Special Considerations for 510(k)s
- 510(k)s for Biologic Products
- Class III Certification and Summary
- Combination Products
- Design Controls
- In Vitro Diagnostic Devices
- Radiation Emitting Products
- Sterilants and High Level Disinfectants
510(k)s for Biologic Products
The Center for Biologics, Evaluation, and Research (CBER) has expertise in blood, blood products, cellular therapies, and other biologics as well as the integral association of certain medical devices with these products. To utilize this expertise, CBER reviews marketing and investigational device submissions (Premarket Notification 510(k), Premarket Approval, and Investigational Device Exemption) for medical devices associated with blood collection and processing procedures as well as those associated with cellular therapies and vaccines. Although these products are reviewed by CBER, the medical device laws and regulations still apply.
Center for Biologics Evaluation and Research
Office of Communication, Outreach and Development
10903 New Hampshire Avenue, WO71-3103
Silver Spring, MD 20993-0002 U.S.A.
Telephone Number: 240-402-8020 or 800-835-4709
For step-by-step recommendations on using the FDA's resources about medical device biocompatibility assessments to prepare medical device submissions, see the Biocompatibility Assessment Resource Center.
Biological evaluation of medical devices is performed to determine if there is a potential adverse biological response resulting from contact of the device’s component materials with the body and whether the associated risks are unacceptable. Evaluation of any new medical device requires information from systematic evaluation of the benefits provided by the final device and the potential risks produced by the device. The analysis should show that contact with the device does not produce unacceptable risk associated with adverse local or systemic effects, either directly or through the release of the device’s material constituents.
FDA recognizes the standard ISO 10993-1, “Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process,” which provides information on evaluating the biological response to medical devices, such as considering the physical and chemical characteristics of device materials and the nature, degree, frequency, and duration of device exposure to the body.
The intended use and the materials used in the manufacture of the new or modified device determines the nature of the biocompatibility information needed. Some devices are made of materials that have been well characterized both chemically and physically and have a long history of safe use. Therefore, it may not be necessary to conduct testing for all endpoints outlined in ISO 10993-,1 provided that materials and manufacturing information demonstrate that there are no new biocompatibility concerns.
Additional information about how to use the ISO 10993-1 standard can be found in the following guidance document: Use of International Standard ISO 10993-1, “Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process”
A submission for a device that comes into direct or indirect contact with a patient or user should include information about all of the materials with direct or indirect contact, and should state if the materials, manufacturing processes, and intended use are identical to those in legally marketed device(s).
If the materials, manufacturing processes, and intended use are not identical to those in legally marketed device(s), or if manufacturing information is not available for a comparator device, additional biocompatibility information should be provided.
Any biocompatibility information, including any testing, should be well organized, complete, and included in a separate, identified biocompatibility section.
For current information regarding color additives, please refer to the following: Color Additives For Medical Devices
Class III Certification and Summary
A preamendment device is one that was legally in commercial distribution before May 28, 1976, the date the Medical Device Amendments were signed into law. After the Medical Device Amendments became law, FDA was required to classify all preamendment type devices. All known devices were classified into Class I, Class II, or Class III. It was intended that all preamendment Class III devices would eventually require Premarket Approval (PMA) for marketing approval. Preamendment Class III devices require a PMA only after FDA publishes a final regulation calling for PMA. After FDA publishes the requirement for PMA, the classification regulation in the Code of Federal Regulations (CFR) will state the effective date that a PMA is required.
If FDA has not required a PMA for the type of device, a Class III device that enters the market after May 28, 1976 must have a cleared Premarket Notification 510(k) prior to marketing. Class III devices for which we have not called for PMAs and require a 510(k) are identified in the CFR as Class III and include the statement "Date premarket approval application (PMA) or notice of completion of product development protocol (PDP) is required. No effective date has been established of the requirement for premarket approval." Examples include intra-aortic balloon and control system (21 CFR 870. 3535), ventricular bypass (assist) device (21 CFR 870.3545), and topical oxygen chamber for extremities (21 CFR 878.5650).
510(k)s for Class III devices must contain a Class III Certification and Summary. The certification states that you have conducted a search for information about your device type. The Class III Summary is a summary of the types of safety and effectiveness problems associated with the type of device being compared and a citation to the information upon which the summary is based. The summary must be comprehensive and describe the problems to which the type of device is susceptible and the causes of such problems. The certification should be signed by the 510(k) submitter, NOT a consultant to the 510(k) submitter, and be clearly identified as "Class III Certification and Summary." The summary of problem data, bibliography or other citations upon which the summary is based should be immediately follow the certification statement. The Class III Certification and Summary should be identified in the table of contents of the 510(k).
A combination product is a product comprised of two or more regulated components (drug/device or biologic/device) that are combined as a single entity or is a product labeled for use with a specified drug, device, or biologic where both are required to achieve the intended use, indication, or effect.
To ease the regulatory burden of industry, FDA has established Intercenter agreements which establishes the lead FDA Center for review and oversight of certain categories of products. Intercenter agreements with CDRH are referenced below.
Intercenter Agreement Between the Center for Biologics Evaluation and Research and the Center for Devices and Radiological Health.
Intercenter Agreement Between the Center for Drug Evaluation and Research and the Center for Devices and Radiological Health.
Some combination products involve cutting edge, novel technologies that raise not only unique scientific and technical questions, but also regulatory challenges related to where and how they should be regulated in order to ensure adequate and consistent regulatory oversight. The Office of Combination Products assigns review responsibility for combination products. The Office is also responsible for designating the component of FDA with primary jurisdiction for the premarket review and regulation of any product requiring a jurisdictional designation.
Additional information regarding combination products can be found at the following website:
Design Controls (§ 820.30)
All manufacturers (including specification developers) of Class II and III devices and select Class I devices (listed below) are required to follow design controls (§820.30) during the development of their device. The design control requirements are basic controls needed to ensure that the device being designed will perform as intended when produced for commercial distribution.
Class I Devices Subject to Design Controls
|868.6810||Catheter, Tracheobronchial Suction.|
|892.5650||System, Applicator, Radionuclide, Manual.|
|892.5740||Source, Radionuclide Teletherapy.|
The manufacturer (including specification developer) must establish and maintain procedures to control the design of the device in order to ensure that specified design requirements are met [820.30(a)]. Design controls include establishing and maintaining plans that describe the design and development activities and also define responsibility for implementation [820.30(b)]. The plans must identify and describe the interfaces with different groups or activities that provide, or result in, input to the design and development process [820.30(b)]. The design process also includes:
- conducting a risk analysis [820.30(g)];
- identifying design input or requirements for the device [820.30(c)];
- developing the design output or specifications for the device [820.30(d)];
- verifying that the design output meets the design input [820.30(f)];
- holding design reviews at appropriate points during the design process to identify significant problems with the design or the design process [820.30(e)];
- validating that the design meets defined user needs and intended uses [820.30(g)];
- validating any software used in the device [820.30(g)];
- transferring the device design to production specifications [820.30(h)];
- controlling changes to the design during the design process and changes in the design of products on the market [820.30(i)]; and
- documenting design control activities in the design history file [820.30(j)].
The manufacturer must have procedures in place and must maintain documentation in the design history file to demonstrate compliance with the design control requirements of §820.30 and completion of the activities identified in the design plan. The design history file must be made available for FDA inspection. FDA will evaluate the adequacy of manufacturers' compliance with design control requirements during routine quality systems inspections for all classes of devices subject to design control.
The following documents provide additional guidance on the design control requirements under the Quality System regulation.
- Design Control Guidance for Manufacturers
- Applying Human Factors and Usability Engineering to Medical Devices
- Quality System Information for Certain Application Reviews; Guidance for Industry and FDA Staff
- Human Factors and Medical Devices
See Good Manufacturing Practices (GMP)/Quality Systems (QS) for additional guidance on 21 CFR 820, Quality System.
In Vitro Diagnostic (IVD) Devices
In vitro diagnostics are medical devices that analyze human body fluids, such as blood or urine, to provide information for the diagnosis, prevention, or treatment of a disease. The device classification for these devices can be found under 21 CFR 862, 21 CFR 864, and 21 CFR 866.
In vitro diagnostic products have special labeling requirements and distribution restrictions under 21 CFR 809, In Vitro Diagnostic Products for Human Use. Additional guidance can be found under "Device Advice Labeling Requirements for In Vitro Diagnostic Devices."
Clinical Laboratory Improvement Amendments (CLIA) of 1988
In addition to FDA regulation under the Federal Food, Drug, and Cosmetic Act, in vitro diagnostic devices are also subject to the Clinical Laboratory Improvement Amendments (CLIA) of 1988. This law established quality standards for laboratory testing and an accreditation program for clinical laboratories.
The requirements that apply vary according to the technical complexity in the testing process and risk of harm in reporting erroneous results. The regulations established three categories of testing on the basis of the complexity of the testing methodology: waived tests, tests of moderate complexity, and tests of high complexity. Laboratories performing moderate- or high-complexity testing or both must meet requirements for proficiency testing, patient test management, quality control, quality assurance, and personnel. These specific requirements do not apply to tests in the waived category.
In January 2000, the categorization of commercially marketed in vitro diagnostic tests under CLIA was transferred from the Centers for Disease Control and Prevention (CDC) to the FDA. OHT7 determines the appropriate complexity categories for clinical laboratory devices as they evaluate premarket submissions. OHT7 also processes waived products, devices exempt from premarket notification, and devices under premarket review by other FDA Centers. Responsibilities currently assigned to the CDC, including review of test systems, assays, or examinations not commercially marketed as IVD products, remain with the CDC.
Below is a list of CLIA Program Information Resources:
- Complexity categorizations
- Assignment of CLIA categories
Center for Medicare and Medicaid Services
- Guidelines for laboratories
- Laboratory certification
- Clinical Laboratory Improvement Advisory Committee (CLIAC)
- Cytology proficiency testing
Additional IVD Guidance
Additional information regarding in vitro diagnostics devices is available from the Office of Health Technology 7: Office of In Vitro Diagnostics.
Two or more separate types of finished devices packaged together for the convenience of the user is considered to be a kit. Kits (or trays) are often utilized in the surgical arena. The classification of the kit is based on the highest classification of the devices that are provided in the kit. Submissions for convenience kits should identify all devices provided in the kit. Certain convenience kits that meet the criteria in the Convenience Kit Interim Regulatory Guidance are under enforcement discretion and do not require a 510(k).
Guidance documents pertaining to convenience kits are provided below.
- Convenience Kits Interim Regulatory Guidance
- Sterilized Convenience Kits for Clinical and Surgical Use
510(k) Kit Certification
If the device is to be marketed as a kit, identify all devices in the kit and document the marketing status of each device in the kit as shown in the Kit Certification. If a 510(k) submission is required, please include the kit certification in your 510(k). If a 510(k) is not required, we recommend you maintain this information in your files.
Drugs in Kits
If the device kit contains components which are subject to regulation as drugs, a substantially equivalent determination of the included devices by CDRH does not apply to the drugs in the kit. For information on applicable FDA requirements for marketing the drugs in a kit, you should contact the Center for Drug Evaluation and Research.
Gloves in Kits
A medical device kit may include medical gloves. Kit manufacturers and assemblers should assure that gloves in their kits are cleared for marketing and that the gloves can meet the appropriate FDA and ASTM standards (such as ASTM D3577, ASTM D3578, ASTM D5250, ASTM D6319) or an equivalent test method after the kit is sterilized.
We recommend that you enclose natural rubber latex gloves in their own packaging within the kit to avoid possible protein contamination of other devices. You must label the kit appropriately for any device or packaging containing natural rubber (21 CFR 801.437).
Additional guidance and other requirements for medical gloves are available in Medical Glove Guidance Manual.
Sutures in Kits
Kit manufacturers and assemblers should assure that sutures in their kits are cleared for marketing. If the kit contains sutures, you should provide evidence that the sterilant does not contact the sutures during sterilization of the kit. Some kit assemblers package the sutures separately from the main tray. After processing and sterilizing the main tray, the package of sutures is piggybacked onto the main tray. Based on the evidence, FDA can conclude if the sutures are or are not further processed. However, including sutures as a component in your kit requires you to comply with the following conditions:
- The labeling, packaging, and method of sterilization of the sutures you have listed cannot be changed without prior notification, review, and approval by FDA; and
- the supplier(s) of the sutures included in your kit cannot be changed without prior notification, review, and clearance by FDA.
Sterilants and High Level Disinfectants
This reference lists FDA-cleared liquid chemical sterilants and high level disinfectants with general claims for processing reusable medical and dental devices. This identifies the 510(k) number, device name, manufacturer, active ingredient, sterilant contact conditions, and high level disinfectant contact conditions.
- FDA-Cleared Sterilants and High Level Disinfectants with General Claims for Processing Reusable Medical and Dental Devices
Radiation Emitting Products
If your medical device also emits electronic product radiation, additional requirements apply under the Electronic Product Radiation Control Provisions of the Food, Drug and Cosmetic Act. Electronic product radiation means:
- any ionizing or non-ionizing electromagnetic or particulate radiation, or
- any sonic, infrasonic, or ultrasonic wave,
- which is emitted from an electronic product as the result of the operation of an electronic circuit in such product.
Examples of products that emit electronic radiation include lasers, ultraviolet lamps, microwave ovens, ultrasound therapy devices and medical diagnostic x-ray equipment.
Regulatory requirements for these products are in place to protect the public from hazardous or unnecessary radiation exposure emitted by these products. Requirements may include submission of reports to FDA, compliance with applicable radiation safety performance standards, retention of certain records, and reporting of accidental radiation occurrences or product defects to FDA. Additional information on requirements for radiation emitting products is available on the Radiological Health Program website.
If the device contains software or is controlled by a computer, the submission should contain documentation of software development and validation appropriate to the level of risk of the software. The submission should include any information, prompts, and cautions displayed by the system. The software documentation should support all performance and safety claims.
The following guidance documents provide guidance on the recommended software documentation for a premarket submission and on software validation.
- Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices - Guidance for Industry and FDA Staff
- Off-The-Shelf Software Use in Medical Devices - Guidance for Industry, FDA Reviewers, and Compliance
- Cybersecurity for Networked Medical Devices Containing Off-the-Shelf (OTS) Software - Guidance for Industry
- General Principles of Software Validation - Final Guidance for Industry and FDA Staff
Conformance with recognized consensus standards can provide a reasonable assurance of safety and/or effectiveness for many aspects of medical devices. Information submitted on conformance with such standards will have a direct bearing on safety and effectiveness determinations made during the review of premarket submissions. If any premarket submission contains a declaration of conformity to the recognized consensus standards, this will, in some cases, eliminate the need for FDA to review the actual test data for those aspects of the device addressed by the standards.
Conformance with recognized consensus standards alone, however, may not be sufficient for FDA to make a regulatory decision . For example, a specific device may raise a safety or effectiveness issue not addressed by any recognized consensus standard, or a specific FDA regulation may require additional information beyond what conformity to the recognized consensus standards provides, such as summary data. Under such circumstances, conformity with recognized standards will not satisfy all requirements for marketing the product in the United States.
FDA recognizes certain consensus standards. If a device conforms to an FDA recognized standard, the applicant may choose to use the Abbreviated 510(k) pathway and provide a declaration of conformity to that standard. An applicant may also provide a declaration of conformity and use any type. Conformance to FDA recognized standards are voluntary and may be used to demonstrate performance or safety of a device.
Additional information on FDAs standard program including a database of FDA recognized standards is located in the CDRH Standards Program section of Device Advice.
Sterilants and High Level Disinfectants
The document below provides a list of 510(k) cleared devices that can be used as a predicate device for a 510(k) submission.
- FDA Cleared Sterilants and High Level Disinfectants with General Claims for Processing Reusable Medical and Dental Devices
For devices that are labeled sterile, the 510(k) should include the following:
- the sterilization method (e.g., dry heat, moist heat, ethylene oxide (EO), radiation);
- the method used to validate the sterilization cycle, but not the validation data itself;
- a description of the packaging to maintain the device's sterility (Do not include packaging integrity test data in the 510(k) submission.);
- the sterility assurance level (SAL), e.g., 10-6 for all devices, except 10-3 for devices only contacting intact skin, for the device that the manufacturer intends to meet;
- the maximum levels of residues of EO and ethylene chlorohydrin that remain on the device when ETO is used to sterilize the device (Note: The ethylene glycol residual level is no longer requested because the recognized standard, "ANSI/AAMI/ISO 10993-7:1995 Biological Evaluation of Medical Devices – Part 7: Ethylene Oxide sterilization residuals," does not include measurement of ethylene glycol residuals);
- for devices that are labeled "pyrogen free," a description of the method used to make that determination, e.g., limulus amebocyte lysate (LAL). Devices contacting blood or cerebrospinal fluids should be pyrogen free.; and
- the radiation dose, if radiation sterilization will be used.
If only parts of the device are labeled sterile or non-pyrogenic, the labeling should clearly identify which parts are sterile and non-pyrogenic.
The labeling for devices intended to be sterilized by the user must identify one validated method of sterilization. The instructions should be detailed and specific enough for the user to follow and obtain the required sterility assurance level. The instructions should also adequately describe any precautions to be followed such as:
- special cleaning methods required;
- any changes in the physical characteristics of the device that may result from reprocessing and re-sterilization, especially those which may affect the safety, effectiveness, or performance; and
- any limit on the number of times re-sterilization and reuse can be done without adversely affecting the safety, effectiveness, or performance of the device.
The manufacture may use an FDA-recognized validation method or an equivalent method to validate the sterilization cycle. You can find consensus standards that FDA has recognized for sterilization by searching the CDRH Standards Database.
Additional Information on Sterilization
- Submission and Review of Sterility Information in Premarket Notification (510(k)) Submissions for Devices Labeled as Sterile