing waste is good for businesses as well as the environment, by reducing off-spec goods and unnecessary transport, they can reduce costs.

Packaging is a large source of waste; one measure could be to force businesses to recover packaging and re-use it. This will also encourage the reduction in unnecessary packaging.

4 Ways to Target Products

Smaller and Lighter: Less material usage

Multi-Functionality: Fewer products need to be made

Reduce Packaging: Less waste from products

Replace with Virtual Products: Less physical resources are used (e.g. Kindle vs. books)

Product Service Systems“Product-service systems (PSS) are business models that provide for

cohesive delivery of products and services. PSS models are emerging as means to enable collaborative consumption of both products and services, with the aim of pro-environmental outcomes.”

Examples of PSS include Servitisation, where the manufacturer continues to own the products and provide maintenance throughout their use, and virtual products, where the physical product itself is replaced by a service that provides the same value to the consumer. PPS systems include:

In-line newspapers OnDemand music/DVD Car Sharing Power by the hour engines (RR) Photocopier leasing (Xerox) Clothing hire

The benefits of PSS include: Reduction in total number of goods More durable products Fewer products, used more intensively Better end-of-life disposal of products Easier upgrading to eco-efficient technologies

The Material Life-CycleMake products and material reusable to save energy is extraction, refining

and producing them, for examples: Re-use pallets Recirculating Water Reusable coffee cups and carrier bags Fix rather than replace

Adopting intelligent recycling means that we only recycle high value products with a low cost to recycle. This only works well if manufacturers are designing products with disposal in mind.