Iba Quality Regulatory And Ehs Department

Published Date: 02 Nov 2017

�Ion Beam Applications (IBA) provides and develops efficient solutions for diagnosing cancer and also cancer treatment. IBA began its existence in 1986, In the first stage the IBA group fo-cused on the healthcare improvement and enhancement of life quality.Putting technology in the service of lifeis the main goal of IBA which achieved by IBA�s unique expertise in engineering consultancy to develop particle accelerators.(Brusasco, 2011)

IBA funded in 1986 and start working as one of the Cyclotron Research Center. The research center belongs to the Catholic University in Louvain-la-Neuve in Belgium. So IBA produced its first cyclotron in 1947.Exploiting a unique expertise in particle accelerator technology was the objective of IBA�s founder, Yves Jongen and of Pierre Mottet, tosatisfygrowing needs in medical device industry. During this period of time, IBA quickly recognized the need to diversifyWhile it was initially active in medical imaging. So, IBAstart focusing onProton Therapy which used as Radiotherapy system and also developed cyclotrons which facilitate treating cancer with a degree of accuracy and efficiency never reached before.( IBA-worldwide, 2013)

Then, IBA continue expanding activities in the Sterilization &Ionization medical industry in 1992. In this point of time IBA group produced Rhodotronwhich was a new type of particle ac-celerator. Good to mention that the concept of a patented idea of the French Atomic Energy Commission was the concept which Rhodotron was made base on that.( IBA-worldwide, 2013)

To increase IBA employee�s involvement, and also reward the employee�s commitment to the success of IBA, in 1997, the IBA employees buy out the shares of company. Moreover Giving opportunity to employees to drive future was another purpose.( IBA-worldwide, 2013)

Raising funds on the Brussels stock market in June 1998 make the situation for IBA to speed up its development by internal development. Acquisition of Radiation Dynamicsconsolidates Pro-vide strength in irradiation technologies for IBA.( IBA-worldwide, 2013)

The acquisition of Radiation Dynamics was realized by IBA as a significant opportunity in Feb-ruary 1999. Actually,as a heat shrinking system and polymer modification applications, RDI was installed and established in 1999 to full fill all these requirements.( IBA-worldwide, 2013)

In 2001, IBA becomesmain shareholder of Eastern Isotopes which was established in 1993 in Sterling, Virginia, USA.

The first cyclotron in the Sterling facility was set up by Eastern Isotopes in August 1998. This enabled part of founders developing plan which was �future of nuclear medicine�. Good to men-tion that, producing the standard nuclear medicine products was one of the main results.

Expanding into the new PET imaging products make the opportunity for IBA torecognized East-ern Isotopes as a front-runner within the PET Imaging Community.( IBA-worldwide, 2013)

Regarding to these kind of achievement, more research isotopes, a global distribution network and access to advanced cyclotron technology,allowed IBA to leverage its international expertise and improvement to offer its clients, and superior access to advanced cyclotron technology.( IBA-worldwide, 2013)

After numerousinvestigation, development and cooperation with clinical partners, in 2001, Mas-sachusetts General Hospital in Boston, was the place which the first treatment with a proton therapy system was done there and represents a great achievement for IBA. .( IBA-worldwide, 2013)

In the field of radical dose cancer therapy, through relentless effortsand passion, IBA known as undisputed leader in treatment modality for radical dose cancer therapy. Moreover, over half of PT centers are installed by IBA, since then IBA become the leading edge treatment modality in that field. .( IBA-worldwide, 2013)

IBA reveal it consideration tothe fight against cancer and also introduced its mission which was Enhance, support and Save Lives, on April 20th 2006, So IBA translated its mission and its real multinational stature in worldwide market through all its branches.( IBA-worldwide, 2013)

the new IBA Molecular business unit set up as a new form of PET Radiopharmaceuticals & Iso-topes activities and Eastern Isotopes. IBA Particle Therapy contain of R&D, production and in-stallation.On the other hand, IBA Dosimetry made by combination of Scanditronix and Wellh�fer. Moreover, integrated activities of e-beam accelerators and RDI activities make IBA Industrial.( IBA-worldwide, 2013)

IBA has tried to make Asian market throughout the recent years. In June 2007, a new facility in Beijing was opened in PRC of China by IBA. After that, as a development program, for support-ing all Business Units in Asia, IBA expands its Asian Headquarters offices and production facili-ties there. IBA planned the development program in Asia to optimize the market opportunities in one China which is one of the fastest growing markets in the world.( IBA-worldwide, 2013)

Distributingradiopharmaceuticals technology and product in Noida (Delhi area) was the first step for IBA to expand its branches in the Indian sub-continent. Moreover reliable supply of PET iso-topes can now make benefit for Nuclear Medicine sector of the Delhi.( IBA-worldwide, 2013)

For creating IBA Molecular Imaging, IBA created a strategic association with SK Capital Part-ners. SK is a jointly-owned company which owns 60% of the company but on the other hand IBA has a 40% stake.( IBA-worldwide, 2013)

The significant goal of the Group is to delivering solutions, developing products and services that protect, enhance and save lives of people.

In molecular imaging field, The company progressively produces and distributes radiopharma-ceuticals system. On the other hand for better diagnosing and treatment IBA offerdosimetry equipment..( IBA-worldwide, 2013)

In addition, the company provides unique environmentally-friendly solutions for industrial steri-lization and ionization. IBA is headquartered in Louvain-la-Neuve (Belgium) and employs about 1350 people throughout the world. Good to mention that, in the list of pan-European stock ex-change Euronext, IBA is also mentioned becauseIBA develops and manufactures medical devic-es. IBA also provide software solutions in medical device industry.

The software used for cancer treatment. All these done by proton beam therapy. In fact The pro-ton beam identifycancer and also used as patient quality assurance.

Good to mention that IBA also set up cancer clinics. The company also made many academic health centers.( IBA-worldwide, 2013)

Throughout the recent years, IBA runs in more than 40 countries, These countries belongs to North America, Europe & Asia.= .( IBA-worldwide, 2013)

IBA products and markets encompassing IBA Industrial product, IBA Particle Therapy product and IBA Molecular. Good to mention that IBA quality system implements the requirements of ISO 9001:2008 and also ISO 13485:2003 to all the products (Industrial, Particle Therapy and Molecular products).

Regarding to European committees, IBA product is categorized as Medical device because ac-cording to definition of medical devicemedical device is an Instrument, apparatus, appliance, software, material or other articlewhich used for For treatment, anticipation, diagnosis, checking, or mitigation of disease.(Brusasco, 2011)

Marketing medical devices (MDs) regulated by low in many countries, For example regulated by FDA in United states, CE marking in Europe and SDA in china.In Europe MDs fall under the COUNCIL DIRECTIVE 93/42/EEC, and It means that Md�s which produce in Europe must fulfill Essential Requirements and then subject to a conformity assessment procedure and also get CE marking to be approved to place in market. (Brusasco, 2011)

Chapter 2

Declaimer:

All the information in this report are based on Directive 98/79/EC of the European Parlia-ment in vitro diagnostic medical devices, EUR-lex Decision Communities, eds. 1998

1 Introduction: Medical device regulation

In the regulation of medical devices industry, there are so many methods, directives and tools to apply for each device that is developed. IBA group in Louvain-la-Neuve, Bel-gium is one of the companies in this industry which is obligated to apply these regula-tions.

In fact, The company has been building its expertise in cancer-focused technologies for more than 23 years. The company is present in more than 40 sites in North America, Eu-rope and Asia, with its headquarters and R&D center in Belgium.

1.1 Overlook of regulatory frame work in Europe

One of the most substantial keystones of European integration is single market which provides an economic space those labors, services, capital and goods can distribute and flow between nations without barriers. Accordingly mould Europe into a single economy. It is considerable achievement of our time, encompassing European Customs Union, the Schengen Convention and many of the policy areas where the EU is most influential. The single market makesa system that unites and combines diverse national economies into a single unit. (Allen, et al., 1998)

The original and innovative instruments to eliminate the barriers to free circulation of la-bor, services, capital and goods have been developed by The European Union. Moreover, the New Approach to product regulation and the Global Approach to conformity assess-ment feel pride of place. Limiting public intervention is kind of The common but essential thread between these complementary approaches but on the other hand meet their public obligations business industry( European Communities, 2000).

Since 1987 The European Union adopts some 20 directives on the basis of the Global Approach and the New Approach which successfully come into force. Among these, adoption of diverging national technical Standards and regulations make new barriers to trade which can be limited through a procedure laid down by Directive 98/34/EC.A cor-nerstone and major of the single market system is Free circulation of goods. Prevention of new barriers to trade, Technical harmonization and mutual recognition are the essential foundation of the mechanisms in places to achieve this goal.( European Communities, 2000)

Integration of economics and political system of member state is the essential goal of EU, accordingly single market which is based on free movement goods, people, money and services is established as a strong and useful tool. Regarding to the establishment of single market, regulations, directive and decisions have more important position and status than other law. EU identifies these laws as binding law in national authorities but also issues recommendations and opinions as non-binding tools which guide to understand how EU institutions and programs work.( European Communities, 2000)

1.1.1 Three types of EU legislations

EU legislation categorize into 3 types: regulations, directives and decisions.EU regulations are similar to a national law but regulation is applicable in all EU. In addition there is differ-ence between regulation and directives since directives are addressed to national authorities, which must be involved to make directives as part of national law. Also regulation is differ-ent from decisions because decisions are applied in special cases so they follow particular authorities or individuals in this case. Moreover, every Member State must achieve certain result by applying EU directives.(European commission, 2000)

there are two main types of directives for :

� Manufacturing of products and services

� the users of these same products or services

1.2 Medical device directives

Medical devices regulatory certification in EU falls under the COUNCIL DIRECTIVE 93/42/EEC. So Products submitted to directives and then directives apply to products which are intended to be placed or put into service on market for the first time and also apply to new products manufactured in the Member States, and to new used and sec-ond-hand, products imported from third countries.(EUR-lex, 1998)

It is the responsible of manufacturer to recognize the scope of one or more directives are applicable for the product or not due to the fact that the concept of product varies be-tween different clauses of directives.(Jefferys, 2001)

It must take into account that if the importance changes are made in product, it should be consider as new product which must comply with the directives before placed on the market and put into service.On the other hand, products, which are repaired not subject to conformity assessment if and only if the process of repairing does not influ-ence on the original performance, purpose or type.Products specially intended for mili-tary or police purposes are exception in this case and excluded from the scope of the directives. (EUR-lex, 1998)

Applicable Medical Devices Directive for IBA:

All electrical equipment should follow Low Voltage Directive (LVD) and electromagnet-ic compatibility (EMC). If the device is industrial equipment it should also follow (LVD), (EMC) and additionally machinery directive (MD). For medical equipment, Low Voltage Directive (LVD) and Medical Device Directive should be considered but for these device (EMC) is not mentioned separately because it is covered by MDD.

1.3 How medical device are regulated

1.3.1 Critical elements for regulatory attention

The product itself and the process of using product are two elements. safety and perfor-mance of medical devices depend on these two elements. The product control is done by Pre-market review, moreover post-market surveillance check the safety and effectiveness of medical devices in use.Presentation of product to user is the third element which is controlled in pre-market stage. Verbal presentation by the vendor should be useful key which prevent misunderstanding in this case. (World Health Organization, 2003)

1.3.2 Stages of regulatory control

Product, use and presentation of product to user are 3 elements which play role in life span of medical devices as during stages of regulatory control.(World Health Organiza-tion, 2003)

Pre-market place on marketpost-market

Figure 3: life span of regulatory control

1.3.3 MD regulation in EU

MDs fall under the COUNCIL DIRECTIVE 93/42/EEC. These directives mention following area :

� Essential Requirements

� Conformity Assessment

� CE marking

1.3.3.1 Essential Requirements

According to MedicalDevice Directive, productscannotbeplaced on the market and put into service unlesstheyfulfill the essential requirements.(EUR-lex, 1998)

Essential Requirements (Annex I, COUNCIL DIRECTIVE, 93/42/EEC) encompassing fol-lowing field.

1.3.3.1.1 General Requirements:

- design and manufacturing Safety

-Clinical Performances

1.3.3.1.2 Design and constructionRequirements:

-Safety of materials, substances and gases,

-Risk mitigation (electrical, mechanical, thermal, radiation risks, misuse, bad calibration)

1.3.3.1.3 Requirements on information to the user

-User Guide

-Labeling

1.3.3.2 Conformity Assessment

Before placing a product on the market,the product must be subjected to conformity as-sessmentprocedure which provided for in the applicable directive, with the view to affixing the CE marking. And it must be done by manufacturer.

IBA is in class IIb so we use annex II except section 4 for the medical devices Conformity Assessment. accordingly IBA choose LRQA as notified body:

� Conformity assessment of the product

� Conformity assessment of the quality system

� Conformity assessment of putting into service

(EUR-lex, 1998)

1.3.3.3 CE marking

CE marking is marks of quality safety which demonstrate that the product comply with all applicable directives in order to medical devices must comply with essential requirements in directivesalso have been subject to a conformity assessment procedure.

Good to take into account that IBA wants to put CE only for medical device not for industrial device.

And because the product fall under class IIb the process to affix CE marking is:

� DesignateEuropean Authorized Representative.

� Determine all applicable EU Directives for the product.

� Classifying the device.

� Choose appropriate conformity assessment module.

� Identify Notified Body,

� Assessing the device according to Essential Requirements.

� Provide the "Technical File".

� Prepare �Declaration of Conformity".

� Affix the CE Marking on the device.

(EUR-lex, 1998)

Chapter 3

2 Compliance with medical device directives

Declaimer:

All the information in this report are based on Directive 98/79/EC of the European Parliament in vitro diagnostic medical devices, EUR-lex Decision Communities, eds. 1998.

Risk management is considered as one of the essential requirement for medical device. Ac-cording,Essential requirement number 2 point out to risk management as a tool which elimi-nates hazards. Effectively risk management is significant tools which help to be conforming to directives. Actually there are many essential requirements on risk. For instance, essential requirement that asks for mitigating risk and also avoiding risk.

So every time they talk about hazards, risk management is one of strongest tool to eliminate hazards.Infact, there are two important processes which help to be conforming to directives. One of these strong tools is quality management ISO 13485 and the other one is risk man-agement process which asked by essential requirement.(International Organization for Stan-dardization, 2003)

In summary as a first step we go through all directives in essential requirement box then be-gin the two Important processes which are standard of quality management and risk man-agement process. Good to take into account that we should go through horizontal standards which touch all phases of product life cycle such as ISO 13485 and ISO 14971.Then as a next step, go through others standards which are technical standards.

In fact the link between regulation and statutory requirement is written in the directives and risk management is one thing that is linked to essential principle more over risk management help to identify statutory requirement. So because this study is more about this link between regulation and statutory requirement therefore risk management can be used as a strong tool to solve this problem.

In the following picture the place and links between risk management and other component of flow chart is illustrated

2.1 Risk Assessment Requirements and Management

It is crucially significant that medical device manufacturers do not only implementa full risk assessment process of a medical device but also ensure that a solid riskmanagement is also implemented (Medical Device School, 2005). In this way, thepotential risk of a product can be readily addressed from the time it was beingconceptualized to the moment when it is re-leased and disposed.

The many regulationsand standards in the field of medical devices risk management, among these the establishment of the Global Harmonization Task Force (GHTF) which harmonize theseregulations and standards globally, will ease the implementation of the risk manage-mentprocess. GHTF includes Australia,Canada, European Union, Japan, and the United States (GHTF, 2009).

2.2 Application of Risk evaluation in all phases of product life cycle

The medical device �life cycle� is shown in the following Figure. The different assignments for the responsible people are emphasized in each stage of the life cycle by an effective risk management.

The safety and also the performance of medical device are guaranteed by two important items which are product and use. While the post market surveillance ensures its use to be continuously safe and effective, product control is governed by Pre-market review.

Misrepresentation is avoided by placing on-market process in between which includes pack-aging, labeling, advertising and sale. In practice, the phases may have intersection or coming together sometimes.

Figure 8: Application of risk evaluation in product life cycle

2.3 Risk Analysis Techniques

The risk analysis techniques encompassing following area :

Risk Acceptance Criteria, Identify Hazard /Preliminary Hazard Analysis (PHA), Hazard Operability Study (HAZOP), Hazard Analysis and Critical Control Point (HACCP), Human Factors/Usability Analysis/Use Failure Mode and Effects Analysis (FMEA), Process FMEA Design FMEA, Risk Benefit Analysis, and Risk Assessment of Customer Complaint.

In the different phases of the design life cycle The use of these techniques was evaluated, which includes conceptualization, initial development, design verification and engineering validation, design transfer, clinical validation, pilot production, manufacturing scale up, pro-duction monitoring and reporting, and field production monitoring and reporting. (Strutt, J. 1993c)

2.3.1.1 Implementation of FTA in IBA

A fault tree depicts the way in which a particular system failure might occur. The failure mode, for example a house fire, forms the top event of the tree. Working downwards through the branches, using �and/or� logic gates, the analysis reveals the combination of events which themselves cause the top event to occur. Thus the components of a fire would be fuel and oxygen and a source of ignition. The source of ignition could be an electrical fault or a discarded cigarette, etc. (Steve, Frosdick, 1997)

The tree stops when no further analysis is practicable or necessary. Such an analysis informs an understanding of how the failure could occur and what effect design modifications might have. In qualitative terms, the preparation of a fault tree analysis for each of the failure modes or deviations identified through a HAZOP or FMECA ensures that the possibilities of failure have been through and designed out as far as is reasonable and practicable.

(Abdul-Nour, et al.,2002)

In IBA, FTA plays a role as a part of Patlog development process, Good to mention that PatLog 2.0 is a patient handling system for Radiotherapy clinics. For this issue FTA is speci-fied by The analysis in the Preliminary Hazard Analysis (PHA).

The specification of product defines the base of FTA, but FTA will be updated based on changes and modification implemented in Patlog. For each part of system separated FTA analysis is constructed. For example in this case different and separated FTA made for the digital control system on the Loading Station and the Transport Trolley.

Two unwanted Events were judged to be the top level event for the FTA:

A. Patient position incorrect

B. User / Patient injured

The fault tree branch describes the unwanted events that lead to the top-level event. The analysis is divided into several lower-level branches. Each lower-level branch ends with one or more Base events. Each Base event has been evaluated to Determine all associated miti-gations. Mitigations are of the type Design, Labeling, Testing or Demonstration. The FTA is described both as structured text and as a flow diagram. The structured text should be re-garded as the complete description, while the flow chart is primarily intended to give an overview of the FTA. The risk analysis is an integrated part of the development, thus not all references for mitigations are complete until the development is finalized.(Ekaette, et al., 2007)

2.3.1.2 The FMECA process in IBA

As indicated above the FMECA is made after the main design is developed and may be trig-gered by various reasons(Steve, Frosdick, 1997).

First of all, the scope which can cover new product or the impact of a change on an existing product needs to be defined. The scope can be the entire system or a sub-system, good to mention that the scope can only mention one single failure mode, its causes and conse-quences(Steve, Frosdick, 1997).

As It mentioned before The FMECA is a bottom up approach; and for each failure mode the possible causes are identified and for each cause a probability of the harm is evaluated and the possible harm is specified to which a severity is attributed. Good to mention that The GRA (general risk analysis) is considered for recognizing anyforeseeable misuse of the sys-tem, whereas the FMECA focuses on failures only (Ben-Daya, M. 2009).

So to apply FMECA for the system, all possible causes for each failure mode should be listed.

Afterward, the effect, their severity, probability and criticality are evaluated. So severity is linked to the effect on the worker or public.

Severity is based on a qualitative measure of the potential consequences of a safety hazard and is defined as one of the four categories below

Description Category Definition

Catastrophic 1 Potential for multiple deaths or serious injuries

Critical 2 Potential for death or serious injury

Marginal 3 Potential for minor injury

Negligible 4 Little or no potential for injury

Next step is making an assessment of the possible need for mitigation based on the identified risk is done. For each risk, a decision is taken whether the risk is acceptable or needs mitiga-tion. To help in this process the �ALARP table�, is used. It indicates for each combination of probability and severity if the resulting risk is �Broadly Acceptable, �ALARP� (as low as reasonably practicable) or �Intolerable� (Melchers, R.E. 2001).

Actually The ALARP table answers the question: �Do we need to implement risk control measures?�

As next step is determining the component level mitigations corresponding to the risks iden-tified in the previous steps.

Then the residual risk must be evaluated after evaluation of the necessary mitigations. The risk criticality is re-analyzed as described, taking into account the reduction of probability and/or severity introduced by the mitigations. Where the estimated risk is still in the �ALARP� region, feasible measures should be taken. When the estimated risk is still in the intolerable region, mitigations must be put in place and the residual risk must be brought down at least to the ALARP zone (Melchers, R.E. 2001).

Good to take into account that It is not acceptable to release a system with risks in the into-lerable region.

2.3.2 PSA

Probabilistic Safety Assessment (PSA) is an analytical technique for assessing the risk by integratingdiverse aspects of design and operation of a Nuclear Power Plant.Risk can be de?ned as the product of the probability of an accident and the consequences from that accident (IAEA, 2010).

In the context of aNuclear Power plant, Core Damage of the reactor represents an acci-dent and release of radioactivity in the public domain and its effectson them will be the consequence. In order to prevent the occurrence of an accident, various Engineered Safe-ty Features (ESFs) aredesigned (IAEA, 2010).

An accident situation occurs when an initiating event iscoupled with the unavailability of one or more Engineered SafetyFeatures. The accident frequency can be minimized by re-ducingthe frequency of initiating event and improving the availability ofsafety systems. This can be achieved by incorporating good designpractices and selection of reliable components (IAEA, 2010).

The consequenceof accident that may occur can be minimized by providing barriers (e.g. reactor containment and exclusion zone) for arresting therelease of radioactivity and reaching the public. This is the underlying principle of risk reduction.

In general PSA aims at (1) identifyingthe Initiating Events that may lead to severe acci-dent in conjunctionwith the unavailability of associated engineered safety features and(2) evaluating the Accident Sequence Frequency (ASF) and resulting Core Damage Frequen-cy (CDF). A PSA analysis can be extendedto evaluation of importance measures for the identi?cation of critical components, which in turn assists in maintenance planning of-Nuclear Power Plant.

Core Damage Frequency = ?All Accident Sequence Frequency

Accident Sequence Frequency= Initiating Event Frequency � Unavailability of ESFs

Probability is the frequency with which an incident may occur during the lifetime of a fa-cility.

PSA is used to evaluate occupational, public and medical exposure. Also in PSA, FMEA is used as a tool to evaluate equipment failure mode and human errors.

2.3.2.1 Disadvantages of PSA

PSA can provide exhaustive list of deviation with probability of occur which might make important adverse outcome; But it is not impossible to use PSA as a tool in a medium size company like IBA because of 2 reasons:

2.3.2.2 Incorrect probability assessment

In a complex product like PROTEUS 235 that contains large amount of component the risk of incorrect probability assessment is too high. And because probability is foundation of PSA so it is not possible to trust probability in this case.

2.3.2.3 Budget

IBA as a medium size company does not capability to use many employers in quality de-partment to make structure of PSA. So it is not feasible to use PSA in this case.

3 Conclusion:

In the first part of this report I explained the framework of medical device regulation in Europe and described requirements which are needed in each step of this procedure. More over I point out to difference between new approach and old approach. Accordingly I included the role of harmonized standard as a strong tool to compliance with medical device directive which is defined as one of the three European legislations.

Then I introduced CE marking necessity in the medical device industry in term of prod-uct classification and moreover I explained the steps which are required to affix CE mark to the product. Finally to support the explanation, the requirement and process of fulfil-ling them is mentioned in detail.

In second chapter I describedhow manufacturer make compliance with medical device di-rective byrisk management (RM), moreover Ireferenced risk management as an essential requirement for medical device in COUNCIL DIRECTIVE, 93/42/EEC.

Also I mentioned the relation between ISO 13485:2003 & Risk Managementwhich is considered in twoclause of ISO 13485. Then I described three phases of device life cyc-leand how Risk evaluation play role in each of these phases. I explained about process of placing on market and putting into service in radiotherapy industry which is different from other type of medical device industry.. In the end of this chapter I point out to some of RM methods and more over explain in summery about IBA risk management process.