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Quality aspects for medical devices, quality system and certification process
Accepted Manuscript Quality aspects for medical devices, quality system and certification process
Fabio Geremia PII: DOI: Reference:
S0026-265X(17)30352-1 doi: 10.1016/j.microc.2017.04.018 MICROC 2795
To appear in:
Microchemical Journal
Received date: Revised date: Accepted date:
15 September 2016 3 April 2017 9 April 2017
Please cite this article as: Fabio Geremia , Quality aspects for medical devices, quality system and certification process. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Microc(2016), doi: 10.1016/ j.microc.2017.04.018
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Quality Aspects for Medical Devices, Quality System and Certification Process Fabio Geremia (CTP Tecnologie di Processo SpA, Milan, Italy) Introduction Medical devices are nowadays every time more and more important in the healthcare industry and the related processes for worldwide regulation and certification are a topic of great interest and actuality.
PT
As represented in Picture 1 here below, Medical Devices world includes an incredibly wide range of products, this leads to the complexity of the regulatory and certification process and to the fact that all possible categories of products and stakeholders in the healthcare industry must be taken into consideration.
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Picture 1
With regards to the importance of Medical Devices field in healthcare industry, a recent article (CountryFocus: Healthcare, Regulatory and Reimbursement Landscape – Italy) estimates that the pharmaceutical market in Italy in the next five years could decrease from 22 billions to 18 billions of USD (3.3% negative trend), while the medical device market in Italy could grow from 13.2 billions to 16.2 billions of USD (4.2% positive trend).
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Regulation Harmonization Process
As in the pharmaceutical world, the need for regulation harmonization for Medical Devices between European Countries (European Regulation), as well as worldwide, is very important both for Regulatory Authorities and for the industry stakeholders. The process of harmonization of Medical Devices International Regulation was an objective of GHTF: Global Harmonization Task Force, an international Organization comprehending Member States as European Union, USA, Canada, Australia and Japan. Many important guidelines have been issued by GHTF, covering many aspects of the Medical Devices lifecycle, starting from product design, validation and production, up to market surveillance. GHTF was substituted by a more recent and enlarged Organization: IMDRF, International Medical Device Regulators Forum (http://www.imdrf.org/) that was conceived in February 2011 as a forum to discuss future directions in Medical Device regulatory harmonization.
RI
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IMDRF is based on a voluntary group of Medical Device regulators from around the world who have come together to build on the strong foundational work of the Global Harmonization Task Force on Medical Devices (GHTF), and to accelerate international Medical Device regulatory harmonization and convergence.
MA
NU
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The IMDRF Management Committee comprehends many regulatory authority representatives, covering the most industrialized countries as well as many emergent markets: - Australia, Therapeutic Goods Administration (TGA) - Brazil, National Health Surveillance Agency (ANVISA) - Canada, Health Canada - China, China Food and Drug Administration - Europe, European Commission Directorate General Health and Consumers - Japan, Pharmaceuticals and Medical Devices Agency and Ministry of Health, Labour and Welfare - Russia, Russian Ministry of Health - United States of America, US Food and Drug Administration (US FDA)
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Official Observer is the World Health Organization (WHO) and affiliate Organizations are the following: - Asian Harmonization Working Party - APEC Life Sciences Innovation Forum, Regulatory Harmonization Steering Committee
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The Medical Device guidelines issued by GHTF have been incorporated in the IMDRF website, then many new important documents have been issued by IMDRF, as shown in Picture 2 (print-screen from IMDRF website).
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The harmonization process will require time and many important aspects and differences between the different Health Authorities and countries have to be considered by medical devices stakeholders and industry. For example, in the registration process, it is crucial to demonstrate the bio-compatibility of medical devices. This is a critical point for which differences still exist between US (that requires GLP studies, while in EU they are not required) and EU requirements.
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Picture 2
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The New European Regulation
NU
In the scenario of the international regulation harmonization process, the European Council's Permanent Representatives Committee and the European Parliament’s Environment and Health Committee, finally endorsed the agreement reached, after years of negotiation, on the continent’s new medical device and in vitro diagnostic (IVD) regulations.
MA
Following a legal-linguistic review of the two documents planned for September, the Council and Parliament could adopt the two draft regulations by the end of 2016, according to the European Council. The new rules will apply three years after publication for medical devices and five years after publication for IVDs.
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The new regulations, which cover not only the design and manufacture of devices, but also clinical testing, authorization and post-market surveillance, will have an impact on every device manufacturer that sells products in the EU. Stricter requirements are being introduced for the notified bodies that authorise medical devices, and in particular high risk devices, such as implants, joint replacements or insulin pumps, will be subject to additional assessments by experts before they can be authorised.
CE
In addition, a stronger pre-market scrutiny and post-marketing surveillance is being introduced, strengthened rules for high-risk devices and certain other categories of devices; and increased transparency and traceability. One of the focal points of the new regulations is the idea that all devices and IVDs have to be safe and effective.
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“This Regulation aims to ensure the smooth functioning of the internal market as regards medical devices, taking as a base a high level of protection of health for patients and users and taking into account the small and medium sized-enterprises that are active in this sector,” the draft text says. “At the same time, this Regulation sets high standards of quality and safety for medical devices to meet common safety concerns as regards these products.” To that end, all medical device manufacturers offering products in the EU will be required to establish risk management systems and quality management systems, though manufacturers of Class I self-certified devices are exempt from requirements whereby their quality management systems are assessed by a notified body. Manufacturers may rely on equivalent products for bringing new devices to market only in limited circumstances, and for implantable devices and those that are Class III, or highest risk, clinical trials must be performed unless it’s a modification by the same manufacturer of an alreadyapproved device. Also included in the texts are new requirements for importers, distributors and accessories to
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sterilized products. Authorized representatives will also be held liable for defective medical devices, meaning they will have to more closely scrutinize non-EU-based manufacturers more carefully. “Importers shall keep a register of complaints, of non-conforming products and of product recalls and withdrawals, and provide the manufacturer, authorised representative and distributors with any information requested by them, in order to allow them to investigate complaints,” the draft text says. And according to the device experts at the Emergo Group consulting company, CE mark certificates issued prior to final implementation of the new regulations in late 2019 or early 2020 will have a maximum validity of five years. However, all CE mark certifications issued before implementation of the new regulations will automatically expire four years after the new regulations come into force. Another important point discussed in the new Regulation is the Unique Device Identification (UDI) system for Medical Devices.
RI
PT
As the United States expands the scope of the FDA Unique Device Identification (UDI) system to include additional medical devices classes, other countries are moving forward to create similar UDI systems to better identify medical devices from the manufacturer, through the supply chain, to the patient.
SC
The International Medical Device Regulators Forum (IMDRF), the European Commission and the U.S. Food and Drug Administration (FDA) are working together with other regulatory agencies across the world toward the ultimate goal of increasing patient safety and optimizing healthcare through the implementation of a globally harmonized, consistent approach to medical device identification.
Other important updates in the ISO guidelines for MD
D
Two very important guidelines for Medical Device manufacturers are ISO 9001 and ISO 13485, which have been recently updated with ISO 9001:2015 version and ISO 13485:2016 version.
PT E
ISO 9001 is a standard that sets out the requirements for a quality management system. It helps businesses and organizations to be more efficient and improve customer satisfaction. A new version of the standard, ISO 9001:2015, has just been launched, replacing the previous version (ISO 9001:2008).
CE
ISO standards are reviewed every five years and revised if needed. This helps ensure they remain useful tools for the marketplace. The challenges faced by business and organizations today are very different from a few decades ago and ISO 9001 has been updated to take this new environment into account. For example, increased globalization has changed the way we do business and organizations often operate more complex supply chains than they did in the past. In addition, there are increased expectations from customers and other interested parties and, with more access to information, today’s wider society has a stronger voice than ever before. ISO 9001 needs to reflect these changes in order to remain relevant.
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Device manufacturers that distribute in the U.S. are likely already familiar with the process that led to the formulation of FDA’s final rule on UDI. It may be helpful, though, to understand how the process is likely to differ in the European Union (EU), which is actively formulating its own UDI regulations.
The most noticeable change to the standard is its new structure. ISO 9001:2015 now follows the same overall structure as other ISO management system standards (known as the High-Level Structure), making it easier for anyone using multiple management systems. Another major difference is the focus on risk-based thinking. While this has always been part of the standard, the new version gives it increased prominence. The new version of the standard brings the user a number of benefits, for example, ISO 9001:2015: • Puts greater emphasis on leadership engagement • Helps address organizational risks and opportunities in a structured manner • Uses simplified language and a common structure and terms, which are particularly helpful to
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organizations using multiple management systems, such as those for the environment, health & safety, or business continuity • Addresses supply chain management more effectively • Is more user-friendly for service and knowledge-based organizations With regards to ISO 13485, Quality System for MD manufacturers, ISO published the final draft of the latest ISO 13485 quality management standard for medical devices and placed it out for voting on October 29, 2015. Accordingly, publication of the 2016 version of ISO 13485 occurred on March 1 2016. There is to be a three-year transition period. Of note, there is now somewhat of a difference between ISO 13485 and the newly published ISO 9001:2015 standard, of which companies that are certifying to both will need to take into account.
PT
According to the Introduction of ISO 13485:2016: “This International Standard is intended to facilitate global alignment of appropriate regulatory requirements for quality management systems applicable to organizations involved in one or more stages of the life-cycle of a medical device.
RI
This International Standard includes some particular requirements for organizations involved in the life-cycle of medical devices and excludes some of the requirements of ISO 9001 that are not appropriate as regulatory requirements. Because of these exclusions, organizations whose quality management systems conform to this International Standard cannot claim conformity to ISO 9001 unless their quality management system meets all the requirements of ISO 9001”.
SC
The ISO 13485 standard specifies risk-based applications, importantly based on these three points: - Actions taken by a business in its operational and management areas must contain measures for controlling risk.
NU
- Critical factors in decisions driving the operations and management of the company must be evaluated as risk and opportunistic (or risk/benefit) driven outcomes.
MA
- Planning becomes an imperative and tangible, documented activity with appropriate actions and review at specified intervals at executive level decision-making. Risk is mentioned some 15 times throughout the standard, to be considered in outsourcing and supplier controls, with respect to software validations, and in the training of personnel commensurate with risks inherent in the processes they perform.
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Risk is to be taken into account in product planning processes. Risk management activities should also be incorporated during the processes of:
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- Verification, validation and revalidation
- Documentation of risk management in product realization - Monitoring, testing and traceability
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- Corrective actions and preventive actions
AC
In this context, management of risk is an explicit part of executive decision-making about company (quality) objectives. Executive management reviews must specifically address how risk management is incorporated into the areas presented at the reviews. The model needs to be applied in actions and reviews. One will recognize alignment with familiar FDA terms, such as establish, implement and maintain documented processes. There is also a requirement to meet the regulations, statutes, ordinances and directives regarding safety and performance of the medical device. In fact, there is also a statement that unique identification, when required, shall be incorporated. In order to comply with ISO 13485:2016, the company must now maintain a medical device file much like the European requirements. The elements of the file are to demonstrate conformity with the standard, and essentially constitute the technical file of the product.
5.
MD Quality System Implementation, Production Start-Up and Certification Process As shown in Picture 3 here below, a project of MD Quality System Implementation, Production Start-Up and Certification, is generally complex and comprehend several steps, which are critical
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for the successful launch of the product on the market.
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Picture 3
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All phases for medical device development and industrialization, from design up to start-up of the production and process validation, should be carefully planned and monitored, for a proper completion in term of quality results, timelines, necessary resources and costs.
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The Manufacturer must demonstrate the accomplishment of the product essential requisites and can refer to harmonized technical standards (presumption of conformity process), such as the already mentioned ISO 13485 for quality system, ISO 14971 for risk management and ISO 10993 for biocompatibility testing. The medical device technical standards present important points for product design and continuous improvement and therefore they are very important guidelines to be followed to guarantee product quality and safety during all life-cycle
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The Manufacturer can decide which standards are applicable (according to the certification process).
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It is important to underline that GMP Regulations have many points in common between Pharma and ISO world. Therefore, an efficient approach for many manufactures, which are involved both in the pharmaceutical and the medical device world, is to apply an integrated Quality System approach, which combines GMP and ISO requirements (e.g. ISO 13485 and ISO 14971), following a Quality Risk Management structure (suggested by ICH Q9 and by the revised ISO 9001:2015 and ISO 13485:2016) and, where applicable, an integrated Quality System structure (suggested by ICH Q10 for pharmaceuticals). Here below some main topics for GMP and integrated Quality System implementation are reported:
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- Personnel – qualification and training - Premises – installation, validation and maintenance - Utilities – installation, validation and maintenance - Equipment and instruments – installation, validation/calibration and maintenance - Materials – management, receiving and storage SOPs - Production – management, reproducibility and IPCs - Quality Control – methods and management SOPs - Documentation – implementation and management.
6.
Qualification and Validation Activities
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With regards to qualification and validation processes, the mail steps are summarized in the following diagram (Picture 4), very common in the pharmaceutical world and applicable also in the Medical Devices field (Picture 5).
Picture 5
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Picture 4
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In addition, the Quality System and Validation Lifecycle should reflect the ISO philosophy of continuous improvement (Picture 6 and Picture 7).
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Picture 6
Picture 7
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The Quality Management System and Process Validation principles for Medical Devices, previously mentioned and represented in the previous diagrams, are well described in the GHTF Process Validation Guidance, which reports the following definitions for the qualification and validation phases: - Installation Qualification:
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“Establishing by objective evidence that all key aspects of the process equipment and ancillary system installation adhere to the manufacturer’s approved specification and that the recommendations of the supplier of the equipment are suitably considered.” - Operational Qualification (Process Performance Qualification): “Establishing by objective evidence process control limits and action levels which result in product that meets all predetermined requirements.”
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- Performance Qualification (Product Performance Qualification) “Establishing by objective evidence that the process, under anticipated conditions, consistently produces a product which meets all predetermined requirements.
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A principle which is emphasized in this GHTF Guidance document is the importance of process knowledge, which is the basis for product and process design steps and for the definition of the product Critical Quality Attributes (CQA) and the Critical Process Parameters (CPP) to be validated. All these elements should be evaluated and documented through Risk Management tools. Another important point of this GHTF Guidance, again in common with the pharmaceutical GMP guidelines, is the application of proper statistical tools for process control and monitoring and detection of eventual quality adverse trends to be solved and prevented. The Guidance suggests the use of Process Capability as efficient statistical tool for process monitoring (see Picture 8).
Picture 8
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7.
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Conclusions
Medical Devices (MDs) are nowadays every time more and more important in the healthcare industry and the related processes for worldwide regulation and certification are a topic of great interest and importance. In particular, the need for regulation harmonization between European Countries (European Regulation), as well as worldwide, is very important both for Regulatory Authorities and for the industry stakeholders. This article briefly covered the recent updates on Medical Devices regulation and provided a description of a typical process for MD development and industrialization phases, taking into consideration all steps from design up to start-up of the production and process validation. All these activities are crucial for the product certification process. Finally the aim of the article was to emphasize the aspects related to the Quality System, Production, Validation and Quality Control, proposing an integrated approach, which combines the GMP and ISO requirements (e.g., ISO 13485 and ISO 14971), following a Quality Risk Management
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(ICH Q9) and, where applicable, an integrated Pharmaceutical Quality System (ICH Q10) structure.
References IMDRF, International Medical Device Regulators Forum (http://www.imdrf.org/) Proposal of European Regulation for Medical Devices and IVDs, which modifies the Directive 2001/83/CE, the Regulation (CE) n. 178/2002 and the Regulation (CE) n. 1223/2009
ISO 9001:2015 Quality Management Systems ISO 13485:2016 Medical Devices – Quality Management Systems
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GHTF Process Validation Guidance (2004).
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ACCEPTED MANUSCRIPT Highlights
Medical Devices (MDs) are nowadays every time more and more important in the healthcare industry and the related processes for worldwide regulation and certification are a topic of great interest and importance.
In particular, the need for regulation harmonization between European Countries (European Regulation), as well as worldwide, is very important both for Regulatory Authorities and for the industry stakeholders.
This article briefly covered the recent updates on Medical Devices regulation and provided a description of a typical process for MD development and industrialization phases, taking into consideration all steps from design up to start-up of the production and process validation. All these activities are crucial for the product certification process.
Finally the aim of the article was to emphasize the aspects related to the Quality System, Production, Validation and Quality Control, proposing an integrated approach, which combines the GMP and ISO requirements (e.g., ISO 13485 and ISO 14971), following a Quality Risk Management (ICH Q9) and, where applicable, an integrated Pharmaceutical Quality System (ICH Q10) structure.
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Fabio Geremia PII: DOI: Reference:
S0026-265X(17)30352-1 doi: 10.1016/j.microc.2017.04.018 MICROC 2795
To appear in:
Microchemical Journal
Received date: Revised date: Accepted date:
15 September 2016 3 April 2017 9 April 2017
Please cite this article as: Fabio Geremia , Quality aspects for medical devices, quality system and certification process. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Microc(2016), doi: 10.1016/ j.microc.2017.04.018
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Quality Aspects for Medical Devices, Quality System and Certification Process Fabio Geremia (CTP Tecnologie di Processo SpA, Milan, Italy) Introduction Medical devices are nowadays every time more and more important in the healthcare industry and the related processes for worldwide regulation and certification are a topic of great interest and actuality.
PT
As represented in Picture 1 here below, Medical Devices world includes an incredibly wide range of products, this leads to the complexity of the regulatory and certification process and to the fact that all possible categories of products and stakeholders in the healthcare industry must be taken into consideration.
CE
PT E
D
MA
NU
SC
RI
Picture 1
With regards to the importance of Medical Devices field in healthcare industry, a recent article (CountryFocus: Healthcare, Regulatory and Reimbursement Landscape – Italy) estimates that the pharmaceutical market in Italy in the next five years could decrease from 22 billions to 18 billions of USD (3.3% negative trend), while the medical device market in Italy could grow from 13.2 billions to 16.2 billions of USD (4.2% positive trend).
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Page 1 of 12
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Regulation Harmonization Process
As in the pharmaceutical world, the need for regulation harmonization for Medical Devices between European Countries (European Regulation), as well as worldwide, is very important both for Regulatory Authorities and for the industry stakeholders. The process of harmonization of Medical Devices International Regulation was an objective of GHTF: Global Harmonization Task Force, an international Organization comprehending Member States as European Union, USA, Canada, Australia and Japan. Many important guidelines have been issued by GHTF, covering many aspects of the Medical Devices lifecycle, starting from product design, validation and production, up to market surveillance. GHTF was substituted by a more recent and enlarged Organization: IMDRF, International Medical Device Regulators Forum (http://www.imdrf.org/) that was conceived in February 2011 as a forum to discuss future directions in Medical Device regulatory harmonization.
RI
PT
IMDRF is based on a voluntary group of Medical Device regulators from around the world who have come together to build on the strong foundational work of the Global Harmonization Task Force on Medical Devices (GHTF), and to accelerate international Medical Device regulatory harmonization and convergence.
MA
NU
SC
The IMDRF Management Committee comprehends many regulatory authority representatives, covering the most industrialized countries as well as many emergent markets: - Australia, Therapeutic Goods Administration (TGA) - Brazil, National Health Surveillance Agency (ANVISA) - Canada, Health Canada - China, China Food and Drug Administration - Europe, European Commission Directorate General Health and Consumers - Japan, Pharmaceuticals and Medical Devices Agency and Ministry of Health, Labour and Welfare - Russia, Russian Ministry of Health - United States of America, US Food and Drug Administration (US FDA)
D
Official Observer is the World Health Organization (WHO) and affiliate Organizations are the following: - Asian Harmonization Working Party - APEC Life Sciences Innovation Forum, Regulatory Harmonization Steering Committee
PT E
The Medical Device guidelines issued by GHTF have been incorporated in the IMDRF website, then many new important documents have been issued by IMDRF, as shown in Picture 2 (print-screen from IMDRF website).
CE
The harmonization process will require time and many important aspects and differences between the different Health Authorities and countries have to be considered by medical devices stakeholders and industry. For example, in the registration process, it is crucial to demonstrate the bio-compatibility of medical devices. This is a critical point for which differences still exist between US (that requires GLP studies, while in EU they are not required) and EU requirements.
AC
2.
Picture 2
Page 2 of 12
The New European Regulation
NU
In the scenario of the international regulation harmonization process, the European Council's Permanent Representatives Committee and the European Parliament’s Environment and Health Committee, finally endorsed the agreement reached, after years of negotiation, on the continent’s new medical device and in vitro diagnostic (IVD) regulations.
MA
Following a legal-linguistic review of the two documents planned for September, the Council and Parliament could adopt the two draft regulations by the end of 2016, according to the European Council. The new rules will apply three years after publication for medical devices and five years after publication for IVDs.
PT E
D
The new regulations, which cover not only the design and manufacture of devices, but also clinical testing, authorization and post-market surveillance, will have an impact on every device manufacturer that sells products in the EU. Stricter requirements are being introduced for the notified bodies that authorise medical devices, and in particular high risk devices, such as implants, joint replacements or insulin pumps, will be subject to additional assessments by experts before they can be authorised.
CE
In addition, a stronger pre-market scrutiny and post-marketing surveillance is being introduced, strengthened rules for high-risk devices and certain other categories of devices; and increased transparency and traceability. One of the focal points of the new regulations is the idea that all devices and IVDs have to be safe and effective.
AC
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ACCEPTED MANUSCRIPT
“This Regulation aims to ensure the smooth functioning of the internal market as regards medical devices, taking as a base a high level of protection of health for patients and users and taking into account the small and medium sized-enterprises that are active in this sector,” the draft text says. “At the same time, this Regulation sets high standards of quality and safety for medical devices to meet common safety concerns as regards these products.” To that end, all medical device manufacturers offering products in the EU will be required to establish risk management systems and quality management systems, though manufacturers of Class I self-certified devices are exempt from requirements whereby their quality management systems are assessed by a notified body. Manufacturers may rely on equivalent products for bringing new devices to market only in limited circumstances, and for implantable devices and those that are Class III, or highest risk, clinical trials must be performed unless it’s a modification by the same manufacturer of an alreadyapproved device. Also included in the texts are new requirements for importers, distributors and accessories to
Page 3 of 12
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sterilized products. Authorized representatives will also be held liable for defective medical devices, meaning they will have to more closely scrutinize non-EU-based manufacturers more carefully. “Importers shall keep a register of complaints, of non-conforming products and of product recalls and withdrawals, and provide the manufacturer, authorised representative and distributors with any information requested by them, in order to allow them to investigate complaints,” the draft text says. And according to the device experts at the Emergo Group consulting company, CE mark certificates issued prior to final implementation of the new regulations in late 2019 or early 2020 will have a maximum validity of five years. However, all CE mark certifications issued before implementation of the new regulations will automatically expire four years after the new regulations come into force. Another important point discussed in the new Regulation is the Unique Device Identification (UDI) system for Medical Devices.
RI
PT
As the United States expands the scope of the FDA Unique Device Identification (UDI) system to include additional medical devices classes, other countries are moving forward to create similar UDI systems to better identify medical devices from the manufacturer, through the supply chain, to the patient.
SC
The International Medical Device Regulators Forum (IMDRF), the European Commission and the U.S. Food and Drug Administration (FDA) are working together with other regulatory agencies across the world toward the ultimate goal of increasing patient safety and optimizing healthcare through the implementation of a globally harmonized, consistent approach to medical device identification.
Other important updates in the ISO guidelines for MD
D
Two very important guidelines for Medical Device manufacturers are ISO 9001 and ISO 13485, which have been recently updated with ISO 9001:2015 version and ISO 13485:2016 version.
PT E
ISO 9001 is a standard that sets out the requirements for a quality management system. It helps businesses and organizations to be more efficient and improve customer satisfaction. A new version of the standard, ISO 9001:2015, has just been launched, replacing the previous version (ISO 9001:2008).
CE
ISO standards are reviewed every five years and revised if needed. This helps ensure they remain useful tools for the marketplace. The challenges faced by business and organizations today are very different from a few decades ago and ISO 9001 has been updated to take this new environment into account. For example, increased globalization has changed the way we do business and organizations often operate more complex supply chains than they did in the past. In addition, there are increased expectations from customers and other interested parties and, with more access to information, today’s wider society has a stronger voice than ever before. ISO 9001 needs to reflect these changes in order to remain relevant.
AC
4.
MA
NU
Device manufacturers that distribute in the U.S. are likely already familiar with the process that led to the formulation of FDA’s final rule on UDI. It may be helpful, though, to understand how the process is likely to differ in the European Union (EU), which is actively formulating its own UDI regulations.
The most noticeable change to the standard is its new structure. ISO 9001:2015 now follows the same overall structure as other ISO management system standards (known as the High-Level Structure), making it easier for anyone using multiple management systems. Another major difference is the focus on risk-based thinking. While this has always been part of the standard, the new version gives it increased prominence. The new version of the standard brings the user a number of benefits, for example, ISO 9001:2015: • Puts greater emphasis on leadership engagement • Helps address organizational risks and opportunities in a structured manner • Uses simplified language and a common structure and terms, which are particularly helpful to
Page 4 of 12
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organizations using multiple management systems, such as those for the environment, health & safety, or business continuity • Addresses supply chain management more effectively • Is more user-friendly for service and knowledge-based organizations With regards to ISO 13485, Quality System for MD manufacturers, ISO published the final draft of the latest ISO 13485 quality management standard for medical devices and placed it out for voting on October 29, 2015. Accordingly, publication of the 2016 version of ISO 13485 occurred on March 1 2016. There is to be a three-year transition period. Of note, there is now somewhat of a difference between ISO 13485 and the newly published ISO 9001:2015 standard, of which companies that are certifying to both will need to take into account.
PT
According to the Introduction of ISO 13485:2016: “This International Standard is intended to facilitate global alignment of appropriate regulatory requirements for quality management systems applicable to organizations involved in one or more stages of the life-cycle of a medical device.
RI
This International Standard includes some particular requirements for organizations involved in the life-cycle of medical devices and excludes some of the requirements of ISO 9001 that are not appropriate as regulatory requirements. Because of these exclusions, organizations whose quality management systems conform to this International Standard cannot claim conformity to ISO 9001 unless their quality management system meets all the requirements of ISO 9001”.
SC
The ISO 13485 standard specifies risk-based applications, importantly based on these three points: - Actions taken by a business in its operational and management areas must contain measures for controlling risk.
NU
- Critical factors in decisions driving the operations and management of the company must be evaluated as risk and opportunistic (or risk/benefit) driven outcomes.
MA
- Planning becomes an imperative and tangible, documented activity with appropriate actions and review at specified intervals at executive level decision-making. Risk is mentioned some 15 times throughout the standard, to be considered in outsourcing and supplier controls, with respect to software validations, and in the training of personnel commensurate with risks inherent in the processes they perform.
D
Risk is to be taken into account in product planning processes. Risk management activities should also be incorporated during the processes of:
PT E
- Verification, validation and revalidation
- Documentation of risk management in product realization - Monitoring, testing and traceability
CE
- Corrective actions and preventive actions
AC
In this context, management of risk is an explicit part of executive decision-making about company (quality) objectives. Executive management reviews must specifically address how risk management is incorporated into the areas presented at the reviews. The model needs to be applied in actions and reviews. One will recognize alignment with familiar FDA terms, such as establish, implement and maintain documented processes. There is also a requirement to meet the regulations, statutes, ordinances and directives regarding safety and performance of the medical device. In fact, there is also a statement that unique identification, when required, shall be incorporated. In order to comply with ISO 13485:2016, the company must now maintain a medical device file much like the European requirements. The elements of the file are to demonstrate conformity with the standard, and essentially constitute the technical file of the product.
5.
MD Quality System Implementation, Production Start-Up and Certification Process As shown in Picture 3 here below, a project of MD Quality System Implementation, Production Start-Up and Certification, is generally complex and comprehend several steps, which are critical
Page 5 of 12
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for the successful launch of the product on the market.
RI
PT
Picture 3
SC
All phases for medical device development and industrialization, from design up to start-up of the production and process validation, should be carefully planned and monitored, for a proper completion in term of quality results, timelines, necessary resources and costs.
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The Manufacturer must demonstrate the accomplishment of the product essential requisites and can refer to harmonized technical standards (presumption of conformity process), such as the already mentioned ISO 13485 for quality system, ISO 14971 for risk management and ISO 10993 for biocompatibility testing. The medical device technical standards present important points for product design and continuous improvement and therefore they are very important guidelines to be followed to guarantee product quality and safety during all life-cycle
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The Manufacturer can decide which standards are applicable (according to the certification process).
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It is important to underline that GMP Regulations have many points in common between Pharma and ISO world. Therefore, an efficient approach for many manufactures, which are involved both in the pharmaceutical and the medical device world, is to apply an integrated Quality System approach, which combines GMP and ISO requirements (e.g. ISO 13485 and ISO 14971), following a Quality Risk Management structure (suggested by ICH Q9 and by the revised ISO 9001:2015 and ISO 13485:2016) and, where applicable, an integrated Quality System structure (suggested by ICH Q10 for pharmaceuticals). Here below some main topics for GMP and integrated Quality System implementation are reported:
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- Personnel – qualification and training - Premises – installation, validation and maintenance - Utilities – installation, validation and maintenance - Equipment and instruments – installation, validation/calibration and maintenance - Materials – management, receiving and storage SOPs - Production – management, reproducibility and IPCs - Quality Control – methods and management SOPs - Documentation – implementation and management.
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Qualification and Validation Activities
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With regards to qualification and validation processes, the mail steps are summarized in the following diagram (Picture 4), very common in the pharmaceutical world and applicable also in the Medical Devices field (Picture 5).
Picture 5
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Picture 4
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In addition, the Quality System and Validation Lifecycle should reflect the ISO philosophy of continuous improvement (Picture 6 and Picture 7).
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Picture 6
Picture 7
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The Quality Management System and Process Validation principles for Medical Devices, previously mentioned and represented in the previous diagrams, are well described in the GHTF Process Validation Guidance, which reports the following definitions for the qualification and validation phases: - Installation Qualification:
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“Establishing by objective evidence that all key aspects of the process equipment and ancillary system installation adhere to the manufacturer’s approved specification and that the recommendations of the supplier of the equipment are suitably considered.” - Operational Qualification (Process Performance Qualification): “Establishing by objective evidence process control limits and action levels which result in product that meets all predetermined requirements.”
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- Performance Qualification (Product Performance Qualification) “Establishing by objective evidence that the process, under anticipated conditions, consistently produces a product which meets all predetermined requirements.
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A principle which is emphasized in this GHTF Guidance document is the importance of process knowledge, which is the basis for product and process design steps and for the definition of the product Critical Quality Attributes (CQA) and the Critical Process Parameters (CPP) to be validated. All these elements should be evaluated and documented through Risk Management tools. Another important point of this GHTF Guidance, again in common with the pharmaceutical GMP guidelines, is the application of proper statistical tools for process control and monitoring and detection of eventual quality adverse trends to be solved and prevented. The Guidance suggests the use of Process Capability as efficient statistical tool for process monitoring (see Picture 8).
Picture 8
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Conclusions
Medical Devices (MDs) are nowadays every time more and more important in the healthcare industry and the related processes for worldwide regulation and certification are a topic of great interest and importance. In particular, the need for regulation harmonization between European Countries (European Regulation), as well as worldwide, is very important both for Regulatory Authorities and for the industry stakeholders. This article briefly covered the recent updates on Medical Devices regulation and provided a description of a typical process for MD development and industrialization phases, taking into consideration all steps from design up to start-up of the production and process validation. All these activities are crucial for the product certification process. Finally the aim of the article was to emphasize the aspects related to the Quality System, Production, Validation and Quality Control, proposing an integrated approach, which combines the GMP and ISO requirements (e.g., ISO 13485 and ISO 14971), following a Quality Risk Management
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(ICH Q9) and, where applicable, an integrated Pharmaceutical Quality System (ICH Q10) structure.
References IMDRF, International Medical Device Regulators Forum (http://www.imdrf.org/) Proposal of European Regulation for Medical Devices and IVDs, which modifies the Directive 2001/83/CE, the Regulation (CE) n. 178/2002 and the Regulation (CE) n. 1223/2009
ISO 9001:2015 Quality Management Systems ISO 13485:2016 Medical Devices – Quality Management Systems
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GHTF Process Validation Guidance (2004).
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ACCEPTED MANUSCRIPT Highlights
Medical Devices (MDs) are nowadays every time more and more important in the healthcare industry and the related processes for worldwide regulation and certification are a topic of great interest and importance.
In particular, the need for regulation harmonization between European Countries (European Regulation), as well as worldwide, is very important both for Regulatory Authorities and for the industry stakeholders.
This article briefly covered the recent updates on Medical Devices regulation and provided a description of a typical process for MD development and industrialization phases, taking into consideration all steps from design up to start-up of the production and process validation. All these activities are crucial for the product certification process.
Finally the aim of the article was to emphasize the aspects related to the Quality System, Production, Validation and Quality Control, proposing an integrated approach, which combines the GMP and ISO requirements (e.g., ISO 13485 and ISO 14971), following a Quality Risk Management (ICH Q9) and, where applicable, an integrated Pharmaceutical Quality System (ICH Q10) structure.
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