New MDR Regulation Implementation; MDR Changes; EU Representative Requests

1. Implementation of the new regulations MDR:

On May 5, 2017, the Official Journal of the European Union officially released the new EU medical device CE regulation (REGULATION (EU) 2017/745, referred to as "MDR"). The MDR will replace the original Medical Directive 93/42/EEC (Medical Devices Directive) 90/385/EEC (Active Implantable Medical Devices Directive). According to the requirements of MDR Article 123, the MDR came into effect on May 26, 2017, and officially replaced the original Medical Directive 93/42/EEC (Medical Device Directive) 90/385/EEC (Active Plant Directive) on May 26, 2020. into the Medical Devices Directive).

Due to the impact of the new crown epidemic, the EU has postponed its implementation by one year, and it will be implemented on May 26, 2021

After the implementation of MDR, medical device manufacturers can still apply for product CE certificates in accordance with Medical Directive 93/42/EEC (Medical Device Directive) and 90/385/EEC (Active Implantable Medical Device Directive) during the three-year transition period. Maintain the validity of the CE certificate. According to the provisions of MDR Article 120 clause 2, the CE certificate reviewed and issued by the notified body during the transition period will continue to be valid, but the validity period will not exceed 5 years from the date of delivery, and will eventually expire on May 27, 2024.

2. The main changes of MDR

Compared with the original medical device MDD directive and medical device AIMDD directive, the new EU medical device CE regulation MDR has added a lot of changes and requirements, such as:

(1) Expanded the scope of application of medical devices

(2) Proposed new concepts and definitions of medical devices

(3) The classification of EU medical devices is refined

(4) Improve the general safety and performance requirements of medical devices

(5) Strengthen the requirements for medical device technical documents

(6) Strengthen post-market supervision of medical devices

(7) Improve the relevant requirements for CE clinical evaluation of medical devices

(8) Propose the establishment and use of Eudamed database for medical devices

(9) Propose the traceability of medical devices (UDI)

(10) Stricter requirements for medical device notified bodies

Expanded scope of application of MDR

The new CE regulation for medical devices, MDR, not only covers all products covered by the original MDD and AIMDD; it also covers devices specially used for cleaning, disinfection or sterilization of devices, as well as products without intended medical purposes listed in MDR Annex XVI, such as the United States. products such as pupils, facial fillers or injections, tattoos, skin improvement and beauty;

Contains certain drug-device combination products, please refer to MDR Article 1 (8, 9) for details;

Contains certain products manufactured from inactive or processed inactive tissue or cell derivatives of human origin;

Contains specific product groups that claim to have cosmetic purposes only or another non-medical purpose, but which are similar in function and risk characteristics to medical devices;

Declare that nanomaterial devices fall within the scope of the MDR and are subject to the most stringent evaluation procedures;

Including devices that emit ionizing radiation and software for medical purposes

MDR proposes new concepts and definitions of devices

Many new concepts have been added to the new regulations for medical device CE, and the MDR has increased from 14 concepts in the original MDD to 71 now. For example, some concepts of clinical trials of devices and post-market supervision of medical devices have been added, such as "recall, withdraw, serious incident, clinical consent, clinical benefit", see MDR Article 2 for details.

MDR changes the classification of medical devices

From the original medical device MDD directive to the new medical device CE regulation MDR, medical devices are still specifically divided into four categories for supervision: Class I, Class IIa, Class IIb, and Class III. In the original MDD, the classification specification is Annex IX in 93/42/EEC and the corresponding guide MEDDEV 2. 4/1 Rev. 9; while Article 51 and Annex VIII in the new CE regulation MDR for medical devices elaborate the classification information of the product . The main change is from "18" in the original MDD to "22" in the MDR.

Rule 1-Rule 4: NON-INVASIVE DEVICES

Rule 3: Addition of human cells, tissues, trachea used in vitro directly from the human body or human embryos, and then implanted or injected into the body. Such devices are Class III.

Rule 5-Rule 8: INVASIVE DEVICES invasive devices

Rule 8: Added on the original basis: active implant devices or their related accessories, breast implants or cardiac repair mesh fabrics, complete or partial joint replacements, and disc replacement implants that directly contact the spine are Class III.

Rule 9-Rule 13: ACTIVE DEVICES Active Devices

Rule 9: On the original basis, "active devices that release ionizing radiation for therapeutic purposes" and "active implantable devices for controlling, monitoring or directly affecting" are added, both of which are Class II b.

Rule 11: Newly added, software for providing decision-making information for diagnosis or treatment purposes and monitoring physiological processes are all Class II a; other software classes are Class I.

Rule 14-Rule 22: SPECIAL RULES special rules

Rule 14: Further refines the requirements for the classification of "medical products derived from human blood or plasma".

Rule 18: Further refine the classification requirements for "devices made from inactive or processed inactive tissues or cells or other derivatives of human or animal origin".

Rule 19: Add classification requirements for nanomaterial devices.

Rule 20: Added classification of invasive devices associated with body orifices by means of inhalation.

Rule 21: Added devices for introducing absorbable substances into the human body.

Rule 22: Added classification of active therapeutic devices with integrated or combined diagnostic capabilities.

Also removed the separate classification of blood bags in MDD

MDR general safety and performance requirements for medical devices

It has been further improved from Annex 1 ESSENTIAL REQUIREMENTS in the original MDD to "ANNEX I GENERAL SAFETY AND PERFORMANCE REQUIREMENTS"; the original 13 articles have been increased to 23 now, and Article 13: Information supplied by the manufacturer in the MDD is used as a Separate chapter "CHAPTER III REQUIREMENTS REGARDING THE INFORMATION SUPPLIED WITH THE DEVICE". A number of performance requirements are refined, and the risk analysis and management of medical devices is emphasized throughout the entire product life cycle of medical devices, including design and production, sales, and post-market supervision.

MDR's new requirements for medical device CE technical documents

In the new regulation MDR for medical device CE, many requirements for the content of medical device CE technical documents have been added, and it is clearly pointed out that the device post-market supervision plan and safety update report (PSUR) are part of the content of CE technical documents. The data collected by the post-market supervision system of the device is updated in time for the corresponding information in the CE technical file. The Annex III Technical Documentation on Post-Market Surveillance in the new medical device regulation MDR stipulates in detail that the documents for post-market supervision of products should be prepared in accordance with Article 83-86, including the post-market supervision plan for medical devices and the post-market supervision of medical devices. Report or Periodic Safety Update Report (PSUR) for medical devices.

At the same time, the Annex IV EU Declaration of Conformity in the new medical device CE regulation MDR also details the specific content of the "CE Declaration of Conformity" document.

MDR strengthens post-market supervision system for medical devices

Chapter VII POST-MARKET SURVEILLANCE, VIGILANCE AND MARKET SURVEILLANCE focuses on post-market surveillance, vigilance and market surveillance of medical devices.

· Establish, implement and maintain a post-market surveillance system for medical devices (see MDR Article 83).

· Emphasize that the post-market supervision system for medical devices runs through the entire life cycle and is constantly updated.

· Establish a "post-market surveillance plan" for medical devices (see MDR Article 84), see MDR Annex III for details.

· Preparation of "Post-Marketing Regulatory Reports" for Class I medical devices (see MDR Article 85).

Preparation of Periodic Safety Update Reports (PSURs) for Class IIa, IIb and III medical devices (see MDR Article 86).

The PSUR needs to be updated regularly as part of the CE technical documentation for medical devices.

· Establish a medical device CE alert system and an electronic post-market supervision system (see MDR Article 92).

During the entire service life of the medical device, the clinical evaluation of the medical device and the medical device CE technical file are updated according to the clinical data of the medical device obtained after the implementation of PMCF (MDR Annex XIV Part B)

MDR requirements for CE clinical evaluation of medical devices

Regarding the clinical evaluation of medical device CE, the new regulation MDR for medical device CE proposes:

(1) Require to perform, evaluate, report and update medical device CE clinical evaluation data in accordance with Article 61 and Appendix XIV partA;

(2) For specific Class III and Class IIb medical devices, the CER shall consider the opinions of the consulting expert group;

(3) For implantable and Class III medical devices, it is proposed to consider clinical research;

(4) Require CER to update the data obtained by PMCF;

(5) For Class III and implantable medical devices, the frequency of CER updates is proposed;

(6) The characteristics that need to be considered to clearly prove the CE substantial equivalence of medical devices;

(7) Requires its interaction with risk management

MDR on Eudamed Database

The new EU medical device CE regulation MDR proposes:

Clarify the purpose of establishing the European Medical Device Database (Eudamed) and the information it contains (see Article 33 for details);

the openness of information;

Class III medical devices and implantable medical devices are required, and the safety and clinical performance information of the products must be made available to the public through Eudamed.

MDR for traceability of medical devices (UDI)

The new EU medical device CE regulation MDR stipulates:

(1) Except for customized and research devices, all other devices need to establish a UDI system;

(2) UDI information is reflected on the label or packaging (excluding the container);

(3) UDI-DI information needs to be stated in the declaration of conformity (see Article 27);

(4) Annex VI Part B proposes the information contained in UDI-DI;

(5) There are special requirements for UDI of implantable, reusable, software, and configurable devices (see Annex VI Part C)

(6) See Article 123 (f) for the time of UDI implementation on the package or label.

(7) The UDI issuing entity is designated by the European Commission.

(8) Transitional: Article 120 states that “until the Commission has designated an issuing entity under Article 27(2), GS1, HIBCC and ICCBBA shall be deemed to be designated issuing entities”

MDR strictly enhances the requirements for medical device notified body NB

Regarding the "Medical Device Notified Body", the new regulations on medical device CE and MDR spend a lot of time describing its functions and requirements, requiring each NB to re-apply for the MDR's third-party audit authorization in accordance with the requirements of Appendix VII, and keep the NB's review at any time. The right to re-examination of the medical device CE technical file. It is conceivable that under the rules of the MDR game, in order to meet the regulatory requirements of the competent authorities, each NB will greatly increase the audit strength and standards of the medical device CE technical documents of the applicant company, and it is difficult for medical device manufacturers to obtain the MDR CE certificate. will be an unprecedented increase.

3. EU Authorized Representative

In order to better protect EU consumers and the environment, EU law requires that, in order to achieve product traceability, CE-marked products placed on the EU market by manufacturers must be marked with the manufacturer's name and contact Address; if the manufacturer is from a country outside the European Economic Area (EEA) (including EU and EFTA), the product must be marked with both the name and contact address of the manufacturer and the manufacturer's authorized representative in the EU. For example, in order to improve the overall efficiency of market surveillance, the European Commission will be responsible for examining the efficiency of market surveillance, and requires all member states to meet minimum legal requirements and strengthen cooperation and exchanges. In addition, the European Commission will work with customs and with relevant stakeholders (manufacturers, EU authorized representatives, importers, distributors) to establish a product traceability system. The European Commission first focuses on high-risk areas, such as medical device products that are closely related to human health.

European Authorised Representative (European Authorised Representative or European

Medical device FDA 510(k) registration; FDA medical device product classification; FDA medical device related regulations; FDA company registration and product listing

1. FDA 510(k) registration for medical devices

The FDA 510(k) registration of medical devices is usually called 510(k) registration because of its corresponding section 510 of the FD&C Act. FDA 510(k) is one of the main ways for medical devices to be marketed in the United States. The vast majority of Class II medical devices and some Class I and Class III medical devices are cleared and marketed through this way. FDA has a basic requirement for the information that must be included in FDA 510(k) registration documents, which are roughly as follows:

(1) Application letter, this part should include the basic information of the applicant (or contact person) and the enterprise, the purpose of FDA 510(K) submission, the name, model and classification information of the device applying for listing, and the product for substantial equivalence comparison ( Predicate Device) name and its 510(k) number;

(2) Table of Contents, which is a list of all the information contained in the FDA 510(k) document (including attachments);

(3) A statement of authenticity assurance, for which the FDA has a standard sample;

(4) The name of the equipment, that is, the generic name of the product, the FDA classification name, and the trade name of the product;

(5) Registration number. If the company has already registered the company when submitting the FDA 510(k), the registration information should be given, and if it is not registered, it should also be indicated;

(6) Classification, that is, the classification group, category, management number and product code of the product;

(7) Performance standards, mandatory or voluntary standards that the product meets;

(8) Product identification, including enterprise packaging identification, instruction manual, packaging accessories, product identification, etc.;

(9) Substantial Equality Comparison (SE);

(10) 510(k) abstracts or statements;

(11) Product description, including the intended use of the product, working principle, power source, components, photos, process drawings, assembly drawings, structural diagrams, etc.;

(12) The safety and effectiveness of the product, including various design and test data;

(13) Biocompatibility;

(14) Color additives (if applicable);

(15) Software verification (if applicable);

(16) Sterilization (if applicable), including description of sterilization method, sterilization verification product packaging and identification, etc.

Substantial Equality Comparison (SE)

Substantial equivalence comparison is to prove that the product applied for listing and the product that has been legally sold in the U.S. market are substantially equivalent in terms of safety and efficacy. Selecting an appropriate product for comparison is a critical step in an FDA 510(K) registration application. The following aspects should be considered when making comparisons:

The enterprise must provide sufficient information to prove that the device being marketed and the device being compared are substantially equivalent (SE), otherwise the FDA 510(k) application will not be approved.

FDA 510(K) Review Process

After receiving the 510(k) information submitted by the enterprise, the FDA first checks whether the information is complete. If the information is complete, it will accept it and issue a confirmation to the enterprise. At the same time, it will give the application acceptance number (K ​​YYXXXX), which will also be used as the official number. The approved number; if it is not complete, the enterprise is required to complete it within the specified time, otherwise it will be abandoned by the enterprise. After the FDA accepts the application, it will enter the internal working procedure, which may also require the enterprise to supplement some information. After the 510(k) application is reviewed, the FDA does not immediately issue an approval letter, but determines whether to conduct an on-site GMP assessment based on the product risk level and whether the market has previously reacted to the enterprise, and then sends it to the enterprise after the assessment is passed. Formal approval letter (Clearance); if on-site GMP assessment is not required, a formal approval letter will be issued immediately after the 510(k) application is approved

2. FDA medical device product classification

The classification principles of medical devices in the United States are recorded in Section 513 of the FD&C Act, which stipulates that medical devices are divided into three categories:

Class I, the implementation of general control (General Control)

These devices can ensure their efficacy and safety as long as they are subject to general control, such as crutches, spectacle lenses, tapes, etc., accounting for about 27% of all medical devices. These controls include:

Prohibit the sale of shoddy and improperly labeled products;

FDA has to ban the sale of substandard products;

Must report to FDA on hazards, repairs, replacements, etc.; restrict the sale, sale, and use of certain equipment;

Implement GMP;

Require domestic manufacturers, importers and sellers to register with the FDA, and manufacturers must list the products they manufacture. Class II and Class III are also subject to the above requirements.

Class II, the implementation of special controls (Special Controls)

In addition to the above general controls, these products must meet the special requirements set by the FDA or other standards recognized by the industry. Such products include medical gloves, electric wheelchairs, hearing aids, sphygmomanometers, diagnostic catheters, etc., accounting for about all equipment 60%. Among the special requirements of the FDA, there are other mandatory standards for specific products (mandatory performance standards), patient registration and post-market surveillance.

Class III, implementation of premarket authorization

Generally speaking, Class III products are mostly devices that maintain, support or implant in the body, which are potentially dangerous to patients and may cause injury or disease, such as cardiac rhythm regulators, intrauterine devices and infant incubators, etc. 8% of all equipment. These devices must obtain FDA's PMA before they can be sold.

In principle, products that have been on the market before 1976 (Preamendment Devices) can continue to be sold without the FDA's PMA unless required by the FDA. Currently, the FDA requires 8 of the 135 Preamendment Devices to apply for pre-market approval, including:

(1) Implantable cerebellar stimulator (1984,6,28)

(2) Implantable diaphragmatic nerve stimulator (1986,4,8);

(3) IUD (1986,8,4);

(4) Transabdominal Amnioscope (Fetoscope) and Auessories (1987, 1, 29)

(5) Alternative Heart (1987,5,13);

(6) Surgical equipment for tubal occlusion (1987,12,31);

(7) Implantable cerebellum/inferior cortex stimulation pain relief device;

(8) Silicone breast fillers (1991,7,9).

Under the provisions of SMDA, FDA can also reclassify the original Class III Preamendment Devices to Class II or Class I as needed. FDA uses the technical advisory committee (Panel) to carry out the work of classification, re-classification and pre-market approval. At present, the FDA has 16 Panels, each of which is composed of a medical expert and six scholars, and has no voting rights. Consumer representatives and industry representatives participated for a term of 4 years.

In addition to grading according to the risk of the device, according to the purpose of the device, the FDA divides the existing medical device products into 16 categories and 1700 kinds in total. These lists can be found in the "Classification Names for Medical Devices and In Vitro Diagnostic Products". Devices and In Vitro Diagnostic Products). There are some in vitro medical devices that were classified as drugs before 1976 and have been reclassified as medical devices, called Transitional Devices, and most of them are Class III. In addition to FDA's voluntary reclassification, manufacturers may also file a reclassification application with the FDA.

3. FDA medical device regulations

The U.S. statutes on the management of medical devices mainly include the following three:

(1) The Federal Food, Drug & Cosmetic Act of 1038 (FD&C Act of 1938) of 1938. There were three major amendments to this Act after 1938, namely:

‧1976 Medical Device Amendments (The Medical Device Amendments of 1976, referred to as the 1976 Amendments)

‧The Safe Medical Devices Act of 1990 (SMDA)

‧1992 Medical Devices Amendments (The Medical Devices Amendments of 1992, referred to as the 1992 Amendments)

(2) Public Health Service Act

(3) Fair Packaging and Labeling Act

The FD&C Act of 1938 prohibited the sale of shoddy and improperly packaged medical devices to the market. The 1976 Amendment significantly amended the relevant provisions, authorizing the FDA to strictly control all medical devices before they are marketed to ensure their efficacy and safety. Control measures include classification, premarket notification, premarket approval, investigational device exemption, good manufacturing practice, and postmarket surveillance. Surveillance), etc., and also strengthens the FDA's jurisdiction over post-marketing products, such as maintenance, replacement, reporting, recording, and marketing of specific products, especially the quality system requirements (GMP) for manufacturers, which makes the United States have medical devices. control is more complete.

The 1990 amendments focused on: medical device report, tracking management of permanently implanted, support or life-sustaining devices, device design changes, postmarket surveillance, fines, recalls, and In requesting FDA to revise the GMP provisions and increase the requirements for design control.

In 1992, the details of the 1990 SMDA were revised, adding the provision of humanitarian device exemption. Special control and PMA review may not be applied to special devices that use less than 4,000 patients to encourage manufacturers to develop Special medical equipment for a small number of patients.

In addition, the Public Health Service Law mainly stipulates the control measures for biological agents (such as serum, blood, vaccines, etc.) and radiation equipment. The packaging and labelling rules detail the packaging and labelling requirements for products.

4. FDA company registration and product listing

According to the requirements of 21 CFR part 807 of the United States Code of Federal Regulations, companies involved in the production and distribution of medical devices for commercial distribution in the United States must register with the United States Food and Drug Administration (FDA) annually. The process of registration is called Establishment Registration; at the same time, these companies must confirm to the FDA that the medical devices they are distributing commercially, including those for export only, a process called Medical Device Listing ).

After clarifying the classification and control requirements of the product, the enterprise can start to prepare the relevant application materials, and report to the FDA according to certain procedures to obtain approval. For any product, companies are required to conduct business registration (Registration) and product listing (Listing). For Class I products (accounting for about 47%), general control is implemented, and most products only need to be registered, listed and implemented GMP specifications, and the products can enter the US market (among which a very small number of products even have GMP standards. Exemption, very few reserved products need to submit a 510 (K) application to the FDA, namely PMN (Premarket Notification). After the registration, it is necessary to implement GMP and submit a 510(K) application (very few products are exempted from 510(K)). After listing, it is necessary to implement GMP and submit a PMA (Premarket Application) application to the FDA (some Class III products are still PMN).

For Class I products, after the company submits relevant information to FDA, the FDA only announces it, and no relevant certificates are issued to the company; for Class II and III devices, the company must submit PMN or PMA. At the same time of the announcement, FDA will give the company a notice. Formal market access approval letter (Clearance), which allows companies to directly sell their products in the US medical device market in their own name. As for whether to go to the enterprise for on-site GMP assessment during the application process, it is determined by the FDA based on comprehensive factors such as product risk level, management requirements and market feedback.

Based on the above content, it can be seen that most products can be approved by the FDA after the enterprise registration, product listing and implementation of GMP, or after submitting a 510(K) application.

Introduction of MDSAP single audit procedure for medical devices; new features of MDSAP; acceptance of MDSAP by regulatory agencies in participating countries; brief description of MDSAP audit procedure; advantages of MDSAP audit procedure

1. Introduction of MDSAP Medical Device Single Audit Procedure

MDSAP is the acronym for Medical Device Single Audit Program in English, and it is translated into Chinese as "Medical Device Single Audit Program" or "Medical Device Integrated Audit Program", "Medical Device Multinational Joint Audit". MDSAP was initiated by IMDRF (International Medical Device Regulators Forum).

The regulatory agencies of the United States, Australia, Brazil, Canada, and Japan have joined the "Medical Device Single Audit Program (MDSAP)" project and implemented it on a trial basis. This procedure aims to establish a single audit process that meets and unifies the audit requirements of the above-mentioned countries, making the audit more comprehensive and effective.

On January 1, 2015, worldwide, manufacturers interested in the US, Australia, Brazil and Canada markets were invited to participate in the project. Last summer, Japan officially became a member of MDSAP, and manufacturers interested in the Japanese market will also be invited by this invitation.

MDSAP is audited by a third party, and the medical device regulatory authorities of participating countries can use this audit report as a basis for judgment. MDSAP not only reduces the work of routine inspections by supervisory authorities, but also enables all supervisory authorities to share the same and reliable audit results. Since regulatory agencies recognize the audit results of MDSAP, manufacturers can reduce the number of audits corresponding to different regulatory agencies and reduce production interference caused by audits. The introduction of MDSAP makes the auditing process international standard and reduces the burden on production enterprises.

The audit of MDSAP is based on the existing medical device quality system regulations of participating countries, and no additional requirements are added. Compliance with regulatory requirements (ISO 13485:2016), Brazilian Good Manufacturing Practice (RDC ANVISA 16/2013), US Quality System Specification (21 CFR Part 820) and other specific pre- and post-market regulatory requirements in MDSAP participating countries. The US FDA accepts MDSAP audits to replace the FDA's routine inspections, and conducts MDSAP audits for all categories of medical devices, including in vitro diagnostic devices, every two years, but premarket audits (PMA) and complaint inspections cannot be replaced by MDSAP.

Through the continuous participation of production enterprises, the MDSAP project will be gradually improved and is expected to be officially launched in 2017. MDSAP will enhance the credibility of third-party institutions, promote the unification of national regulations and audit standards, and expand the global safety net for patient protection.

Since the beginning of 2017, after the United States, Canada and other countries announced the approval of MDSAP, the medical device quality management system audit has entered the era of multi-national joint audit. The implementation of MDSAP has improved the supervision efficiency of the competent authorities and reduced the cost of quality management of enterprises, but it has also increased the difficulty of meeting the audit. Since IMDRF started MDSAP, the agency has successively developed a number of procedures such as third-party agency accreditation, audit methods and audit tasks, audit report accreditation, etc., but the audit basis directly refers to the relevant standards and regulations of MDSAP participating countries. If medical devices are sold to multiple MDSAP participating countries at the same time, the applicant company must meet the requirements of ISO13485:2016, national medical device quality management system regulations for multiple purposes and other relevant regulations at the same time. This is undoubtedly for medical device companies. is a huge challenge.

2. New features of MDSAP

MDSAP (Medical Device Single Audit Program) is the International Medical Device Regulators Forum (IMDRF) in order to simplify the regulatory burden of medical device authorities and promote industrial development, without affecting public health, for the quality management system of medical device manufacturers. A set of procedures developed to monitor audit work. New features of MDSAP:

(1) What is the relationship between ISO13485 and MDSAP

ISO13485 is the basis of MDSAP; the requirements of MDSAP are higher/more than those of ISO13485;

ISO13485 is a standard. In addition to ISO13485, MDSAP also has regulatory requirements for participating in the medical device quality management system of the five countries;

(2) Background and trend of ISO13485 and MDSAP and risk management

ISO 13485 requires that the organization shall document one or more processes for risk management;

US 21CFR820 requirements: risk management is mentioned in the design and development confirmation, but it is not specified;

Brazil RDC16 requirements: an independent chapter explains risk management, but does not explain the specific integration of risk management sub-processes and quality system processes;

According to the characteristics of the US FDA and Brazil's ANVISA inspectors' review, the follow-up will combine risk monitoring with CAPA;

(3) The relationship between product design and process design

"Incorporating the design and development of the process into the design and development management" is indirectly required in the Brazilian RDC16 regulation; it is also specified in 13485:2003, but it is not complete. However, ISO13485:2016 clearly states that the design and development should include the design and development of the process. The requirements for process validation are not put forward in the process control link, resulting in failure to integrate the requirements of process design and development with the product design and development process in the actual operation of the enterprise, which is also the reason why the FDA often issues warning letters for process validation;

Now the regulations of various countries attach great importance to process design, and some specific special process standards have been developed, such as sterilization, which will become an essential part of design and development activities in the future. Enterprises need to take process design as part of the design and development tasks when they carry out product design and development.

(4) Design changes and continuous compliance of design and development

Design changes, including process changes, may seriously affect the safety and performance of the finished device, which necessarily involves the assessment of regulatory compliance. In fact, during the FDA review process, it is necessary to review or evaluate regulatory compliance issues caused by changes in design and development, and restart the compliance assessment procedure if necessary, such as supplementary registration or re-registration. It has become a self-evident requirement, and enterprises can join in the internal quality system control in advance.

(5) Can MDSAP completely replace the audit of the competent authorities of participating countries?

Recognition of the MDSAP audit results by no means means that the competent authority has given up its supervisory authority. The purpose of MDSAP implementation is to reduce the supervision cost of the competent authorities of the participating countries, and at the same time reduce the management cost of the regulated enterprises. Audits can still be conducted when the competent authority deems it necessary. The degree of recognition of the relevant countries is as follows:

United States: Substitute for FDA's routine inspection (except for FDA-specific and PMA products);

Brazil: For Class III and Class IV medical devices, it can replace ANVISA's pre-market GMP inspection and post-market routine inspections (except for special inspections);

Japan: For Class II, Class III, and Class IV medical device products, on-site factory audits can be exempted;

Canada: Compulsory replacement of CMDCAS from 2019, and as the only way for medical device products classified in Class II and above to enter the Canadian market;

Australia: Exemption from TGA audits, supporting the issuance and maintenance of TGA compliance audit certificates.

3. Acceptance of MDSAP by regulatory agencies in participating countries

The pilot program of MDSAP started on January 1, 2014, and was planned to end in 2016. The MDSAP project officially began to be fully implemented on January 1, 2017.

(1) USA FDA

FDA will accept MDSAP pilot audit reports in lieu of routine FDA inspections (biennially). FDA will not accept MDSAP inspections as a substitute for an initial review or for a "for cause" or "Compliance Follow-up" review.

(2) Health Canada

From January 1, 2017 to January 1, 2019, Health Canada will accept certificates issued in accordance with CMDCAS and MDSAP requirements, but from January 1, 2019, only MDSAP certificates will be accepted.

(3) Brazil ANVISA

ANVISA may use the MDSAP pilot audit to replace the pre-market audit conducted by ANVISA for GMP certificate applications for Class III or IV medical device products that apply for listing in Brazil. ANVISA may also use MDSAP pilot audits in place of ANVISA's full inspections for applications for GMP certificates that need to be renewed every two years.

(4) Australian TGA

The TGA will take into account the MDSAP pilot audit report when assessing whether to issue or maintain a conformity assessment certificate for product manufacturers as required by regulation. In some cases, manufacturers are exempt from routine audits by the TGA. When ISO 13485:2003 is used to demonstrate that a manufacturer complies with some of the requirements of the Australian Conformity Assessment Procedure, the TGA will accept an MDSAP certificate as evidence of compliance with this standard.

(5) Japan MHLW & PMDA

The Japanese Ministry of Health and Welfare and the Japan Pharmaceutical and Medical Devices Agency will use MDSAP audit reports instead of on-site J-QMS audits in pre-market and regular post-market surveillance audits in Japan in accordance with regulatory requirements.

4. Brief description of MDSAP audit procedures

The MDSAP initial certification audit is a compliance audit of documents and overall readiness, usually including a review of planning documents.

The MDSAP certification audit is to evaluate the compliance with ISO13485 and other regulations of the regulatory agencies participating in the MDSAP for the medical device quality management system.

MDSAP Surveillance Audits are conducted annually to assess any changes to a manufacturer's medical device product or quality management system process after the initial certification audit.

MDSAP recertification audits reassess the ongoing adequacy and effectiveness of a manufacturer's medical device quality management system in meeting MDSAP's quality management system requirements.

5. Advantages of the MDSAP Audit Program

(1) Reduce the regulatory burden

(2) Unified audit requirements

(3) Broadening the scope of accreditation of audit reports

(4) Reduce the overall audit time and cost

(5) Shorten the result response time

(6) Expand the choice of third-party audit institutions

(7) Improve regulatory transparency and consistency of regulators