(a) This part sets forth the classification of hematology and pathology devices intended for human use that are in commercial distribution.

(b) The identification of a device in a regulation in this part is not a precise description of every device that is, or will be, subject to the regulation. A manufacturer who submits a premarket notification submission for a device under part 807 may not show merely that the device is accurately described by the section title and identification provisions of a regulation in this part, but shall state why the device is substantially equivalent to other devices, as required by § 807.87.

(c) References in this part to regulatory sections of the Code of Federal Regulations are to chapter I of title 21, unless otherwise noted.

(d) Guidance documents referenced in this part are available on the Internet at http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/default.htm.

A device included in this part that is classified into class III (premarket approval) shall not be commercially distributed after the date shown in the regulation classifying the device unless the manufacturer has an approval under section 515 of the act (unless an exemption has been granted under section 520(g)(2) of the act). An approval under section 515 of the act consists of FDA's issuance of an order approving an application for premarket approval (PMA) for the device or declaring completed a product development protocol (PDP) for the device.

(a) Before FDA requires that a device commercially distributed before the enactment date of the amendments, or a device that has been found substantially equivalent to such a device, has an approval under section 515 of the act FDA must promulgate a regulation under section 515(b) of the act requiring such approval, except as provided in paragraph (b) of this section. Such a regulation under section 515(b) of the act shall not be effective during the grace period ending on the 90th day after its promulgation or on the last day of the 30th full calendar month after the regulation that classifies the device into class III is effective, whichever is later. See section 501(f)(2)(B) of the act. Accordingly, unless an effective date of the requirement for premarket approval is shown in the regulation for a device classified into class III in this part, the device may be commercially distributed without FDA's issuance of an order approving a PMA or declaring completed a PDP for the device. If FDA promulgates a regulation under section 515(b) of the act requiring premarket approval for a device, section 501(f)(1)(A) of the act applies to the device.

(b) Any new, not substantially equivalent, device introduced into commercial distribution on or after May 28, 1976, including a device formerly marketed that has been substantially altered, is classified by statute (section 513(f) of the act) into class III without any grace period and FDA must have issued an order approving a PMA or declaring completed a PDP for the device before the device is commercially distributed unless it is reclassified. If FDA knows that a device being commercially distributed may be a “new” device as defined in this section because of any new intended use or other reasons, FDA may codify the statutory classification of the device into class III for such new use. Accordingly, the regulation for such a class III device states that as of the enactment date of the amendments, May 28, 1976, the device must have an approval under section 515 of the act before commercial distribution.

The exemption from the requirement of premarket notification (section 510(k) of the act) for a generic type of class I or II device is only to the extent that the device has existing or reasonably foreseeable characteristics of commercially distributed devices within that generic type or, in the case of in vitro diagnostic devices, only to the extent that misdiagnosis as a result of using the device would not be associated with high morbidity or mortality. Accordingly, manufacturers of any commercially distributed class I or II device for which FDA has granted an exemption from the requirement of premarket notification must still submit a premarket notification to FDA before introducing or delivering for introduction into interstate commerce for commercial distribution the device when:

(a) The device is intended for a use different from the intended use of a legally marketed device in that generic type of device; e.g., the device is intended for a different medical purpose, or the device is intended for lay use where the former intended use was by health care professionals only;

(b) The modified device operates using a different fundamental scientific technology than a legally marketed device in that generic type of device; e.g., a surgical instrument cuts tissue with a laser beam rather than with a sharpened metal blade, or an in vitro diagnostic device detects or identifies infectious agents by using deoxyribonucleic acid (DNA) probe or nucleic acid hybridization technology rather than culture or immunoassay technology; or

(c) The device is an in vitro device that is intended:

(1) For use in the diagnosis, monitoring, or screening of neoplastic diseases with the exception of immunohistochemical devices;

(2) For use in screening or diagnosis of familial or acquired genetic disorders, including inborn errors of metabolism;

(3) For measuring an analyte that serves as a surrogate marker for screening, diagnosis, or monitoring life-threatening diseases such as acquired immune deficiency syndrome (AIDS), chronic or active hepatitis, tuberculosis, or myocardial infarction or to monitor therapy;

(4) For assessing the risk of cardiovascular diseases;

(5) For use in diabetes management;

(6) For identifying or inferring the identity of a microorganism directly from clinical material;

(7) For detection of antibodies to microorganisms other than immunoglobulin G (IgG) or IgG assays when the results are not qualitative, or are used to determine immunity, or the assay is intended for use in matrices other than serum or plasma;

(8) For noninvasive testing as defined in § 812.3(k) of this chapter; and

(9) For near patient testing (point of care).

(a) Identification. Dye and chemical solution stains for medical purposes are mixtures of synthetic or natural dyes or nondye chemicals in solutions used in staining cells and tissues for diagnostic histopathology, cytopathology, or hematology.

(b) Classification. Class I (general controls). These devices are exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9. These devices are also exempt from the current good manufacturing practice requirements of the quality system regulation in part 820 of this chapter, with the exception of § 820.180, with respect to general requirements concerning records, and § 820.198, with respect to complaint files.

(a) Identification. Immunohistochemistry test systems (IHC's) are in vitro diagnostic devices consisting of polyclonal or monoclonal antibodies labeled with directions for use and performance claims, which may be packaged with ancillary reagents in kits. Their intended use is to identify, by immunological techniques, antigens in tissues or cytologic specimens. Similar devices intended for use with flow cytometry devices are not considered IHC's.

(b) Classification of immunohistochemistry devices. (1) Class I (general controls). Except as described in paragraphs (b)(2) and (b)(3) of this section, these devices are exempt from the premarket notification requirements in part 807, subpart E of this chapter. This exemption applies to IHC's that provide the pathologist with adjunctive diagnostic information that may be incorporated into the pathologist's report, but that is not ordinarily reported to the clinician as an independent finding. These IHC's are used after the primary diagnosis of tumor (neoplasm) has been made by conventional histopathology using nonimmunologic histochemical stains, such as hematoxylin and eosin. Examples of class I IHC's are differentiation markers that are used as adjunctive tests to subclassify tumors, such as keratin.

(2) Class II (special control, guidance document: “FDA Guidance for Submission of Immunohistochemistry Applications to the FDA,” Center for Devices and Radiologic Health, 1998). These IHC's are intended for the detection and/or measurement of certain target analytes in order to provide prognostic or predictive data that are not directly confirmed by routine histopathologic internal and external control specimens. These IHC's provide the pathologist with information that is ordinarily reported as independent diagnostic information to the ordering clinician, and the claims associated with these data are widely accepted and supported by valid scientific evidence. Examples of class II IHC's are those intended for semiquantitative measurement of an analyte, such as hormone receptors in breast cancer.

(3) Class III (premarket approval). IHC's intended for any use not described in paragraphs (b)(1) or (b)(2) of this section.

(c) Date of PMA or notice of completion of a PDP is required. As of May 28, 1976, an approval under section 515 of the Federal Food, Drug, and Cosmetic Act is required for any device described in paragraph (b)(3) of this section before this device may be commercially distributed. See § 864.3.

(a) Identification. A cervical intraepithelial neoplasia (CIN) test system is a device used to detect a biomarker associated with CIN in human tissues. The device is indicated as an adjunct test and not to be used as a stand-alone device. The test results must be interpreted in the context of the patient's clinical history including, but not limited to, prior and current cervical biopsy results, Papanicolaou (Pap) test results, human papillomavirus (HPV) test results, and morphology on hematoxylin and eosin (H&E) stained sections. This device is not intended to detect the presence of HPV.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) Premarket notification submissions must include the following information:

(i) The indications for use must specify the biomarker that is intended to be identified and its adjunct use (e.g., adjunct to examination of H&E stained slides) to improve consistency in the diagnosis of CIN.

(ii) Summary of professional society recommendations, as applicable.

(iii) A detailed device description including:

(A) A detailed description of all test components, including all provided reagents and required, but not provided, ancillary reagents.

(B) A detailed description of instrumentation and equipment, including illustrations or photographs of non-standard equipment or manuals.

(C) If applicable, detailed documentation of the device software, including, but not limited to, stand-alone software applications and hardware-based devices that incorporate software.

(D) A detailed description of appropriate positive and negative controls that are recommended or provided.

(E) Detailed specifications for sample collection, processing, and storage.

(F) A detailed description of methodology and assay procedure.

(G) A description of the assay cutoff (the medical decision point between positive and negative) or other relevant criteria that distinguishes positive and negative results, including the rationale for the chosen cutoff or other relevant criteria and results supporting validation of the cutoff.

(H) Detailed specification of the criteria for test results interpretation and reporting.

(iv) Detailed information demonstrating the performance characteristics of the device, including:

(A) Analytical specificity studies such as, but not limited to, antibody characterization (e.g., Western Blot, peptide inhibition analysis), studies conducted on panels of normal tissues and neoplastic tissues, interference by endogenous and exogenous substances as well as cross-reactivity, as applicable.

(B) Device analytical sensitivity data generated by testing an adequate number of samples from individuals with the target condition including limit of blank, limit of detection, and limit of quantification, as applicable.

(C) Device precision/reproducibility data to evaluate within-run, between-run, between-day, between-lot, between-site, between-reader, within-reader and total precision, as applicable, using a panel of samples covering the device measuring range and/or the relevant disease categories (e.g. No CIN, CIN1, CIN2, CIN3, cervical cancer) and testing in replicates across multiple, nonconsecutive days.

(D) Device robustness/guardbanding studies to assess the tolerance ranges for various critical test and specimen parameters.

(E) Device stability data, including real-time stability and shipping stability under various storage times, temperatures, and freeze-thaw conditions.

(F) Data from a clinical study demonstrating clinical validity using well-characterized prospectively or retrospectively obtained clinical specimens, as appropriate, representative of the intended use population. The study must evaluate the consistency of the diagnosis of CIN, for example, by comparing the levels of agreements of diagnoses rendered by community pathologists to those rendered by a panel of expert pathologists. Agreement for each CIN diagnostic category (e.g., No CIN, CIN1, CIN2, CIN3, cancer) and for alternate diagnostic categories (e.g., No CIN, low grade squamous intraepithelial lesion (LSIL)-histology, high grade squamous intraepithelial lesion (HSIL)-histology, cancer) between reference diagnosis by expert pathologist and community pathologist must be evaluated, as applicable. In addition, agreements for CIN binary categories as ≥CIN2 (i.e., CIN2 or CIN3 or cancer) and ≤CIN1 (i.e., No CIN or CIN1) between reference diagnosis by expert pathologist with H&E staining and community pathologist with H&E staining and agreements for alternate CIN binary categories as ≥HSIL-histology (i.e., HSIL-histology or cancer) and ≤LSIL-histology (i.e., No CIN or LSIL-histology) between reference diagnosis by an expert pathologist with H&E + [biomarker specified in paragraph (b)(1)(i) of this section] and a community pathologist with H&E + [biomarker specified in paragraph (b)(1)(i) of this section] must be evaluated and compared, as applicable.

(G) The staining performance of the device as determined by the community pathologists during review of the study slides must be evaluated. The staining performance criteria assessed must include overall staining acceptability, background staining acceptability, and morphology acceptability, as applicable.

(H) Appropriate training requirements for users, including interpretation manual, as applicable.

(I) Identification of risk mitigation elements used by the device, including a description of all additional procedures, methods, and practices incorporated into the instructions for use that mitigate risks associated with testing.

(2) The device's 21 CFR 809.10(b) compliant labeling must include a detailed description of the protocol, including the information described in paragraph (b)(1)(ii) of this section, as applicable, and a detailed description of the performance studies performed and the summary of the results, including those that relate to paragraph (b)(1)(ii) of this section, as applicable.

(a) Identification. Lynch syndrome test systems are in vitro diagnostic tests for use with tumor tissue to identify previously diagnosed cancer patients at risk for having Lynch syndrome.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) Premarket notification submissions must include the following information, as appropriate:

(i) A detailed description of all test components, including all provided reagents, and required but not provided, ancillary reagents.

(ii) A detailed description of instrumentation and equipment, including illustrations or photographs of non-standard equipment or manuals.

(iii) Detailed documentation of the device software, including, but not limited to, standalone software applications and hardware-based devices that incorporate software.

(iv) A detailed description of quality controls including appropriate positive and negative controls that are recommended or provided.

(v) Detailed specifications for sample collection, processing, and storage.

(vi) A detailed description of methodology and assay procedure.

(vii) A description of the assay cut-off (i.e., the medical decision point between positive and negative results) or other relevant criteria that distinguishes positive and negative results, or ordinal classes of marker expression, including the rationale for the chosen cut-off or other relevant criteria and results supporting validation of the cut-off.

(viii) Detailed specification of the criteria for test result interpretation and reporting.

(ix) Detailed information demonstrating the performance characteristics of the device, including:

(A) Data from an appropriate study demonstrating clinical accuracy using well-characterized clinical specimens representative of the intended use population (i.e., concordance to Deoxyribonucleic Acid (DNA) sequencing results of the Lynch syndrome associated genes or method comparison to the predicate device using samples with known alterations in genes representative of Lynch syndrome). Pre-specified acceptance criteria must be provided and followed.

(B) Appropriate device reproducibility data investigating all sources of variance (e.g., for distributed tests, data generated using a minimum of three sites, of which at least two sites must be external sites). Each site must perform testing over a minimum of 5 nonconsecutive days evaluating a sample panel that spans the claimed measuring range, and includes the clinical threshold. Pre-specified acceptance criteria must be provided and followed.

(C) Data demonstrating reader reproducibility, both within-reader and between-reader, assessed by three readers over 3 nonconsecutive days at each site, including a 2 week washout period between reads, as appropriate.

(D) Device precision data using clinical samples spanning the measuring range and controls to evaluate the within-lot, between-lot, within-run, between run, and total variation.

(E) Analytical specificity studies including as appropriate, western blots, peptide inhibition, testing in normal tissues and neoplastic tissues, interference by endogenous and exogenous substances, and cross-reactivity and cross contamination testing.

(F) Device analytical sensitivity data generated by testing an adequate number of samples from individuals with the target condition such that prevalence of the biomarker in the target population is established.

(G) Device stability data, including real-time stability and in-use stability, and stability evaluating various storage times, temperatures, and freeze-thaw conditions, as appropriate.

(H) The staining performance criteria assessed must include overall staining acceptability, background staining acceptability, and morphology acceptability, as appropriate.

(I) Appropriate training requirements for users, including interpretation manual, as applicable.

(J) Identification of risk mitigation elements used by the device, including a description of all additional procedures, methods, and practices incorporated into the instructions for use that mitigate risks associated with testing.

(2) The device's § 809.10(b) of this chapter compliant labeling must include a detailed description of the protocol, including the information described in paragraphs (b)(1)(i) through (viii) of this section, as appropriate, and a detailed description of the performance studies performed and the summary of the results, including those that relate to paragraph (b)(1)(ix) of this section, as appropriate.

(a) Identification. An early growth response 1 (EGR1) gene fluorescence in-situ hybridization (FISH) test system for specimen characterization is a device intended to detect the EGR1 probe target on chromosome 5q in bone marrow specimens from patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). The assay results are intended to be interpreted only by a qualified pathologist or cytogeneticist. These devices do not include automated systems that directly report results without review and interpretation by a qualified pathologist or cytogeneticist. These devices also do not include any device intended for use to select patient therapy, predict patient response to therapy, or to screen for disease as well as any device with a claim for a particular diagnosis, prognosis, monitoring, or risk assessment.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) Premarket notification submissions must also include the following information:

(i) A detailed description of all probes included in the kit;

(ii) Purpose of each probe;

(iii) Probe molecular specificity;

(iv) Probe specificity;

(v) Probe limits;

(vi) Probe sensitivity;

(vii) Specification of required ancillary reagents, instrumentation, and equipment;

(viii) Specification of the specimen collection, processing, storage and slide preparation methods;

(ix) Specification of the assay procedure;

(x) Specification of control elements that are incorporated into the recommended testing procedures;

(xi) Specification of risk mitigation elements: Description of all additional procedures, methods, and practices incorporated into the directions for use that mitigate risks associated with testing;

(xii) Specification of the criteria for test result interpretation and reporting;

(xiii) Device analytical sensitivity data;

(xiv) Device analytical specificity data;

(xv) Device reference limit data;

(xvi) Device precision/reproducibility data;

(xvii) Device stability data to include:

(A) Real-time stability,

(B) Freeze-thaw stability,

(C) Transport and temperature stability,

(D) Post-hybridization signal stability,

(E) Photostability of probe, and

(xviii) Documentation that demonstrates the clinical validity of the device. The documentation must include data from clinical studies, a minimum of two peer-reviewed published literature references using the specific device seeking marketing clearance, or both. Documentation for the clinical studies and peer-reviewed published literature references cited must include the following elements:

(A) Documentation that the sponsor's probe was used in the literature reference,

(B) Number and type of specimens,

(C) Target population studied,

(D) Upper reference limit, and

(E) Range of positive probe results.

(2) Your § 809.10(b)(12) of this chapter compliant labeling must include a statement summarizing the data identified in paragraphs (b)(1)(xiii) through (xviii) of this section and a description of the studies supporting the information, including the pre-specified acceptance criteria for these performance studies, justification for the pre-specified acceptance criteria, and whether the pre-specified acceptance criteria were met.

(3) Your § 809.10 of this chapter compliant labeling must include:

(i) A warning that reads “The assay results are intended to be interpreted only by a qualified pathologist or cytogeneticist.”

(ii) A warning that reads “This device is not for high-risk uses such as selecting therapy, predicting therapeutic response or disease screening.”

(iii) A warning that reads “The use of this device for diagnosis, monitoring or risk assessment has not been established.”

(a) Identification. Synthetic cell and tissue culture media and components are substances that are composed entirely of defined components (e.g., amino acids, vitamins, inorganic salts) that are essential for the survival and development of cell lines of humans and other animals. This does not include tissue culture media for human ex vivo tissue and cell culture processing applications as described in § 876.5885 of this chapter.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

(a) Identification. Cell and tissue culture supplies and equipment are devices that are used to examine, propagate, nourish, or grow cells and tissue cultures. These include such articles as slide culture chambers, perfusion and roller apparatus, cell culture suspension systems, and tissue culture flasks, disks, tubes, and roller bottles.

(b) Classification. Class I (general controls). These devices are exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9. If the devices are not labeled or otherwise represented as sterile, they are exempt from the current good manufacturing practice requirements of the quality system regulation in part 820 of this chapter, with the exception of § 820.180, with respect to general requirements concerning records, and § 820.198, with respect to complaint files.

(a) Identification. A chromosome culture kit is a device containing the necessary ingredients (e.g., Minimum Essential Media (MEM) of McCoy's 5A culture media, phytohemagglutinin, fetal calf serum, antibiotics, and heparin) used to culture tissues for diagnosis of congenital chromosome abnormalities.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

(a) Identification. Cultured animal and human cells are in vitro cultivated cell lines from the tissue of humans or other animals which are used in various diagnostic procedures, particularly diagnostic virology and cytogenetic studies.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 864.9.

(a) Identification. Mycoplasma detection media and components are used to detect and isolate mycoplasma pleuropneumonia-like organisms (PPLO), a common microbial contaminant in cell cultures.

(b) Classification. Class I (general controls). These devices are exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

(a) Identification. Animal and human sera are biological products, obtained from the blood of humans or other animals, that provide the necessary growth-promoting nutrients in a cell culture system.

(b) Classification. Class I (general controls). These devices are exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

(a) Identification. A balanced salt solution or formulation is a defined mixture of salts and glucose in a simple medium. This device is included as a necessary component of most cell culture systems. This media component controls for pH, osmotic pressure, energy source, and inorganic ions.

(b) Classification. Class I (general controls). These devices are exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

(a) Identification. Tissue processing equipment consists of devices used to prepare human tissue specimens for diagnostic histological examination by processing specimens through the various stages of decalcifying, infiltrating, sectioning, and mounting on microscope slides.

(b) Classification. Class I (general controls). These devices are exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9. The devices are also exempt from the current good manufacturing practice requirements of the quality system regulation in part 820 of this chapter, with the exception of § 820.180, with respect to general requirements concerning records, and § 820.198, with respect to complaint files.

(a) Identification. A specimen transport and storage container, which may be empty or prefilled, is a device intended to contain biological specimens, body waste, or body exudate during storage and transport in order that the matter contained therein can be destroyed or used effectively for diagnostic examination. If prefilled, the device contains a fixative solution or other general purpose reagent to preserve the condition of a biological specimen added to the container. This section does not apply to specimen transport and storage containers that are intended for use as part of an over-the-counter test sample collection system for drugs of abuse testing.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 864.9. If the device is not labeled or otherwise represented as sterile, it is exempt from the current good manufacturing practice requirements of the quality system regulation in part 820 of this chapter, with the exception of § 820.180 of this chapter, with respect to general requirements concerning records, and § 820.198 of this chapter, with respect to complaint files.

(a) Identification. An over-the-counter (OTC) test sample collection system for drugs of abuse testing is a device intended to: Collect biological specimens (such as hair, urine, sweat, or saliva), outside of a medical setting and not on order of a health care professional (e.g., in the home, insurance, sports, or workplace setting); maintain the integrity of such specimens during storage and transport in order that the matter contained therein can be tested in a laboratory for the presence of drugs of abuse or their metabolites; and provide access to test results and counseling. This section does not apply to collection, transport, or laboratory testing of biological specimens for the presence of drugs of abuse or their metabolites that is performed to develop evidence for law enforcement purposes.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification requirements in part 807, subpart E of this chapter subject to the limitations in § 864.9 if it is sold, distributed, and used in accordance with the restrictions set forth in § 809.40 of this chapter. If the device is not labeled or otherwise represented as sterile, it is exempt from the current good manufacturing practice requirements of the quality system regulation in part 820 of this chapter, with the exception of § 820.198 of this chapter with respect to complaint files.

(a) Identification. A cytocentrifuge is a centrifuge used to concentrate cells from biological cell suspensions (e.g., cerebrospinal fluid) and to deposit these cells on a glass microscope slide for cytological examination.

(b) Classification. Class I (general controls). This device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

(a) Identification. A device for sealing microsections is an automated instrument used to seal stained cells and microsections for histological and cytological examination.

(b) Classification. Class I (general controls). This device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

(a) Identification. Microscopes and accessories are optical instruments used to enlarge images of specimens, preparations, and cultures for medical purposes. Variations of microscopes and accessories (through a change in the light source) used for medical purposes include the following:

(1) Phase contrast microscopes, which permit visualization of unstained preparations by altering the phase relationship of light that passes around the object and through the object.

(2) Fluorescense microscopes, which permit examination of specimens stained with fluorochromes that fluoresce under ultraviolet light.

(3) Inverted stage microscopes, which permit examination of tissue cultures or other biological specimens contained in bottles or tubes with the light source mounted above the specimen.

(b) Classification. Class I (general controls). These devices are exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9. If the device is not labeled or otherwise represented as sterile, it is exempt from the current good manufacturing practice requirements of the quality system regulation in part 820 of this chapter, with the exception of § 820.180, with respect to general requirements concerning records, and § 820.198, with respect to complaint files.

(a) Identification. The whole slide imaging system is an automated digital slide creation, viewing, and management system intended as an aid to the pathologist to review and interpret digital images of surgical pathology slides. The system generates digital images that would otherwise be appropriate for manual visualization by conventional light microscopy.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) Premarket notification submissions must include the following information:

(i) The indications for use must specify the tissue specimen that is intended to be used with the whole slide imaging system and the components of the system.

(ii) A detailed description of the device and bench testing results at the component level, including for the following, as appropriate:

(A) Slide feeder;

(B) Light source;

(C) Imaging optics;

(D) Mechanical scanner movement;

(E) Digital imaging sensor;

(F) Image processing software;

(G) Image composition techniques;

(H) Image file formats;

(I) Image review manipulation software;

(J) Computer environment; and

(K) Display system.

(iii) Detailed bench testing and results at the system level, including for the following, as appropriate:

(A) Color reproducibility;

(B) Spatial resolution;

(C) Focusing test;

(D) Whole slide tissue coverage;

(E) Stitching error; and

(F) Turnaround time.

(iv) Detailed information demonstrating the performance characteristics of the device, including, as appropriate:

(A) Precision to evaluate intra-system and inter-system precision using a comprehensive set of clinical specimens with defined, clinically relevant histologic features from various organ systems and diseases. Multiple whole slide imaging systems, multiple sites, and multiple readers must be included.

(B) Reproducibility data to evaluate inter-site variability using a comprehensive set of clinical specimens with defined, clinically relevant histologic features from various organ systems and diseases. Multiple whole slide imaging systems, multiple sites, and multiple readers must be included.

(C) Data from a clinical study to demonstrate that viewing, reviewing, and diagnosing digital images of surgical pathology slides prepared from tissue slides using the whole slide imaging system is non-inferior to using an optical microscope. The study should evaluate the difference in major discordance rates between manual digital (MD) and manual optical (MO) modalities when compared to the reference (e.g., main sign-out diagnosis).

(D) A detailed human factor engineering process must be used to evaluate the whole slide imaging system user interface(s).

(2) Labeling compliant with 21 CFR 809.10(b) must include the following:

(i) The intended use statement must include the information described in paragraph (b)(1)(i) of this section, as applicable, and a statement that reads, “It is the responsibility of a qualified pathologist to employ appropriate procedures and safeguards to assure the validity of the interpretation of images obtained using this device.”

(ii) A description of the technical studies and the summary of results, including those that relate to paragraphs (b)(1)(ii) and (iii) of this section, as appropriate.

(iii) A description of the performance studies and the summary of results, including those that relate to paragraph (b)(1)(iv) of this section, as appropriate.

(iv) A limiting statement that specifies that pathologists should exercise professional judgment in each clinical situation and examine the glass slides by conventional microscopy if there is doubt about the ability to accurately render an interpretation using this device alone.

(a) Identification. An automated slide stainer is a device used to stain histology, cytology, and hematology slides for diagnosis.

(b) Classification. Class I (general controls). This device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

(a) Identification. An automated tissue processor is an automated system used to process tissue specimens for examination through fixation, dehydration, and infiltration.

(b) Classification. Class I (general controls). This device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

(a) A general purpose reagent is a chemical reagent that has general laboratory application, that is used to collect, prepare, and examine specimens from the human body for diagnostic purposes, and that is not labeled or otherwise intended for a specific diagnostic application. It may be either an individual substance, or multiple substances reformulated, which, when combined with or used in conjunction with an appropriate analyte specific reagent (ASR) and other general purpose reagents, is part of a diagnostic test procedure or system constituting a finished in vitro diagnostic (IVD) test. General purpose reagents are appropriate for combining with one or more than one ASR in producing such systems and include labware or disposable constituents of tests; but they do not include laboratory machinery, automated or powered systems. General purpose reagents include cytological preservatives, decalcifying reagents, fixative and adhesives, tissue processing reagents, isotonic solutions and pH buffers. Reagents used in tests for more than one individual chemical substance or ligand are general purpose reagents (e.g., Thermus aquaticus (TAQ) polymerase, substrates for enzyme immunoassay (EIA)).

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9. If the device is not labeled or otherwise represented as sterile, it is exempt from the current good manufacturing practice requirements of the quality system regulation in part 820 of this chapter, with the exception of § 820.180, with respect to general requirements concerning records, and § 820.198, with respect to complaint files.

(a) Identification. Analyte specific reagents (ASR's) are antibodies, both polyclonal and monoclonal, specific receptor proteins, ligands, nucleic acid sequences, and similar reagents which, through specific binding or chemical reaction with substances in a specimen, are intended for use in a diagnostic application for identification and quantification of an individual chemical substance or ligand in biological specimens. ASR's that otherwise fall within this definition are not within the scope of subpart E of this part when they are sold to:

(1) In vitro diagnostic manufacturers; or

(2) Organizations that use the reagents to make tests for purposes other than providing diagnostic information to patients and practitioners, e.g., forensic, academic, research, and other nonclinical laboratories.

(b) Classification. (1) Class I (general controls). Except as described in paragraphs (b)(2) and (b)(3) of this section, these devices are exempt from the premarket notification requirements in part 807, subpart E of this chapter.

(2) Class II (special controls/guidance documents), when the analyte is used in blood banking tests that have been classified as class II devices (e.g., certain cytomegalovirus serological and treponema pallidum nontreponemal test reagents). Guidance Documents:

(3) Class III (premarket approval), when:

(i) The analyte is intended as a component in a test intended for use in the diagnosis of a contagious condition that is highly likely to result in a fatal outcome and prompt, accurate diagnosis offers the opportunity to mitigate the public health impact of the condition (e.g., human immunodeficiency virus (HIV/AIDS)or tuberculosis (TB)); or

(ii) The analyte is intended as a component in a test intended for use in donor screening for conditions for which FDA has recommended or required testing in order to safeguard the blood supply or establish the safe use of blood and blood products (e.g., tests for hepatitis or tests for identifying blood groups).

(c) Date of 510(k), or date of PMA or notice of completion of a product development protocol is required. (1) Preamendments ASR's; No effective date has been established for the requirement for premarket approval for the device described in paragraph (b)(3) of this section. See § 864.3.

(2) For postamendments ASR's; November 23, 1998.

(d) Restrictions. Restrictions on the sale, distribution and use of ASR's are set forth in § 809.30 of this chapter.

(a) Identification. Enzyme preparations are products that are used in the histopathology laboratory for the following purposes:

(1) To disaggregate tissues and cells already in established cultures for preparation into subsequent cultures (e.g., trypsin);

(2) To disaggregate fluid specimens for cytological examination (e.g., papain for gastric lavage or trypsin for sputum liquefaction);

(3) To aid in the selective staining of tissue specimens (e.g., diastase for glycogen determination).

(b) Classification. Class I (general controls). This device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

(a) Identification. An automated cell counter is a fully-automated or semi-automated device used to count red blood cells, white blood cells, or blood platelets using a sample of the patient's peripheral blood (blood circulating in one of the body's extremities, such as the arm). These devices may also measure hemoglobin or hematocrit and may also calculate or measure one or more of the red cell indices (the erythrocyte mean corpuscular volume, the mean corpuscular hemoglobin, or the mean corpuscular hemoglobin concentration). These devices may use either an electronic particle counting method or an optical counting method.

(b) Classification. Class II (performance standards).

(a) Identification. An automated differential cell counter is a device used to identify one or more of the formed elements of the blood. The device may also have the capability to flag, count, or classify immature or abnormal hematopoietic cells of the blood, bone marrow, or other body fluids. These devices may combine an electronic particle counting method, optical method, or a flow cytometric method utilizing monoclonal CD (cluster designation) markers. The device includes accessory CD markers.

(b) Classification. Class II (special controls). The special control for this device is the FDA document entitled “Class II Special Controls Guidance Document: Premarket Notifications for Automated Differential Cell Counters for Immature or Abnormal Blood Cells; Final Guidance for Industry and FDA.”

(a) Identification. An automated blood cell diluting apparatus is a fully automated or semi-automated device used to make appropriate dilutions of a blood sample for further testing.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 864.9.

(a) Identification. An automated cell-locating device is a device used to locate blood cells on a peripheral blood smear, allowing the operator to identify and classify each cell according to type. (Peripheral blood is blood circulating in one of the body's extremities, such as the arm.)

(b) Classification. Class II (performance standards).

(a) Identification. A red cell indices device, usually part of a larger system, calculates or directly measures the erythrocyte mean corpuscular volume (MCV), the mean corpuscular hemoglobin (MCH), and the mean corpuscular hemoglobin concentration (MCHC). The red cell indices are used for the differential diagnosis of anemias.

(b) Classification. Class II (performance standards).

(a) Identification. A microsedimentation centrifuge is a device used to sediment red cells for the microsedimentation rate test.

(b) Classification. Class I (general controls). This device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

(a) Identification. A coagulation instrument is an automated or semiautomated device used to determine the onset of clot formation for in vitro coagulation studies.

(b) Classification. Class II (special controls). A fibrometer or coagulation timer intended for use with a coagulation instrument is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

(a) Identification. A multipurpose system for in vitro coagulation studies is a device consisting of one automated or semiautomated instrument and its associated reagents and controls. The system is used to perform a series of coagulation studies and coagulation factor assays.

(b) Classification. Class II (special controls). A control intended for use with a multipurpose system for in vitro coagulation studies is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

(a) Identification. An automated hematocrit instrument is a fully automated or semi-automated device which may or may not be part of a larger system. This device measures the packed red cell volume of a blood sample to distinguish normal from abnormal states, such as anemia and erythrocytosis (an increase in the number of red cells).

(b) Classification. Class II (performance standards).

(a) Identification. An automated hemoglobin system is a fully automated or semi-automated device which may or may not be part of a larger system. The generic type of device consists of the reagents, calibrators, controls, and instrumentation used to determine the hemoglobin content of human blood.

(b) Classification. Class II (performance standards).

(a) Identification. An automated heparin analyzer is a device used to determine the heparin level in a blood sample by mixing the sample with protamine (a heparin-neutralizing substance) and determining photometrically the onset of air-activated clotting. The analyzer also determines the amount of protamine necessary to neutralize the heparin in the patient's circulation.

(b) Classification. Class II (special controls).

(a) Identification. An automated platelet aggregation system is a device used to determine changes in platelet shape and platelet aggregation following the addition of an aggregating reagent to a platelet-rich plasma.

(b) Classification. Class II (performance standards).

(a) Identification. An automated sedimentation rate device is an instrument that measures automatically the erythrocyte sedimentation rate in whole blood. Because an increased sedimentation rate indicates tissue damage or inflammation, the erythrocyte sedimentation rate device is useful in monitoring treatment of a disease.

(b) Classification. Class I (general controls). This device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

(a) Identification. An automated slide spinner is a device that prepares automatically a blood film on a microscope slide using a small amount of peripheral blood (blood circulating in one of the body's extremities, such as the arm).

(b) Classification. Class I (general controls). This device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

(a) Identification. A blood volume measuring device is a manual, semiautomated, or automated system that is used to calculate the red cell mass, plasma volume, and total blood volume.

(b) Classification. Class II (performance standards).

(a) Identification. A bleeding time device is a device, usually employing two spring-loaded blades, that produces two small incisions in the patient's skin. The length of time required for the bleeding to stop is a measure of the effectiveness of the coagulation system, primarily the platelets.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 864.9.

(a) Identification. A capillary blood collection tube is a plain or heparinized glass tube of very small diameter used to collect blood by capillary action.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 864.9.

(a) Identification. A manual blood cell counting device is a device used to count red blood cells, white blood cells, or blood platelets.

(b) Classification. Class I (general controls). This device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

(a) Identification. A hematocrit measuring device is a system consisting of instruments, tubes, racks, and a sealer and a holder. The device is used to measure the packed red cell volume in blood to determine whether the patient's total red cell volume is normal or abnormal. Abnormal states include anemia (an abnormally low total red cell volume) and erythrocytosis (an abnormally high total red cell mass). The packed red cell volume is produced by centrifuging a given volume of blood.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 864.9.

(a) Identification. An occult blood test is a device used to detect occult blood in urine or feces. (Occult blood is blood present in such small quantities that it can be detected only by chemical tests of suspected material, or by microscopic or spectroscopic examination.)

(b) Classification. Class II (special controls). A control intended for use with an occult blood test is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

(a) Identification. An osmotic fragility test is a device used to determine the resistance of red blood cells to hemolysis (destruction) in varying concentrations of hypotonic saline solutions.

(b) Classification. Class I (general controls). This device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

(a) Identification. A platelet adhesion test is a device used to determine in vitro platelet function.

(b) Classification. Class II (performance standards).

(a) Identification. A platelet aggregometer is a device, used to determine changes in platelet shape and platelet aggregation following the addition of an aggregating reagent to a platelet rich plasma.

(b) Classification. Class II (performance standards).

(a) Identification. An erythrocyte sedimentation rate test is a device that measures the length of time required for the red cells in a blood sample to fall a specified distance or a device that measures the degree of sedimentation taking place in a given length of time. An increased rate indicates tissue damage or inflammation.

(b) Classification. Class I (general controls). This device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

(a) Identification. A flow cytometric test for hematopoietic neoplasms is a device that consists of reagents for immunophenotyping of human cells in relation to the level of expression, antigen density, and distribution of specific cellular markers. These reagents are used as an aid in the differential diagnosis or monitoring of hematologically abnormal patients having or suspected of having hematopoietic neoplasms. The results should be interpreted by a pathologist or equivalent professional in conjunction with other clinical and laboratory findings.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) Premarket notification submissions must include the following information:

(i) The indications for use must indicate the clinical hematopoietic neoplasms for which the assay was designed and validated, for example, chronic leukemia or lymphoma.

(ii) A detailed device description including the following:

(A) A detailed description of all test components, all required reagents, and all instrumentation and equipment, including illustrations or photographs of nonstandard equipment or methods.

(B) Detailed documentation of the device software including, but not limited to, standalone software applications and hardware-based devices that incorporate software.

(C) A detailed description of methodology and assay procedure.

(D) A description of appropriate internal and external quality control materials that are recommended or provided. The description must identify those control elements that are incorporated into the testing procedure, if applicable.

(E) Detailed specifications for sample collection, processing, and storage.

(F) Detailed specification of the criteria for test results interpretation and reporting including pre-established templates.

(G) If applicable, based on the output of the results, a description of the specific number of events to collect, result outputs, and analytical sensitivity of the assay that will be reported.

(iii) Information that demonstrates the performance characteristics of the test, including:

(A) Device performance data from either a method comparison study comparing the specific lymphocyte cell markers to a predicate device or data collected through a clinical study demonstrating clinical validity using well-characterized clinical specimens. Samples must be representative of the intended use population of the device including hematologic neoplasms and the specific sample types for which the test is indicated for use.

(B) If applicable, device performance data from a clinical study demonstrating clinical validity for parameters not established in a predicate device of this generic type using well-characterized prospectively obtained clinical specimens including all hematologic neoplasms and the specific sample types for which the device is indicated for use.

(C) Device precision data using clinical samples to evaluate the within-lot, between-lot, within-run, between run, site-to-site and total variation using a minimum of three sites, of which at least two sites must be external sites. Results shall be reported as the standard deviation and percentage coefficient of variation for each level tested.

(D) Reproducibility data generated using a minimum of three lots of reagents to evaluate mean fluorescence intensity and variability of the recovery of the different markers and/or cell populations.

(E) Data from specimen and reagent carryover testing performed using well-established methods (e.g., CLSI H26-A2).

(F) Specimen and prepared sample stability data established for each specimen matrix in the anticoagulant combinations and storage/use conditions that will be indicated.

(G) A study testing anticoagulant equivalency in all claimed specimen type/anticoagulant combinations using clinical specimens that are representative of the intended use population of the device.

(H) Analytic sensitivity data using a dilution panel created from clinical samples.

(I) Analytical specificity data, including interference and cross-contamination.

(J) Device stability data, including real-time stability of reagents under various storage times and temperatures.

(K) For devices that include polyclonal antibodies, Fluorescence Minus One (FMO) studies to evaluate non-specific binding for all polyclonal antibodies. Each FMO tube is compared to reagent reference to demonstrate that no additional population appears when one marker is absent. Pre-specified acceptance criteria must be provided and followed.

(L) For devices indicated for use as a semi-quantitative test, linearity data using a dilution panel created from clinical samples.

(M) For devices indicated for use as a semi-quantitative test, clinically relevant analytical sensitivity data, including limit of blank, limit of detection, and limit of quantification.

(iv) Identification of risk mitigation elements used by the device, including a detailed description of all additional procedures, methods, and practices incorporated into the instructions for use that mitigate risks associated with testing the device.

(2) The 21 CFR 809.10 compliant labeling must include the following:

(i) The intended use statement in the 21 CFR 809.10(a)(2) and (b)(2) compliant labeling must include a statement that the results should be interpreted by a pathologist or equivalent professional in conjunction with other clinical and laboratory findings. The intended use statement must also include information on what the device detects and measures, whether the device is qualitative, semi-quantitative, and/or quantitative, the clinical indications for which the device is to be used, and the specific population(s) for which the device is intended.

(ii) A detailed description of the performance studies conducted to comply with paragraph (b)(1)(iii) of this section and a summary of the results.

(3) As part of the risk management activities performed under 21 CFR 820.30 design controls, product labeling and instruction manuals must include clear examples of all expected phenotypic patterns and gating strategies using well-defined clinical samples representative of both abnormal and normal cellular populations. These samples must be selected based upon the indications described in paragraph (b)(1)(i) of this section.

(a) Identification. An adenosine triphosphate release assay is a device that measures the release of adenosine triphosphate (ATP) from platelets following aggregation. This measurement is made on platelet-rich plasma using a photometer and a luminescent firefly extract. Simultaneous measurements of platelet aggregation and ATP release are used to evaluate platelet function disorders.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

(a) Identification. An antithrombin III assay is a device that is used to determine the plasma level of antithrombin III (a substance which acts with the anticoagulant heparin to prevent coagulation). This determination is used to monitor the administration of heparin in the treatment of thrombosis. The determination may also be used in the diagnosis of thrombophilia (a congenital deficiency of antithrombin III).

(b) Classification. Class II (performance standards).

(a) Identification. Red blood cell enzyme assay is a device used to measure the activity in red blood cells of clinically important enzymatic reactions and their products, such as pyruvate kinase or 2,3-diphosphoglycerate. A red blood cell enzyme assay is used to determine the enzyme defects responsible for a patient's hereditary hemolytic anemia.

(b) Classification. Class II (performance standards).

(a) Identification. An activated whole blood clotting time tests is a device, used to monitor heparin therapy for the treatment of venous thrombosis or pulmonary embolism by measuring the coagulation time of whole blood.

(b) Classification. Class II (performance standards).

(a) Identification. A erythropoietin assay is a device that measures the concentration of erythropoietin (an enzyme that regulates the production of red blood cells) in serum or urine. This assay provides diagnostic information for the evaluation of erythrocytosis (increased total red cell mass) and anemia.

(b) Classification. Class II. The special control for this device is FDA's “Document for Special Controls for Erythropoietin Assay Premarket Notification (510(k)s).”

(a) Identification. A euglobulin lysis time test is a device that measures the length of time required for the lysis (dissolution) of a clot formed from fibrinogen in the euglobulin fraction (that fraction of the plasma responsible for the formation of plasmin, a clot lysing enzyme). This test evaluates natural fibrinolysis (destruction of a blood clot after bleeding has been arrested). The test also will detect accelerated fibrinolysis.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

(a) Identification. Factor V Leiden deoxyribonucleic acid (DNA) mutation detection systems are devices that consist of different reagents and instruments which include polymerase chain reaction (PCR) primers, hybridization matrices, thermal cyclers, imagers, and software packages. The detection of the Factor V Leiden mutation aids in the diagnosis of patients with suspected thrombophilia.

(b) Classification. Class II (special controls). The special control is FDA's guidance entitled “Class II Special Controls Guidance Document: Factor V Leiden DNA Mutation Detection Systems.” (See § 864.1(d) for the availability of this guidance document.)

(a) Identification. A factor deficiency test is a device used to diagnose specific coagulation defects, to monitor certain types of therapy, to detect coagulation inhibitors, and to detect a carrier state (a person carrying both a recessive gene for a coagulation factor deficiency such as hemophilia and the corresponding normal gene).

(b) Classification. Class II (performance standards).

(a) Identification. A fibrin monomer paracoagulation test is a device used to detect fibrin monomer in the diagnosis of disseminated intravascular coagulation (nonlocalized clotting within a blood vessel) or in the differential diagnosis between disseminated intravascular coagulation and primary fibrinolysis (dissolution of the fibrin in a blood clot).

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9. The special control for this device is FDA's “In Vitro Diagnostic Fibrin Monomer Paracoagulation Test.” See § 864.1(d) for information on obtaining this document.

(a) Identification. A fibrinogen/fibrin degradation products assay is a device used to detect and measure fibrinogen degradation products and fibrin degradation products (protein fragments produced by the enzymatic action of plasmin on fibrinogen and fibrin) as an aid in detecting the presence and degree of intravascular coagulation and fibrinolysis (the dissolution of the fibrin in a blood clot) and in monitoring therapy for disseminated intravascular coagulation (nonlocalized clotting in the blood vessels).

(b) Classification. Class II (performance standards).

(a) Identification. A fibrinogen determination system is a device that consists of the instruments, reagents, standards, and controls used to determine the fibrinogen levels in disseminated intravascular coagulation (nonlocalized clotting within the blood vessels) and primary fibrinolysis (the dissolution of fibrin in a blood clot).

(b) Classification. Class II (special controls). A control or fibrinogen standard intended for use with a fibrinogen determination system is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

(a) Identification. An erythrocytic glucose-6-phosphate dehydrogenase assay is a device used to measure the activity of the enzyme glucose-6-phosphate dehydrogenase or of glucose-6-phosphate dehydrogenase isoenzymes. The results of this assay are used in the diagnosis and treatment of nonspherocytic congenital hemolytic anemia or drug-induced hemolytic anemia associated with a glucose-6-phosphate dehydrogenase deficiency. This generic device includes assays based on fluorescence, electrophoresis, methemoglobin reduction, catalase inhibition, and ultraviolet kinetics.

(b) Classification. Class II (performance standards).

(a) Identification. A glutathione reductase assay is a device used to determine the activity of the enzyme glutathione reductase in serum, plasma, or erythrocytes by such techniques as fluorescence and photometry. The results of this assay are used in the diagnosis of liver disease, glutathione reductase deficiency, or riboflavin deficiency.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

(a) Identification. A hemoglobin A2 assay is a device used to determine the hemoglobin A2 content of human blood. The measurement of hemoglobin A2 is used in the diagnosis of the thalassemias (hereditary hemolytic anemias characterized by decreased synthesis of one or more types of hemoglobin polypeptide chains).

(b) Classification. Class II (performance standards).

(a) Identification. An abnormal hemoglobin assay is a device consisting of the reagents, apparatus, instrumentation, and controls necessary to isolate and identify abnormal genetically determined hemoglobin types.

(b) Classification. Class II (special controls). A control intended for use with an abnormal hemoglobin assay is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

(a) Identification. A carboxyhemoglobin assay is a device used to determine the carboxyhemoglobin (the compound formed when hemoglobin is exposed to carbon monoxide) content of human blood as an aid in the diagnosis of carbon monoxide poisoning. This measurement may be made using methods such as spectroscopy, colorimetry, spectrophotometry, and gasometry.

(b) Classification. Class II (performance standards).

(a) Identification. An electrophoretic hemoglobin analysis system is a device that electrophoretically separates and identifies normal and abnormal hemoglobin types as an aid in the diagnosis of anemia or erythrocytosis (increased total red cell mass) due to a hemoglobin abnormality.

(b) Classification. Class II (performance standards).

(a) Identification. A fetal hemoglobin assay is a device that is used to determine the presence and distribution of fetal hemoglobin (hemoglobin F) in red cells or to measure the amount of fetal hemoglobin present. The assay may be used to detect fetal red cells in the maternal circulation or to detect the elevated levels of fetal hemoglobin exhibited in cases of hemoglobin abnormalities such as thalassemia (a hereditary hemolytic anemia characterized by a decreased synthesis of one or more types of hemoglobin polypeptide chains). The hemoglobin determination may be made by methods such as electrophoresis, alkali denaturation, column chromatography, or radial immunodiffusion.

(b) Classification. Class II (special controls). A fetal hemoglobin stain intended for use with a fetal hemoglobin assay is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

(a) Identification. A glycosylated hemoglobin assay is a device used to measure the glycosylated hemoglobins (A1a, A1b, and A1c) in a patient's blood by a column chromatographic procedure. Measurement of glycosylated hemoglobin is used to assess the level of control of a patient's diabetes and to determine the proper insulin dosage for a patient. Elevated levels of glycosylated hemoglobin indicate uncontrolled diabetes in a patient.

(b) Classification. Class II (performance standards).

(a) Identification. A sulfhemoglobin assay is a device consisting of the reagents, calibrators, controls, and instrumentation used to determine the sulfhemoglobin (a compound of sulfur and hemoglobin) content of human blood as an aid in the diagnosis of sulfhemoglobinemia (presence of sulfhemoglobin in the blood due to drug administration or exposure to a poison). This measurement may be made using methods such as spectroscopy, colorimetry, spectrophotometry, or gasometry.

(b) Classification. Class II (performance standards).

(a) Identification. A whole blood hemoglobin assay is a device consisting or reagents, calibrators, controls, or photometric or spectrophotometric instrumentation used to measure the hemoglobin content of whole blood for the detection of anemia. This generic device category does not include automated hemoglobin systems.

(b) Classification. Class II (special controls). An acid hematin intended for use with whole blood hemoglobin assays is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

(a) Identification. A heparin assay is a device used to determine the level of the anticoagulant heparin in the patient's circulation. These assays are quantitative clotting time procedures using the effect of heparin on activated coagulation factor X (Stuart factor) or procedures based on the neutralization of heparin by protamine sulfate (a protein that neutralizes heparin).

(b) Classification. Class II (performance standards).

(a) Identification. A leukocyte alkaline phosphatase test is a device used to identify the enzyme leukocyte alkaline phosphatase in neutrophilic granulocytes (granular leukocytes stainable by neutral dyes). The cytochemical identification of alkaline phosphatase depends on the formation of blue granules in cells containing alkaline phosphatase. The results of this test are used to differentiate chronic granulocytic leukemia (a malignant disease characterized by excessive overgrowth of granulocytes in the bone marrow) and reactions that resemble true leukemia, such as those occuring in severe infections and polycythemia (increased total red cell mass).

(b) Classification. Class I (general controls). This device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

(a) Identification. A leukocyte peroxidase test is a device used to distinguish certain myeloid cells derived from the bone marrow, i.e., neutrophils, eosinophils, and monocytes, from lymphoid cells of the lymphatic system and erythroid cells of the red blood cell series on the basis of their peroxidase activity as evidenced by staining. The results of this test are used in the differential diagnosis of the leukemias.

(b) Classification. Class I (general controls). This device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

(a) Identification. A platelet factor 4 radioimmunoassay is a device used to measure the level of platelet factor 4, a protein released during platelet activation by radioimmunoassay. This device measures platelet activiation, which may indicate a coagulation disorder, such as myocardial infarction or coronary artery disease.

(b) Classification. Class II (performance standards).

(a) Identification. A prothrombin consumption tests is a device that measures the patient's capacity to generate thromboplastin in the coagulation process. The test also is an indirect indicator of qualitative or quantitative platelet abnormalities. It is a screening test for thrombocytopenia (decreased number of blood platelets) and hemophilia A and B.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

(a) Identification. The prothrombin-proconvertin test and thrombotest are devices used in the regulation of coumarin therapy (administration of a coumarin anticoagulant such as sodium warfarin in the treatment of venous thrombosis and pulmonary embolism) and as a diagnostic test in conjunction with, or in place of, the Quick prothrombin time test to detect coagulation disorders.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

(a) Identification. A prothrombin time test is a device used as a general screening procedure for the detection of possible clotting factor deficiencies in the extrinsic coagulation pathway, which involves the reaction between coagulation factors III and VII, and to monitor patients receiving coumarin therapy (the administration of one of the coumarin anticoagulants in the treatment of venous thrombosis or pulmonary embolism).

(b) Classification. Class II (performance standards).

(a) Identification. A sickle cell test is a device used to determine the sickle cell hemoglobin content of human blood to detect sickle cell trait or sickle cell diseases.

(b) Classification. Class II (performance standards).

(a) Identification. A thrombin time test is a device used to measure fibrinogen concentration and detect fibrin or fibrinogen split products for the evaluation of bleeding disorders.

(b) Classification. Class II (performance standards).

(a) Identification. A thromboplastin generation test is a device used to detect and identify coagulation factor deficiencies and coagulation inhibitors.

(b) Classification. Class I (general controls). This device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

(a) Identification. A partial thromboplastin time test is a device used for primary screening for coagulation abnormalities, for evaluation of the effect of therapy on procoagulant disorders, and as an assay for coagulation factor deficiencies of the intrinsic coagulation pathway.

(b) Classification. Class II (performance standards).

(a) Identification. A Bothrops atrox reagent is a device made from snake venom and used to determine blood fibrinogen levels to aid in the evaluation of disseminated intravascular coagulation (nonlocalized clotting in the blood vessels) in patients receiving heparin therapy (the administration of the anticoagulant heparin in the treatment of thrombosis) or as an aid in the classification of dysfibrinogenemia (presence in the plasma of functionally defective fibrinogen).

(b) Classification. Class II (performance standards).

(a) Identification. A calibrator for cell indices is a device that approximates whole blood or certain blood cells and that is used to set an instrument intended to measure mean cell volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC), or other cell indices. It is a suspension of particles or cells whose size, shape, concentration, and other characteristics have been precisely and accurately determined.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

(a) Identification. A calibrator for hemoglobin or hematocrit measurement is a device that approximates whole blood, red blood cells, or a hemoglobin derivative and that is used to set instruments intended to measure hemoglobin, the hematocrit, or both. It is a material whose characteristics have been precisely and accurately determined.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

(a) Identification. A calibrator for platelet counting is a device that resembles platelets in plasma or whole blood and that is used to set a platelet counting instrument. It is a suspension of particles or cells whose size, shape concentration, and other characteristics have been precisely and accurately determined.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

(a) Identification. A calibrator for red cell and white cell counting is a device that resembles red or white blood cells and that is used to set instruments intended to count red cells, white cells, or both. It is a suspension of particles or cells whose size, shape, concentration, and other characteristics have been precisely and accurately determined.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

(a) Identification. A blood cell diluent is a device used to dilute blood for further testing, such as blood cell counting.

(b) Classification. Class I (general controls). This device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

(a) Identification. A lymphocyte separation medium is a device used to isolate lymphocytes from whole blood.

(b) Classification. Class I (general controls). This device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

(a) Identification. A red cell lysing reagent is a device used to lyse (destroy) red blood cells for hemoglobin determinations or aid in the counting of white blood cells.

(b) Classification. Class I (general controls). This device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

(a) Identification. A hematology quality control mixture is a device used to ascertain the accuracy and precision of manual, semiautomated, and automated determinations of cell parameters such as white cell count (WBC), red cell count (RBC), platelet count (PLT), hemoglobin, hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC).

(b) Classification. Class II (special controls). Except when intended for use in blood components, the device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

(a) Identification. Russell viper venom reagent is a device used to determine the cause of an increase in the prothrombin time.

(b) Classification. Class I (general controls).

(a) Identification. Blood bank supplies are general purpose devices intended for in vitro use in blood banking. This generic type of device includes products such as blood bank pipettes, blood grouping slides, blood typing tubes, blood typing racks, and cold packs for antisera reagents. The device does not include articles that are licensed by the Center for Biologics Evaluation and Research of the Food and Drug Administration.

(b) Classification. Class I (general controls).

(a) Identification. An empty container for the collection and processing of blood and blood components is a device intended for medical purposes that is an empty plastic bag or plastic or glass bottle used to collect, store, or transfer blood and blood components for further processing.

(b) Classification. Class II (performance standards).

(a) Identification. A vacuum-assisted blood collection system is a device intended for medical purposes that uses a vacuum to draw blood for subsequent reinfusion.

(b) Classification. Class I (general controls). The manual device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 864.9.

(a) Identification. A processing system for frozen blood is a device used to glycerolize red blood cells prior to freezing to minimize hemolysis (disruption of the red cell membrane accompanied by the release of hemoglobin) due to freezing and thawing of red blood cells and to deglycerolize and wash thawed cells for subsequent reinfusion.

(b) Classification. Class II (performance standards).

(a) Identification. Blood group substances of nonhuman origin for in vitro diagnostic use are materials, such as blood group specific substances prepared from nonhuman sources (e.g., pigs, cows, and horses) used to detect, identify, or neutralize antibodies to various human blood group antigens. This generic type of device does not include materials that are licensed by the Center for Biologics Evaluation and Research of the Food and Drug Administration.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 864.9.

(a) Identification. Blood establishment computer software (BECS) is a device used in the manufacture of blood and blood components to assist in the prevention of disease in humans by identifying ineligible donors, by preventing the release of unsuitable blood and blood components for transfusion or for further manufacturing into products for human treatment or diagnosis, by performing compatibility testing between donor and recipient, or by performing positive identification of patients and blood components at the point of transfusion to prevent transfusion reactions. This generic type of device may include a BECS accessory, a device intended for use with BECS to augment the performance of the BECS or to expand or modify its indications for use.

(b) Classification. Class II (special controls). The special controls for these devices are:

(1) Software performance and functional requirements including detailed design specifications (e.g., algorithms or control characteristics, alarms, device limitations, and safety requirements).

(2) Verification and validation testing and hazard analysis must be performed.

(3) Labeling must include:

(i) Software limitations;

(ii) Unresolved anomalies, annotated with an explanation of the impact on safety or effectiveness;

(iii) Revision history; and

(iv) Hardware and peripheral specifications.

(4) Traceability matrix must be performed.

(5) Performance testing to ensure the safety and effectiveness of the system must be performed, including when adding new functional requirements (e.g., electrical safety, electromagnetic compatibility, or wireless coexistence).

(a) Identification. An automated blood grouping and antibody test system is a device used to group erythrocytes (red blood cells) and to detect antibodies to blood group antigens.

(b) Classification. Class II (performance standards).

(a) Identification. A blood grouping view box is a device with a glass or plastic viewing surface, which may be illuminated and heated, that is used to view cell reactions in antigen-antibody testing.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 864.9.

(a) Identification. A blood mixing device is a device intended for medical purposes that is used to mix blood or blood components by agitation. A blood weighing device is a device intended for medical purposes that is used to weigh blood or blood components as they are collected.

(b) Classification. Class I (general controls). The manual device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 864.9.

(a) Nonelectromagnetic blood or plasma warming device - (1) Identification. A nonelectromagnetic blood and plasma warming device is a device that warms blood or plasma, by means other than electromagnetic radiation, prior to administration.

(2) Classification. Class II (performance standards).

(b) Electromagnetic blood and plasma warming device - (1) Identification. An electromagnetic blood and plasma warming device is a device that employs electromagnetic radiation (radiowaves or microwaves) to warm a bag or bottle of blood or plasma prior to administration.

(2) Classfication. Class III (premarket approval).

(c) Date PMA or notice of completion of a PDP is required. No effective date has been established of the requirement for premarket approval for the device described in paragraph (b)(1). See § 864.3.

(a) Identification. Cell-freezing apparatus and reagents for in vitro diagnostic use are devices used to freeze human red blood cells for in vitro diagnostic use.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 864.9.

(a) Identification. An automated blood cell separator is a device that uses a centrifugal or filtration separation principle to automatically withdraw whole blood from a donor, separate the whole blood into blood components, collect one or more of the blood components, and return to the donor the remainder of the whole blood and blood components. The automated blood cell separator device is intended for routine collection of blood and blood components for transfusion or further manufacturing use.

(b) Classification. Class II (special controls). The special control for this device is a guidance for industry and FDA staff entitled “Class II Special Controls Guidance Document: Automated Blood Cell Separator Device Operating by Centrifugal or Filtration Separation Principle.”

(a) Identification. A blood bank centrifuge for in vitro diagnostic use is a device used only to separate blood cells for further diagnostic testing.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 864.9.

(a) Identification. An automated cell-washing centrifuge for immuno-hematology is a device used to separate and prepare cells and sera for further in vitro diagnostic testing.

(b) Classification. Class II (performance standards).

(a) Identification. An automated Coombs test system is a device used to detect and identify antibodies in patient sera or antibodies bound to red cells. The Coombs test is used for the diagnosis of hemolytic disease of the newborn, and autoimmune hemolytic anemia. The test is also used in crossmatching and in investigating transfusion reactions and drug-induced red cell sensitization.

(b) Classification. Class II (performance standards).

(a) Identification. A copper sulfate solution for specific gravity determinations is a device used to determine whether the hemoglobin content of a potential donor's blood meets the required level (12.5 grams per 100 milliliters of blood for women and 13.5 grams per 100 milliliters of blood for men).

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 864.9.

(a) Identification. A stabilized enzyme solution is a reagent intended for medical purposes that is used to enhance the reactivity of red blood cells with certain antibodies, including antibodies that are not detectable by other techniques. These enzyme solutions include papain, bromelin, ficin, and trypsin.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

(a) Identification. Lectins and protectins are proteins derived from plants and lower animals that cause cell agglutination in the presence of certain antigens. These substances are used to detect blood group antigens for in vitro diagnostic purposes.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 864.9.

(a) Identification. An environmental chamber for storage of platelet concentrate is a device used to hold platelet-rich plasma within a preselected temperature range.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 864.9.

(a) Identification. Potentiating media for in vitro diagnostic use are media, such as bovine albumin, that are used to suspend red cells and to enhance cell reactions for antigen-antibody testing.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 864.9.

(a) Identification. A quality control kit for blood banking reagents is a device that consists of sera, cells, buffers, and antibodies used to determine the specificity, potency, and reactivity of the cells and reagents used for blood banking.

(b) Classification. Class II (performance standards).

(a) Identification. A blood storage refrigerator and a blood storage freezer are devices intended for medical purposes that are used to preserve blood and blood products by storing them at cold or freezing temperatures.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 864.9.

(a) Identification. A heat-sealing device is a device intended for medical purposes that uses heat to seal plastic bags containing blood or blood components.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 864.9.

(a) Identification. A transfer set is a device intended for medical purposes that consists of a piece of tubing with suitable adaptors used to transfer blood or plasma from one container to another.

(b) Classification. Class II (performance standards).

(a) Identification. A cord blood processing system and storage container is a device intended for use in the processing and the storage of cord blood. This device is a functionally closed processing system that includes containers, other soft goods, and a centrifugation system for cord blood concentration, and a final container for the cryopreservation and the storage of a cord blood product.

(b) Classification. Class II (special controls). The special control for this device is FDA's guidance document entitled “Class II Special Controls Guidance Document: Cord Blood Processing System and Storage Container.” For the availability of this guidance document, see § 864.1(d).