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Among the challenges medical device companies face in their efforts to achieve regulatory compliance is the reduction of redesign work and duplication of documentation during the development cycle from concept to final product.
Two major aspects need to be addressed when global marketing is the goal:
- Identify what regulatory requirements apply to the design and manufacturing process in the major markets; and
- Identify what documentation deliverables (on product and process design) are required by regulators in major markets.
Regulatory requirements
Regulators in Europe, Canada and, more recently, Australia define general principles or requirements for the safety and effectiveness of medical devices (European Medical Devices Directive 93/42/EEC: Annex I Essential Requirements; Canadian Medical Devices Regulation: Safety and Effectiveness Requirements; Australian Therapeutic Goods [Medical Devices] Regulations 2001: Schedule 1 Essential Principles). These lay down generic requirements for medical devices such as effectiveness, electromagnetic compatibility, biocompatibility, protection against cross-contamination, and electrical, mechanical, chemical and radiation safety.
The Global Harmonisation Task Force (GHTF), founded by Australia, United States, European Union, Japan and Canada, also issued a document: Essential Principles of Safety & Performance of Medical Devices (SG1-N020R5), which is based largely on the European MDD Annex I.
FDA does not define generic requirements for all medical devices, but rather issues guidance documents for categories of devices (e.g. for annuloplastic rings, for ventilators, for implantable cardioverter-defibrillators, for electro-optical sensors for the in vivo detection of cervical cancer and its precursors).
In the Premarket Notification 510(k): Regulatory Requirements For Medical Devices (HHS Publication FDA 95-4158) however, FDA gives a list of areas that manufacturers are expected to address when comparing devices to one or more predicate devices to which they claim equivalency. These include: indications for use, performance, biocompatibility, compatibility with environment and other devices, and electrical, mechanical, chemical, thermal and radiation.
It becomes obvious that the Essential Principles defined by GHTF, as well as the European, Canadian and Australian regulations overlap a great deal with the areas FDA wants to see covered for claims of safety and efficacy.
For example, Section 9.1 of Annex I (European MDD) requires that “If the device is intended for use in combination with other devices or equipment, the whole combination, including the connection system must be safe and must not impair the specified performances of the devices. Any restrictions on use must be indicated on the label or in the instructions for use.” Section 9.1 of the GHTF Essential Principles of Safety & Performance of Medical Devices (SG1-N020R5) is identical with the Section 9.1 of MDD Annex I.
The equivalent requirements in the Canadian and Australian regulations are:
Section 18 of the Canadian Medical Devices Regulation: Safety and Effectiveness Requirements: “A medical device that is part of a system shall be compatible with every other component or part of the system with which it interacts and shall not adversely affect the performance of the system” and Section 9.1 of the Australian Therapeutic Goods [Medical Devices] Regulations 2001: Essential Principles: “A medical device that is intended by the manufacturer to be used in combination with other medical device or other equipment (including a connection system) must be designed and manufactured in a way that ensures that: (a) the medical devices, and any other device or equipment with which it is used, operate in a safe way; and (b) the intended performance of the device, and any other device or equipment with which it is used, is not impaired.”
While there are some differences in the way they are worded, Section 9.1 of the European MDD Annex I and of the GHTF document, Section 18 of the Canadian regulation and Section 9.1 of the Australian regulation are equivalent. FDA has a similar requirement, in that a comparison to a predicate device should include “compatibility with environment and other devices” in Premarket Notification 510(k): Regulatory Requirements for Medical Devices, Section 3-2 510(k) Contents, item 9 Substantial Equivalence Comparison. The manufacturer will ensure compliance with all these by testing the safety and performance of the medical device in combination with other equipment, as per indications for use.
It is important to consider these regulatory requirements early in the development process, as design inputs (in addition to specific clinical and marketing design inputs), for streamlining the tasks related to global regulatory compliance. A comparison table for European, Canadian and Australian essential principles/requirements of safety and performance, and corresponding FDA requirements for comparison to predicate devices is given below.
The manufacturer is required to document how the essential principles/requirements have been addressed, usually by performing verification testing to EN, ISO, IEC and other standards, as well as validation of product and process. Legally binding documents such as the Declaration of Conformity for CE Marking and the Application for a New Medical Device License for Health Canada – Class II require the manufacturer to take responsibility for compliance with these essential principles/requirements. Similarly, the Truthful and Accurate Statement required by FDA obliges the manufacturer to ensure that “no facts material for a review of the substantial equivalence of this device have been knowingly omitted…”
Documentation deliverables
Various guidance documents assist manufacturers with the task of generating documentation on medical devices, which is required either for submissions prior to marketing or for keeping and maintaining at the manufacturer’s site for subsequent auditing:
- Europe: Recommendation NB-MED/2.5.1 on Technical Documentation;
- USA: Premarket Notification 510(k): Regulatory Requirements for Medical Devices, Section 3-2 510(k) Contents; PMA Manual, Chapter 3 How to submit a PMA;
- GHTF: Summary Technical Documentation for Demonstrating Conformity to the Essential Principles of Safety and Performance of Medical Devices (SG1-N011R16).
It is generally accepted that if the technical documentation satisfies the European and FDA requirements, it will satisfy the requirements in other regions as well. The regulatory professional can help reduce duplication and omissions in documentation by ensuring that the design and development process will generate documentation addressing the regulatory requirements on deliverables.
For example, the documentation deliverables for the Technical File (Europe) and the Premarket Notification or 510(k) are listed and compared in Table 1.
Table 1
EC Technical File Documentation | Premarket Notification 510(k) Submission Documentation |
| Product description: | Substantial Equivalence Comparison: |
| A general description of the device | Identification of legally marketed predicate device
A comparison table and discussion of the similarities and differences of the device compared to one or more predicate devices to which equivalency is claimed, in following areas: |
| A description of the intended use and operation of the device | Indications for use- Statement
Target population
Anatomical sites
Where used: hospital, home, ambulance etc. |
| Description of the methods of manufacture envisaged (summary) | Not required for 510(k) submission, but auditable by FDA during facility inspections |
| Description of the accessories, adaptors and other devices or equipment and other interfaces, which are intended by the manufacturer to be used in combination with the devices (V&V data of the safety and performance of such combinations) | Compatibility with [environment and] other devices
An identification of the required V&V activities, including the methods or tests used and the acceptance criteria to be applied (for Special 510k only) |
| Technical requirements: |  |
| Essential Requirements Checklist (a traceability matrix showing how the Essential Requirements in MDD Annex I have been addressed) | Performance/ Compliance with performance standards
Sterility
Biocompatibility data for all patient-contacting materials, or certification of identical material/formulation
Mechanical safety
Chemical safety
Energy used and/or delivered
Compatibility with environment [and other devices]
Standards met
Electrical safety
Thermal safety
Radiation safety |
| Design: | Design |
| Risk Analysis | Risk Analysis (for Special 510k only)
Human factors |
| Specification of materials, and manufacturing/ special processing (e.g. moulding) | Materials |
| Specifications, drawings and circuit diagrams for components, sub-assemblies and the complete product including packaging, where appropriate | Description of the device including diagrams, engineering drawings, photographs or service manuals |
| Software documentation |
| The specifications of the checks, tests and trials, that are intended to be carried out as part of routine production | Not required for 510(k) submission, but auditable by FDA during facility inspections |
| The performances and compatibilities intended by the manufacturer | Covered by Performance and Compatibility with environment and other devices |
| Labelling, including any instructions for use | Proposed labelling, including the device name (both the trade, common, or proprietary name) and the classification name of the device; |
| Indication of ‘shelf-life’ reflected by any ‘use by’ date, or other ‘lifetime’ of the device | Covered by Indications for use |
| Results of bench testing | Covered by verification and validation data |
| Clinical data | Clinical data |
Valentina Theisz, RAC, is a regulatory affairs professional with ResMed in Sydney. She has been a technical certifier and technology auditor for the application of QA systems for medical devices for TÜV Product Service in Frankfurt, Tokyo and Hong Kong. She has also been a QA manager for a start-up medical devices company in Sydney.
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