21 CFR Ch. I (4–1–20 Edition)

Home , Fetal hemoglobin, Sickle cell trait, Sulfhemoglobinemia, Thalassemia

§ 862.3880 21 CFR Ch. I (4–1–20 Edition)

cannabidiol, cannabinol, and § 862.3910 Tricyclic antidepressant cannabichromene. Measurements ob- drugs test system. tained by this device are used in the di- (a) Identification. A tricyclic agnosis and treatment of cannabinoid antidepressant drugs test system is a use or abuse and in monitoring levels device intended to measure any of the of cannabinoids during clinical inves- tricyclic antidepressant drugs in tigational use. serum. The tricyclic antidepressant (b) Classification. Class II (special drugs include imipramine, controls). A cannabinoid test system is desipramine, amitriptyline, not exempt if it is intended for any use nortriptyline, protriptyline, and other than employment or insurance doxepin. Measurements obtained by testing or is intended for Federal drug this device are used in the diagnosis testing programs. The device is exempt and treatment of chronic depression to from the premarket notification proce- ensure appropriate therapy. (b) Classification. Class II (special dures in subpart E of part 807 of this controls). A tricyclic antidepressant chapter subject to the limitations in drugs test system is not exempt if it is § 862.9, provided the test system is in- intended for any use other than em- tended for employment and insurance ployment or insurance testing or is in- testing and includes a statement in the tended for Federal drug testing pro- labeling that the device is intended grams. The device is exempt from the solely for use in employment and in- premarket notification procedures in surance testing, and does not include subpart E of part 807 of this chapter devices intended for Federal drug test- subject to the limitations in § 862.9, ing programs (e.g., programs run by the provided the test system is intended Substance Abuse and Mental Health for employment and insurance testing Services Administration (SAMHSA), and includes a statement in the label- the Department of Transportation ing that the device is intended solely (DOT), and the U.S. military). for use in employment and insurance testing, and does not include devices [52 FR 16122, May 1, 1987, as amended at 84 intended for Federal drug testing pro- FR 71799, Dec. 30, 2019] grams (e.g., programs run by the Sub- § 862.3880 Theophylline test system. stance Abuse and Mental Health Serv- ices Administration (SAMHSA), the (a) Identification. A theophylline test Department of Transportation (DOT), system is a device intended to measure and the U.S. military). theophylline (a drug used for stimula- tion of the muscles in the cardio- [52 FR 16122, May 1, 1987, as amended at 84 FR 71799, Dec. 30, 2019] vascular, respiratory, and central nerv- ous systems) in serum and plasma. § 862.3950 Vancomycin test system. Measurements obtained by this device (a) Identification. A vancomycin test are used in the diagnosis and treat- system is a device intended to measure ment of theophylline overdose or in vancomycin, an antibiotic drug, in monitoring levels of theophylline to serum. Measurements obtained by this ensure appropriate therapy. device are used in the diagnosis and (b) Classification. Class II. treatment of vancomycin overdose and in monitoring the level of vancomycin § 862.3900 Tobramycin test system. to ensure appropriate therapy. (a) Identification. A tobramycin test (b) Classification. Class II. system is a device intended to measure tobramycin, an aminoglycoside anti- PART 864—HEMATOLOGY AND biotic drug, in plasma and serum. PATHOLOGY DEVICES Measurements obtained by this device are used in the diagnosis and treat- Subpart A—General Provisions ment of tobramycin overdose and in Sec. monitoring levels of tobramycin to en- 864.1 Scope. sure appropriate therapy. 864.3 Effective dates of requirement for pre- (b) Classification. Class II. market approval.

262

VerDate Sep<11>2014 17:19 Sep 28, 2020 Jkt 250077 PO 00000 Frm 00272 Fmt 8010 Sfmt 8010 Q:\21\21V8.TXT PC31 kpayne on VMOFRWIN702 with $$_JOB Food and Drug Administration, HHS Pt. 864

864.9 Limitations of exemptions from sec- 864.5600 Automated hematocrit instrument. tion 510(k) of the Federal Food, Drug, 864.5620 Automated hemoglobin system. and Cosmetic Act (the act). 864.5680 Automated heparin analyzer. 864.5700 Automated platelet aggregation Subpart B—Biological Stains system. 864.5800 Automated sedimentation rate de- 864.1850 Dye and chemical solution stains. vice. 864.1860 Immunohistochemistry reagents 864.5850 Automated slide spinner. and kits. 864.5950 Blood volume measuring device. 864.1865 Cervical intraepithelial neoplasia (CIN) test system. Subpart G—Manual Hematology Devices 864.1866 Lynch syndrome test systems. 864.1870 Early growth response 1 (EGR1) 864.6100 Bleeding time device. gene fluorescence in-situ hybridization 864.6150 Capillary blood collection tube. (FISH) test system for specimen charac- 864.6160 Manual blood cell counting device. terization. 864.6400 Hematocrit measuring device. 864.6550 Occult blood test. Subpart C—Cell and Tissue Culture 864.6600 Osmotic fragility test. Products 864.6650 Platelet adhesion test. 864.6675 Platelet aggregometer. 864.2220 Synthetic cell and tissue culture 864.6700 Erythrocyte sedimentation rate media and components. test. 864.2240 Cell and tissue culture supplies and equipment. Subpart H—Hematology Kits and 864.2260 Chromosome culture kit. Packages 864.2280 Cultured animal and human cells. 864.2360 Mycoplasma detection media and 864.7010 Flow cytometric test system for components. hematopoietic neoplasms. 864.2800 Animal and human sera. 864.7040 Adenosine triphosphate release 864.2875 Balanced salt solutions or formula- assay. tions. 864.7060 Antithrombin III assay. 864.7100 Red blood cell enzyme assay. Subpart D—Pathology Instrumentation and 864.7140 Activated whole blood clotting time Accessories tests. 864.7250 Erythropoietin assay. 864.3010 Tissue processing equipment. 864.7275 Euglobulin lysis time tests. 864.3250 Specimen transport and storage 864.7280 Factor V Leiden DNA mutation de- container. tection systems. 864.3260 OTC test sample collection systems 864.7290 Factor deficiency test. for drugs of abuse testing. 864.7300 Fibrin monomer paracoagulation 864.3300 Cytocentrifuge. test. 864.3400 Device for sealing microsections. 864.7320 Fibrinogen/fibrin degradation prod- 864.3600 Microscopes and accessories. ucts assay. 864.3700 Whole slide imaging system. 864.7340 Fibrinogen determination system. 864.3800 Automated slide stainer. 864.7360 Erythrocytic glucose-6-phosphate 864.3875 Automated tissue processor. dehydrogenase assay. Subpart E—Specimen Preparation 864.7375 Glutathione reductase assay. 864.7400 Hemoglobin A2 assay. Reagents 864.7415 Abnormal hemoglobin assay. 864.4010 General purpose reagent. 864.7425 Carboxyhemoglobin assay. 864.4020 Analyte specific reagents. 864.7440 Electrophoretic hemoglobin anal- 864.4400 Enzyme preparations. ysis system. 864.7455 Fetal hemoglobin assay. Subpart F—Automated and Semi- 864.7470 Glycosylated hemoglobin assay. Automated Hematology Devices 864.7490 Sulfhemoglobin assay. 864.7500 Whole blood hemoglobin assays. 864.5200 Automated cell counter. 864.7525 Heparin assay. 864.5220 Automated differential cell 864.7660 Leukocyte alkaline phosphatase counter. test. 864.5240 Automated blood cell diluting appa- 864.7675 Leukocyte peroxidase test. ratus. 864.7695 Platelet factor 4 864.5260 Automated cell-locating device. radioimmunoassay. 864.5300 Red cell indices device. 864.7720 Prothrombin consumption test. 864.5350 Microsedimentation centrifuge. 864.7735 Prothrombin-proconvertin test and 864.5400 Coagulation instrument. thrombotest. 864.5425 Multipurpose system for in vitro 864.7750 Prothrombin time test. coagulation studies. 864.7825 Sickle cell test.

263

VerDate Sep<11>2014 17:19 Sep 28, 2020 Jkt 250077 PO 00000 Frm 00273 Fmt 8010 Sfmt 8010 Q:\21\21V8.TXT PC31 kpayne on VMOFRWIN702 with $$_JOB § 864.1 21 CFR Ch. I (4–1–20 Edition)

864.7875 Thrombin time test. 864.9875 Transfer set. 864.7900 Thromboplastin generation test. 864.7925 Partial thromboplastin time tests. Subpart K—Products Used In Establish- ments That Manufacture Human Cells, Subpart I—Hematology Reagents Tissues, and Cellular and Tissue-Based Products (HCT/Ps) 864.8100 Bothrops atrox reagent. 864.8150 Calibrator for cell indices. 864.9900 Cord blood processing system and 864.8165 Calibrator for hemoglobin or hem- storage container. atocrit measurement. AUTHORITY: 21 U.S.C. 351, 360, 360c, 360e, 864.8175 Calibrator for platelet counting. 360j, 360l, 371. 864.8185 Calibrator for red cell and white EDITORIAL NOTE: Nomenclature changes to cell counting. part 864 appear at 73 FR 35341, June 23, 2008. 864.8200 Blood cell diluent. 864.8500 Lymphocyte separation medium. 864.8540 Red cell lysing reagent. Subpart A—General Provisions 864.8625 Hematology quality control mixture. § 864.1 Scope. 864.8950 Russell viper venom reagent. (a) This part sets forth the classification of hematology and pathology de- Subpart J—Products Used In Establishments vices intended for human use that are That Manufacture Blood and Blood in commercial distribution. Products (b) The identification of a device in a regulation in this part is not a precise 864.9050 Blood bank supplies. description of every device that is, or 864.9100 Empty container for the collection and processing of blood and blood compo- will be, subject to the regulation. A nents. manufacturer who submits a pre- 864.9125 Vacuum-assisted blood collection market notification submission for a system. device under part 807 may not show 864.9145 Processing system for frozen blood. merely that the device is accurately 864.9160 Blood group substances of described by the section title and iden- nonhuman origin for in vitro diagnostic tification provisions of a regulation in use. this part, but shall state why the de- 864.9165 Blood establishment computer soft- vice is substantially equivalent to ware and accessories. other devices, as required by § 807.87. 864.9175 Automated blood grouping and (c) References in this part to regu- antibody test system. latory sections of the Code of Federal 864.9185 Blood grouping view box. Regulations are to chapter I of title 21, 864.9195 Blood mixing devices and blood unless otherwise noted. weighing devices. (d) Guidance documents referenced in 864.9205 Blood and plasma warming device. this part are available on the Internet 864.9225 Cell-freezing apparatus and reagents for in vitro diagnostic use. at http://www.fda.gov/MedicalDevices/ 864.9245 Automated blood cell separator. DeviceRegulationandGuidance/ 864.9275 Blood bank centrifuge for in vitro GuidanceDocuments/default.htm. diagnostic use. [52 FR 17732, May 11, 1987, as amended at 69 864.9285 Automated cell-washing centrifuge FR 12273, Mar. 16, 2004; 78 FR 18233, Mar. 26, for immuno-hematology. 2013; 79 FR 50552, Aug. 25, 2014] 864.9300 Automated Coombs test systems. 864.9320 Copper sulfate solution for specific § 864.3 Effective dates of requirement gravity determinations. for premarket approval. 864.9400 Stabilized enzyme solution. A device included in this part that is 864.9550 Lectins and protectins. classified into class III (premarket ap- 864.9575 Environmental chamber for storage proval) shall not be commercially dis- of platelet concentrate. tributed after the date shown in the 864.9600 Potentiating media for in vitro diagnostic use. regulation classifying the device unless 864.9650 Quality control kit for blood bank- the manufacturer has an approval ing reagents. under section 515 of the act (unless an 864.9700 Blood storage refrigerator and exemption has been granted under sec- blood storage freezer. tion 520(g)(2) of the act). An approval 864.9750 Heat-sealing device. under section 515 of the act consists of

264

VerDate Sep<11>2014 17:19 Sep 28, 2020 Jkt 250077 PO 00000 Frm 00274 Fmt 8010 Sfmt 8010 Q:\21\21V8.TXT PC31 kpayne on VMOFRWIN702 with $$_JOB Food and Drug Administration, HHS § 864.9

FDA’s issuance of an order approving tion 515 of the act before commercial an application for premarket approval distribution. (PMA) for the device or declaring completed a product development protocol [52 FR 17732, May 11, 1987] (PDP) for the device. § 864.9 Limitations of exemptions from (a) Before FDA requires that a device section 510(k) of the Federal Food, commercially distributed before the Drug, and Cosmetic Act (the act). enactment date of the amendments, or a device that has been found substan- The exemption from the requirement tially equivalent to such a device, has of premarket notification (section an approval under section 515 of the act 510(k) of the act) for a generic type of FDA must promulgate a regulation class I or II device is only to the extent under section 515(b) of the act requir- that the device has existing or reason- ing such approval, except as provided ably foreseeable characteristics of in paragraph (b) of this section. Such a commercially distributed devices with- regulation under section 515(b) of the in that generic type or, in the case of act shall not be effective during the in vitro diagnostic devices, only to the grace period ending on the 90th day extent that misdiagnosis as a result of after its promulgation or on the last using the device would not be associ- day of the 30th full calendar month ated with high morbidity or mortality. after the regulation that classifies the Accordingly, manufacturers of any device into class III is effective, which- commercially distributed class I or II ever is later. See section 501(f)(2)(B) of device for which FDA has granted an the act. Accordingly, unless an effec- exemption from the requirement of tive date of the requirement for pre- premarket notification must still sub- market approval is shown in the regu- mit a premarket notification to FDA lation for a device classified into class before introducing or delivering for in- III in this part, the device may be commercially distributed without FDA’s troduction into interstate commerce issuance of an order approving a PMA for commercial distribution the device or declaring completed a PDP for the when: device. If FDA promulgates a regula- (a) The device is intended for a use tion under section 515(b) of the act re- different from the intended use of a le- quiring premarket approval for a de- gally marketed device in that generic vice, section 501(f)(1)(A) of the act ap- type of device; e.g., the device is in- plies to the device. tended for a different medical purpose, (b) Any new, not substantially equiv- or the device is intended for lay use alent, device introduced into commer- where the former intended use was by cial distribution on or after May 28, health care professionals only; 1976, including a device formerly mar- (b) The modified device operates keted that has been substantially al- using a different fundamental sci- tered, is classified by statute (section entific technology than a legally mar- 513(f) of the act) into class III without keted device in that generic type of de- any grace period and FDA must have vice; e.g., a surgical instrument cuts issued an order approving a PMA or de- tissue with a laser beam rather than claring completed a PDP for the device with a sharpened metal blade, or an in before the device is commercially dis- vitro diagnostic device detects or iden- tributed unless it is reclassified. If tifies infectious agents by using FDA knows that a device being com- deoxyribonucleic acid (DNA) probe or mercially distributed may be a ‘‘new’’ device as defined in this section be- nucleic acid hybridization technology cause of any new intended use or other rather than culture or immunoassay reasons, FDA may codify the statutory technology; or classification of the device into class (c) The device is an in vitro device III for such new use. Accordingly, the that is intended: regulation for such a class III device (1) For use in the diagnosis, moni- states that as of the enactment date of toring, or screening of neoplastic dis- the amendments, May 28, 1976, the de- eases with the exception of vice must have an approval under sec- immunohistochemical devices;

265

VerDate Sep<11>2014 17:19 Sep 28, 2020 Jkt 250077 PO 00000 Frm 00275 Fmt 8010 Sfmt 8010 Q:\21\21V8.TXT PC31 kpayne on VMOFRWIN702 with $$_JOB § 864.1850 21 CFR Ch. I (4–1–20 Edition)

(2) For use in screening or diagnosis § 864.1860 Immunohistochemistry re- of familial or acquired genetic dis- agents and kits. orders, including inborn errors of me- (a) Identification. tabolism; Immunohistochemistry test systems (3) For measuring an analyte that (IHC’s) are in vitro diagnostic devices serves as a surrogate marker for consisting of polyclonal or monoclonal screening, diagnosis, or monitoring antibodies labeled with directions for life-threatening diseases such as ac- use and performance claims, which quired immune deficiency syndrome may be packaged with ancillary re- (AIDS), chronic or active hepatitis, tu- agents in kits. Their intended use is to berculosis, or myocardial infarction or identify, by immunological techniques, to monitor therapy; antigens in tissues or cytologic speci- (4) For assessing the risk of cardio- mens. Similar devices intended for use vascular diseases; with flow cytometry devices are not (5) For use in diabetes management; considered IHC’s. (6) For identifying or inferring the identity of a microorganism directly (b) Classification of from clinical material; immunohistochemistry devices. (1) Class I (7) For detection of antibodies to (general controls). Except as described microorganisms other than in paragraphs (b)(2) and (b)(3) of this immunoglobulin G (IgG) or IgG assays section, these devices are exempt from when the results are not qualitative, or the premarket notification require- are used to determine immunity, or the ments in part 807, subpart E of this assay is intended for use in matrices chapter. This exemption applies to other than serum or plasma; IHC’s that provide the pathologist with (8) For noninvasive testing as defined adjunctive diagnostic information that in § 812.3(k) of this chapter; and may be incorporated into the patholo- (9) For near patient testing (point of gist’s report, but that is not ordinarily care). reported to the clinician as an independent finding. These IHC’s are used [65 FR 2310, Jan. 14, 2000] after the primary diagnosis of tumor (neoplasm) has been made by conven- Subpart B—Biological Stains tional histopathology using nonimmunologic histochemical stains, § 864.1850 Dye and chemical solution such as hematoxylin and eosin. Exam- stains. ples of class I IHC’s are differentiation (a) Identification. Dye and chemical markers that are used as adjunctive solution stains for medical purposes tests to subclassify tumors, such as are mixtures of synthetic or natural keratin. dyes or nondye chemicals in solutions (2) Class II (special control, guidance used in staining cells and tissues for di- document: ‘‘FDA Guidance for Submis- agnostic histopathology, sion of Immunohistochemistry Appli- cytopathology, or hematology. cations to the FDA,’’ Center for De- (b) Classification. Class I (general con- vices and Radiologic Health, 1998). trols). These devices are exempt from These IHC’s are intended for the detec- the premarket notification procedures tion and/or measurement of certain in subpart E of part 807 of this chapter target analytes in order to provide subject to the limitations in § 864.9. prognostic or predictive data that are These devices are also exempt from the not directly confirmed by routine current good manufacturing practice histopathologic internal and external requirements of the quality system control specimens. These IHC’s provide regulation in part 820 of this chapter, the pathologist with information that with the exception of § 820.180, with re- is ordinarily reported as independent spect to general requirements con- diagnostic information to the ordering cerning records, and § 820.198, with re- clinician, and the claims associated spect to complaint files. with these data are widely accepted [45 FR 60583, Sept. 12, 1980, as amended at 54 and supported by valid scientific evi- FR 25044, June 12, 1989; 66 FR 38789, July 25, dence. Examples of class II IHC’s are 2001] those intended for semiquantitative

266

VerDate Sep<11>2014 17:19 Sep 28, 2020 Jkt 250077 PO 00000 Frm 00276 Fmt 8010 Sfmt 8010 Q:\21\21V8.TXT PC31 kpayne on VMOFRWIN702 with $$_JOB Food and Drug Administration, HHS § 864.1865

measurement of an analyte, such as (C) If applicable, detailed documenta- hormone receptors in breast cancer. tion of the device software, including, (3) Class III (premarket approval). but not limited to, stand-alone soft- IHC’s intended for any use not de- ware applications and hardware-based scribed in paragraphs (b)(1) or (b)(2) of devices that incorporate software. this section. (D) A detailed description of appro- (c) Date of PMA or notice of completion priate positive and negative controls of a PDP is required. As of May 28, 1976, that are recommended or provided. an approval under section 515 of the (E) Detailed specifications for sample Federal Food, Drug, and Cosmetic Act collection, processing, and storage. is required for any device described in (F) A detailed description of method- paragraph (b)(3) of this section before ology and assay procedure. this device may be commercially dis- (G) A description of the assay cutoff tributed. See § 864.3. (the medical decision point between [63 FR 30142, June 3, 1998] positive and negative) or other relevant criteria that distinguishes posi- § 864.1865 Cervical intraepithelial neo- tive and negative results, including the plasia (CIN) test system. rationale for the chosen cutoff or other (a) Identification. A cervical relevant criteria and results supporting intraepithelial neoplasia (CIN) test validation of the cutoff. system is a device used to detect a bio- (H) Detailed specification of the cri- marker associated with CIN in human teria for test results interpretation and tissues. The device is indicated as an reporting. adjunct test and not to be used as a (iv) Detailed information dem- stand-alone device. The test results onstrating the performance character- must be interpreted in the context of istics of the device, including: the patient’s clinical history including, (A) Analytical specificity studies but not limited to, prior and current such as, but not limited to, antibody cervical biopsy results, Papanicolaou characterization (e.g., Western Blot, (Pap) test results, human peptide inhibition analysis), studies papillomavirus (HPV) test results, and conducted on panels of normal tissues morphology on hematoxylin and eosin and neoplastic tissues, interference by (H&E) stained sections. This device is endogenous and exogenous substances not intended to detect the presence of as well as cross-reactivity, as applica- HPV. ble. (b) Classification. Class II (special (B) Device analytical sensitivity data controls). The special controls for this generated by testing an adequate num- device are: ber of samples from individuals with (1) Premarket notification submis- the target condition including limit of sions must include the following infor- blank, limit of detection, and limit of mation: quantification, as applicable. (i) The indications for use must (C) Device precision/reproducibility specify the biomarker that is intended data to evaluate within-run, between- to be identified and its adjunct use run, between-day, between-lot, be- (e.g., adjunct to examination of H&E tween-site, between-reader, within- stained slides) to improve consistency reader and total precision, as applica- in the diagnosis of CIN. ble, using a panel of samples covering (ii) Summary of professional society the device measuring range and/or the recommendations, as applicable. relevant disease categories (e.g. No (iii) A detailed device description in- CIN, CIN1, CIN2, CIN3, cervical cancer) cluding: and testing in replicates across mul- (A) A detailed description of all test tiple, nonconsecutive days. components, including all provided re- (D) Device robustness/guardbanding agents and required, but not provided, studies to assess the tolerance ranges ancillary reagents. for various critical test and specimen (B) A detailed description of instru- parameters. mentation and equipment, including il- (E) Device stability data, including lustrations or photographs of non- real-time stability and shipping sta- standard equipment or manuals. bility under various storage times,

267

VerDate Sep<11>2014 17:19 Sep 28, 2020 Jkt 250077 PO 00000 Frm 00277 Fmt 8010 Sfmt 8010 Q:\21\21V8.TXT PC31 kpayne on VMOFRWIN702 with $$_JOB § 864.1866 21 CFR Ch. I (4–1–20 Edition)

temperatures, and freeze-thaw condi- that mitigate risks associated with tions. testing. (F) Data from a clinical study dem- (2) The device’s 21 CFR 809.10(b) com- onstrating clinical validity using well- pliant labeling must include a detailed characterized prospectively or retro- description of the protocol, including spectively obtained clinical specimens, the information described in paragraph as appropriate, representative of the (b)(1)(ii) of this section, as applicable, intended use population. The study and a detailed description of the per- must evaluate the consistency of the formance studies performed and the diagnosis of CIN, for example, by com- summary of the results, including paring the levels of agreements of diag- those that relate to paragraph (b)(1)(ii) noses rendered by community patholo- of this section, as applicable. gists to those rendered by a panel of [83 FR 234, Jan. 3, 2018] expert pathologists. Agreement for each CIN diagnostic category (e.g., No § 864.1866 Lynch syndrome test sys- CIN, CIN1, CIN2, CIN3, cancer) and for tems. alternate diagnostic categories (e.g., (a) Identification. Lynch syndrome No CIN, low grade squamous test systems are in vitro diagnostic intraepithelial lesion (LSIL)-histology, tests for use with tumor tissue to iden- high grade squamous intraepithelial le- tify previously diagnosed cancer pa- sion (HSIL)-histology, cancer) between tients at risk for having Lynch syn- reference diagnosis by expert patholo- drome. gist and community pathologist must (b) Classification. Class II (special be evaluated, as applicable. In addi- controls). The special controls for this tion, agreements for CIN binary cat- device are: egories as ≥CIN2 (i.e., CIN2 or CIN3 or (1) Premarket notification submis- cancer) and ≤CIN1 (i.e., No CIN or CIN1) sions must include the following infor- between reference diagnosis by expert mation, as appropriate: pathologist with H&E staining and (i) A detailed description of all test community pathologist with H&E components, including all provided re- staining and agreements for alternate agents, and required but not provided, CIN binary categories as ≥HSIL-his- ancillary reagents. tology (i.e., HSIL-histology or cancer) (ii) A detailed description of instru- and ≤LSIL-histology (i.e., No CIN or mentation and equipment, including il- LSIL-histology) between reference di- lustrations or photographs of non- agnosis by an expert pathologist with standard equipment or manuals. H&E + [biomarker specified in para- (iii) Detailed documentation of the graph (b)(1)(i) of this section] and a device software, including, but not lim- community pathologist with H&E + ited to, standalone software applica- [biomarker specified in paragraph tions and hardware-based devices that (b)(1)(i) of this section] must be evalu- incorporate software. ated and compared, as applicable. (iv) A detailed description of quality (G) The staining performance of the controls including appropriate positive device as determined by the commu- and negative controls that are rec- nity pathologists during review of the ommended or provided. study slides must be evaluated. The (v) Detailed specifications for sample staining performance criteria assessed collection, processing, and storage. must include overall staining accept- (vi) A detailed description of method- ability, background staining accept- ology and assay procedure. ability, and morphology acceptability, (vii) A description of the assay cut- as applicable. off (i.e., the medical decision point be- (H) Appropriate training require- tween positive and negative results) or ments for users, including interpreta- other relevant criteria that distin- tion manual, as applicable. guishes positive and negative results, (I) Identification of risk mitigation or ordinal classes of marker expression, elements used by the device, including including the rationale for the chosen a description of all additional proce- cut-off or other relevant criteria and dures, methods, and practices incor- results supporting validation of the porated into the instructions for use cut-off.

268

VerDate Sep<11>2014 17:19 Sep 28, 2020 Jkt 250077 PO 00000 Frm 00278 Fmt 8010 Sfmt 8010 Q:\21\21V8.TXT PC31 kpayne on VMOFRWIN702 with $$_JOB Food and Drug Administration, HHS § 864.1870

(viii) Detailed specification of the age times, temperatures, and freeze- criteria for test result interpretation thaw conditions, as appropriate. and reporting. (H) The staining performance criteria (ix) Detailed information dem- assessed must include overall staining onstrating the performance character- acceptability, background staining ac- istics of the device, including: ceptability, and morphology accept- (A) Data from an appropriate study ability, as appropriate. demonstrating clinical accuracy using (I) Appropriate training requirements well-characterized clinical specimens for users, including interpretation representative of the intended use pop- manual, as applicable. ulation (i.e., concordance to (J) Identification of risk mitigation Deoxyribonucleic Acid (DNA) sequenc- elements used by the device, including ing results of the Lynch syndrome as- a description of all additional proce- sociated genes or method comparison dures, methods, and practices incor- to the predicate device using samples porated into the instructions for use with known alterations in genes rep- that mitigate risks associated with resentative of Lynch syndrome). Pre- testing. specified acceptance criteria must be (2) The device’s § 809.10(b) of this provided and followed. chapter compliant labeling must in- (B) Appropriate device reproduc- clude a detailed description of the pro- ibility data investigating all sources of tocol, including the information de- variance (e.g., for distributed tests, scribed in paragraphs (b)(1)(i) through data generated using a minimum of (viii) of this section, as appropriate, three sites, of which at least two sites and a detailed description of the per- must be external sites). Each site must formance studies performed and the perform testing over a minimum of 5 summary of the results, including nonconsecutive days evaluating a sam- those that relate to paragraph (b)(1)(ix) ple panel that spans the claimed meas- of this section, as appropriate. uring range, and includes the clinical threshold. Pre-specified acceptance cri- [83 FR 8357, Feb. 27, 2018] teria must be provided and followed. (C) Data demonstrating reader repro- § 864.1870 Early growth response 1 ducibility, both within-reader and be- (EGR1) gene fluorescence in-situ tween-reader, assessed by three readers hybridization (FISH) test system for specimen characterization. over 3 nonconsecutive days at each site, including a 2 week washout period (a) Identification. An early growth re- between reads, as appropriate. sponse 1 (EGR1) gene fluorescence in- (D) Device precision data using clin- situ hybridization (FISH) test system ical samples spanning the measuring for specimen characterization is a de- range and controls to evaluate the vice intended to detect the EGR1 probe within-lot, between-lot, within-run, be- target on chromosome 5q in bone mar- tween run, and total variation. row specimens from patients with (E) Analytical specificity studies in- acute myeloid leukemia (AML) or cluding as appropriate, western blots, myelodysplastic syndrome (MDS). The peptide inhibition, testing in normal assay results are intended to be inter- tissues and neoplastic tissues, interpreted only by a qualified pathologist ference by endogenous and exogenous or cytogeneticist. These devices do not substances, and cross-reactivity and include automated systems that di- cross contamination testing. rectly report results without review (F) Device analytical sensitivity data and interpretation by a qualified pa- generated by testing an adequate num- thologist or cytogeneticist. These de- ber of samples from individuals with vices also do not include any device in- the target condition such that preva- tended for use to select patient ther- lence of the biomarker in the target apy, predict patient response to ther- population is established. apy, or to screen for disease as well as (G) Device stability data, including any device with a claim for a par- real-time stability and in-use stability, ticular diagnosis, prognosis, moni- and stability evaluating various stor- toring, or risk assessment.

269

VerDate Sep<11>2014 17:19 Sep 28, 2020 Jkt 250077 PO 00000 Frm 00279 Fmt 8010 Sfmt 8010 Q:\21\21V8.TXT PC31 kpayne on VMOFRWIN702 with $$_JOB § 864.2220 21 CFR Ch. I (4–1–20 Edition)

(b) Classification. Class II (special erature references cited must include controls). The special controls for this the following elements: device are: (A) Documentation that the spon- (1) Premarket notification submis- sor’s probe was used in the literature sions must also include the following reference, information: (B) Number and type of specimens, (i) A detailed description of all (C) Target population studied, probes included in the kit; (D) Upper reference limit, and (ii) Purpose of each probe; (E) Range of positive probe results. (iii) Probe molecular specificity; (2) Your § 809.10(b)(12) of this chapter (iv) Probe specificity; compliant labeling must include a (v) Probe limits; statement summarizing the data iden- (vi) Probe sensitivity; tified in paragraphs (b)(1)(xiii) through (vii) Specification of required ancil- (xviii) of this section and a description lary reagents, instrumentation, and of the studies supporting the informa- equipment; tion, including the pre-specified ac- (viii) Specification of the specimen ceptance criteria for these performance collection, processing, storage and studies, justification for the pre-speci- slide preparation methods; fied acceptance criteria, and whether (ix) Specification of the assay proce- the pre-specified acceptance criteria dure; were met. (x) Specification of control elements (3) Your § 809.10 of this chapter com- that are incorporated into the rec- pliant labeling must include: ommended testing procedures; (i) A warning that reads ‘‘The assay (xi) Specification of risk mitigation results are intended to be interpreted elements: Description of all additional only by a qualified pathologist or procedures, methods, and practices in- cytogeneticist.’’ corporated into the directions for use (ii) A warning that reads ‘‘This de- that mitigate risks associated with vice is not for high-risk uses such as testing; selecting therapy, predicting thera- (xii) Specification of the criteria for peutic response or disease screening.’’ test result interpretation and report- (iii) A warning that reads ‘‘The use of ing; this device for diagnosis, monitoring or (xiii) Device analytical sensitivity risk assessment has not been estab- data; lished.’’ (xiv) Device analytical specificity data; [79 FR 52196, Sept. 3, 2014] (xv) Device reference limit data; (xvi) Device precision/reproducibility Subpart C—Cell And Tissue data; Culture Products (xvii) Device stability data to include: § 864.2220 Synthetic cell and tissue (A) Real-time stability, culture media and components. (B) Freeze-thaw stability, (a) Identification. Synthetic cell and (C) Transport and temperature sta- tissue culture media and components bility, are substances that are composed en- (D) Post-hybridization signal sta- tirely of defined components (e.g., bility, amino acids, vitamins, inorganic salts) (E) Photostability of probe, and that are essential for the survival and (xviii) Documentation that dem- development of cell lines of humans onstrates the clinical validity of the and other animals. This does not in- device. The documentation must include tissue culture media for human clude data from clinical studies, a min- ex vivo tissue and cell culture proc- imum of two peer-reviewed published essing applications as described in literature references using the specific § 876.5885 of this chapter. device seeking marketing clearance, or (b) Classification. Class I (general con- both. Documentation for the clinical trols). The device is exempt from the studies and peer-reviewed published lit- premarket notification procedures in

270

VerDate Sep<11>2014 17:19 Sep 28, 2020 Jkt 250077 PO 00000 Frm 00280 Fmt 8010 Sfmt 8010 Q:\21\21V8.TXT PC31 kpayne on VMOFRWIN702 with $$_JOB Food and Drug Administration, HHS § 864.2875

subpart E of part 807 of this chapter cell lines from the tissue of humans or subject to the limitations in § 864.9. other animals which are used in various diagnostic procedures, particu- [45 FR 60583, Sept. 12, 1980, as amended at 54 FR 25044, June 12, 1989; 66 FR 27024, May 16, larly diagnostic virology and cyto- 2001; 66 FR 38789, July 25, 2001] genetic studies. (b) Classification. Class I (general con- § 864.2240 Cell and tissue culture sup- trols). The device is exempt from the plies and equipment. premarket notification procedures in (a) Identification. Cell and tissue cul- subpart E of part 807 of this chapter ture supplies and equipment are de- subject to § 864.9. vices that are used to examine, propa- [45 FR 60585, Sept. 12, 1980, as amended at 65 gate, nourish, or grow cells and tissue FR 2310, Jan. 14, 2000] cultures. These include such articles as slide culture chambers, perfusion and § 864.2360 Mycoplasma detection roller apparatus, cell culture suspen- media and components. sion systems, and tissue culture flasks, (a) Identification. Mycoplasma detec- disks, tubes, and roller bottles. tion media and components are used to (b) Classification. Class I (general con- detect and isolate mycoplasma trols). These devices are exempt from pleuropneumonia-like organisms the premarket notification procedures (PPLO), a common microbial contami- in subpart E of part 807 of this chapter nant in cell cultures. subject to the limitations in § 864.9. If (b) Classification. Class I (general con- the devices are not labeled or otherwise trols). These devices are exempt from represented as sterile, they are exempt the premarket notification procedures from the current good manufacturing in subpart E of part 807 of this chapter practice requirements of the quality subject to the limitations in § 864.9. system regulation in part 820 of this chapter, with the exception of § 820.180, [45 FR 60586, Sept. 12, 1980, as amended at 54 FR 25044, June 12, 1989; 66 FR 38789, July 25, with respect to general requirements 2001] concerning records, and § 820.198, with respect to complaint files. § 864.2800 Animal and human sera. [45 FR 60584, Sept. 12, 1980, as amended at 54 (a) Identification. Animal and human FR 25044, June 12, 1989; 66 FR 38789, July 25, sera are biological products, obtained 2001] from the blood of humans or other animals, that provide the necessary § 864.2260 Chromosome culture kit. growth-promoting nutrients in a cell (a) Identification. A chromosome cul- culture system. ture kit is a device containing the nec- (b) Classification. Class I (general con- essary ingredients (e.g., Minimum Es- trols). These devices are exempt from sential Media (MEM) of McCoy’s 5A the premarket notification procedures culture media, phytohemagglutinin, in subpart E of part 807 of this chapter fetal calf serum, antibiotics, and hep- subject to the limitations in § 864.9. arin) used to culture tissues for diag- [45 FR 60586, Sept. 12, 1980, as amended at 54 nosis of congenital chromosome abnor- FR 25044, June 12, 1989; 66 FR 38789, July 25, malities. 2001] (b) Classification. Class I (general controls). The device is exempt from the § 864.2875 Balanced salt solutions or premarket notification procedures in formulations. subpart E of part 807 of this chapter (a) Identification. A balanced salt so- subject to the limitations in § 864.9. lution or formulation is a defined mix- [45 FR 60585, Sept. 12, 1980, as amended at 54 ture of salts and glucose in a simple FR 25044, June 12, 1989; 66 FR 38789, July 25, medium. This device is included as a 2001] necessary component of most cell culture systems. This media component § 864.2280 Cultured animal and human controls for pH, osmotic pressure, en- cells. ergy source, and inorganic ions. (a) Identification. Cultured animal (b) Classification. Class I (general con- and human cells are in vitro cultivated trols). These devices are exempt from

271

VerDate Sep<11>2014 17:19 Sep 28, 2020 Jkt 250077 PO 00000 Frm 00281 Fmt 8010 Sfmt 8010 Q:\21\21V8.TXT PC31 kpayne on VMOFRWIN702 with $$_JOB § 864.3010 21 CFR Ch. I (4–1–20 Edition)

the premarket notification procedures (b) Classification. Class I (general con- in subpart E of part 807 of this chapter trols). The device is exempt from the subject to the limitations in § 864.9. premarket notification procedures in subpart E of part 807 of this chapter [45 FR 60586, Sept. 12, 1980, as amended at 54 subject to § 864.9. If the device is not la- FR 25044, June 12, 1989; 66 FR 38789, July 25, 2001] beled or otherwise represented as sterile, it is exempt from the current good manufacturing practice requirements Subpart D—Pathology of the quality system regulation in Instrumentation and Accessories part 820 of this chapter, with the exception of § 820.180 of this chapter, with re- § 864.3010 Tissue processing equip- spect to general requirements con- ment. cerning records, and § 820.198 of this (a) Identification. Tissue processing chapter, with respect to complaint equipment consists of devices used to files. prepare human tissue specimens for di- [54 FR 47206, Nov. 13, 1989, as amended at 65 agnostic histological examination by FR 2310, Jan. 14, 2000; 65 FR 18234, Apr. 7, processing specimens through the var- 2000] ious stages of decalcifying, infiltrating, sectioning, and mounting on micro- § 864.3260 OTC test sample collection scope slides. systems for drugs of abuse testing. (b) Classification. Class I (general con- (a) Identification. An over-the-counter trols). These devices are exempt from (OTC) test sample collection system the premarket notification procedures for drugs of abuse testing is a device in subpart E of part 807 of this chapter intended to: Collect biological speci- subject to the limitations in § 864.9. The mens (such as hair, urine, sweat, or sa- devices are also exempt from the cur- liva), outside of a medical setting and rent good manufacturing practice re- not on order of a health care profes- quirements of the quality system regu- sional (e.g., in the home, insurance, lation in part 820 of this chapter, with sports, or workplace setting); maintain the exception of § 820.180, with respect the integrity of such specimens during to general requirements concerning storage and transport in order that the records, and § 820.198, with respect to matter contained therein can be tested complaint files. in a laboratory for the presence of [45 FR 60587, Sept. 12, 1980, as amended at 54 drugs of abuse or their metabolites; FR 25044, June 12, 1989; 66 FR 38789, July 25, and provide access to test results and 2001] counseling. This section does not apply to collection, transport, or laboratory § 864.3250 Specimen transport and testing of biological specimens for the storage container. presence of drugs of abuse or their me- (a) Identification. A specimen trans- tabolites that is performed to develop port and storage container, which may evidence for law enforcement purposes. be empty or prefilled, is a device in- (b) Classification. Class I (general con- tended to contain biological specimens, trols). The device is exempt from the body waste, or body exudate during premarket notification requirements storage and transport in order that the in part 807, subpart E of this chapter matter contained therein can be de- subject to the limitations in § 864.9 if it stroyed or used effectively for diag- is sold, distributed, and used in accord- nostic examination. If prefilled, the de- ance with the restrictions set forth in vice contains a fixative solution or § 809.40 of this chapter. If the device is other general purpose reagent to pre- not labeled or otherwise represented as serve the condition of a biological spec- sterile, it is exempt from the current good manufacturing practice require- imen added to the container. This sec- ments of the quality system regulation tion does not apply to specimen trans- in part 820 of this chapter, with the ex- port and storage containers that are ception of § 820.198 of this chapter with intended for use as part of an over-the- respect to complaint files. counter test sample collection system for drugs of abuse testing. [65 FR 18234, Apr. 7, 2000]

272

VerDate Sep<11>2014 17:19 Sep 28, 2020 Jkt 250077 PO 00000 Frm 00282 Fmt 8010 Sfmt 8010 Q:\21\21V8.TXT PC31 kpayne on VMOFRWIN702 with $$_JOB Food and Drug Administration, HHS § 864.3700

§ 864.3300 Cytocentrifuge. (b) Classification. Class I (general controls). These devices are exempt from (a) Identification. A cytocentrifuge is the premarket notification procedures a centrifuge used to concentrate cells in subpart E of part 807 of this chapter from biological cell suspensions (e.g., subject to the limitations in § 864.9. If cerebrospinal fluid) and to deposit the device is not labeled or otherwise these cells on a glass microscope slide represented as sterile, it is exempt for cytological examination. from the current good manufacturing (b) Classification. Class I (general con- practice requirements of the quality trols). This device is exempt from the system regulation in part 820 of this premarket notification procedures in chapter, with the exception of § 820.180, subpart E of part 807 of this chapter with respect to general requirements subject to the limitations in § 864.9. concerning records, and § 820.198, with [45 FR 60588, Sept. 12, 1980, as amended at 54 respect to complaint files. FR 25044, June 12, 1989; 66 FR 38789, July 25, 2001] [45 FR 60590, Sept. 12, 1980, as amended at 54 FR 25044, June 12, 1989; 66 FR 38789, July 25, § 864.3400 Device for sealing microsec- 2001] tions. § 864.3700 Whole slide imaging system. (a) Identification. A device for sealing (a) Identification. The whole slide im- microsections is an automated instru- aging system is an automated digital ment used to seal stained cells and slide creation, viewing, and manage- microsections for histological and ment system intended as an aid to the cytological examination. pathologist to review and interpret dig- (b) Classification. Class I (general con- ital images of surgical pathology trols). This device is exempt from the slides. The system generates digital premarket notification procedures in images that would otherwise be appro- subpart E of part 807 of this chapter priate for manual visualization by con- subject to the limitations in § 864.9. ventional light microscopy. [45 FR 60589, Sept. 12, 1980, as amended at 54 (b) Classification. Class II (special FR 25044, June 12, 1989; 66 FR 38789, July 25, controls). The special controls for this 2001] device are: (1) Premarket notification submis- § 864.3600 Microscopes and acces- sions must include the following infor- sories. mation: (a) Identification. Microscopes and ac- (i) The indications for use must cessories are optical instruments used specify the tissue specimen that is in- to enlarge images of specimens, prep- tended to be used with the whole slide arations, and cultures for medical pur- imaging system and the components of poses. Variations of microscopes and the system. accessories (through a change in the (ii) A detailed description of the de- light source) used for medical purposes vice and bench testing results at the include the following: component level, including for the fol- (1) Phase contrast microscopes, lowing, as appropriate: which permit visualization of (A) Slide feeder; unstained preparations by altering the (B) Light source; phase relationship of light that passes (C) Imaging optics; around the object and through the ob- (D) Mechanical scanner movement; ject. (E) Digital imaging sensor; (2) Fluorescense microscopes, which (F) Image processing software; permit examination of specimens (G) Image composition techniques; stained with fluorochromes that fluo- (H) Image file formats; resce under ultraviolet light. (I) Image review manipulation soft- (3) Inverted stage microscopes, which ware; permit examination of tissue cultures (J) Computer environment; and or other biological specimens con- (K) Display system. tained in bottles or tubes with the (iii) Detailed bench testing and re- light source mounted above the speci- sults at the system level, including for men. the following, as appropriate:

273

VerDate Sep<11>2014 17:19 Sep 28, 2020 Jkt 250077 PO 00000 Frm 00283 Fmt 8010 Sfmt 8010 Q:\21\21V8.TXT PC31 kpayne on VMOFRWIN702 with $$_JOB § 864.3800 21 CFR Ch. I (4–1–20 Edition)

(A) Color reproducibility; (iii) A description of the performance (B) Spatial resolution; studies and the summary of results, in- (C) Focusing test; cluding those that relate to paragraph (D) Whole slide tissue coverage; (b)(1)(iv) of this section, as appropriate. (E) Stitching error; and (iv) A limiting statement that speci- fies that pathologists should exercise (F) Turnaround time. professional judgment in each clinical (iv) Detailed information dem- situation and examine the glass slides onstrating the performance character- by conventional microscopy if there is istics of the device, including, as ap- doubt about the ability to accurately propriate: render an interpretation using this de- (A) Precision to evaluate intra-sys- vice alone. tem and inter-system precision using a comprehensive set of clinical speci- [83 FR 22, Jan. 2, 2018] mens with defined, clinically relevant § 864.3800 Automated slide stainer. histologic features from various organ systems and diseases. Multiple whole (a) Identification. An automated slide slide imaging systems, multiple sites, stainer is a device used to stain his- and multiple readers must be included. tology, cytology, and hematology (B) Reproducibility data to evaluate slides for diagnosis. inter-site variability using a com- (b) Classification. Class I (general con- prehensive set of clinical specimens trols). This device is exempt from the with defined, clinically relevant premarket notification procedures in histologic features from various organ subpart E of part 807 of this chapter systems and diseases. Multiple whole subject to the limitations in § 864.9. slide imaging systems, multiple sites, [45 FR 60591, Sept. 12, 1980, as amended at 54 and multiple readers must be included. FR 25044, June 12, 1989; 66 FR 38789, July 25, (C) Data from a clinical study to 2001] demonstrate that viewing, reviewing, § 864.3875 Automated tissue processor. and diagnosing digital images of surgical pathology slides prepared from (a) Identification. An automated tis- tissue slides using the whole slide im- sue processor is an automated system aging system is non-inferior to using used to process tissue specimens for ex- an optical microscope. The study amination through fixation, dehydra- should evaluate the difference in major tion, and infiltration. discordance rates between manual dig- (b) Classification. Class I (general con- ital (MD) and manual optical (MO) mo- trols). This device is exempt from the dalities when compared to the ref- premarket notification procedures in erence (e.g., main sign-out diagnosis). subpart E of part 807 of this chapter (D) A detailed human factor engi- subject to the limitations in § 864.9. neering process must be used to evalu- [45 FR 60591, Sept. 12, 1980, as amended at 54 ate the whole slide imaging system FR 25045, June 12, 1989; 66 FR 38789, July 25, user interface(s). 2001] (2) Labeling compliant with 21 CFR 809.10(b) must include the following: Subpart E—Specimen Preparation (i) The intended use statement must Reagents include the information described in paragraph (b)(1)(i) of this section, as § 864.4010 General purpose reagent. applicable, and a statement that reads, (a) A general purpose reagent is a ‘‘It is the responsibility of a qualified chemical reagent that has general lab- pathologist to employ appropriate pro- oratory application, that is used to col- cedures and safeguards to assure the lect, prepare, and examine specimens validity of the interpretation of images from the human body for diagnostic obtained using this device.’’ purposes, and that is not labeled or (ii) A description of the technical otherwise intended for a specific diag- studies and the summary of results, in- nostic application. It may be either an cluding those that relate to paragraphs individual substance, or multiple sub- (b)(1)(ii) and (iii) of this section, as ap- stances reformulated, which, when propriate. combined with or used in conjunction

274

VerDate Sep<11>2014 17:19 Sep 28, 2020 Jkt 250077 PO 00000 Frm 00284 Fmt 8010 Sfmt 8010 Q:\21\21V8.TXT PC31 kpayne on VMOFRWIN702 with $$_JOB Food and Drug Administration, HHS § 864.4020

with an appropriate analyte specific re- (2) Organizations that use the reagent (ASR) and other general purpose agents to make tests for purposes other reagents, is part of a diagnostic test than providing diagnostic information procedure or system constituting a fin- to patients and practitioners, e.g., fo- ished in vitro diagnostic (IVD) test. rensic, academic, research, and other General purpose reagents are appro- nonclinical laboratories. priate for combining with one or more (b) Classification. (1) Class I (general than one ASR in producing such sys- controls). Except as described in para- tems and include labware or disposable graphs (b)(2) and (b)(3) of this section, constituents of tests; but they do not these devices are exempt from the pre- include laboratory machinery, auto- market notification requirements in mated or powered systems. General part 807, subpart E of this chapter. purpose reagents include cytological (2) Class II (special controls/guidance preservatives, decalcifying reagents, documents), when the analyte is used fixative and adhesives, tissue proc- in blood banking tests that have been essing reagents, isotonic solutions and classified as class II devices (e.g., cer- pH buffers. Reagents used in tests for tain cytomegalovirus serological and more than one individual chemical sub- treponema pallidum nontreponemal stance or ligand are general purpose re- test reagents). Guidance Documents: agents (e.g., Thermus aquaticus (TAQ) 1. ‘‘Specifications for Immunological Test- polymerase, substrates for enzyme ing for Infectious Disease; Approved Guide- immunoassay (EIA)). line,’’ NCCLS Document I/LA18–A, December (b) Classification. Class I (general con- 1994. 2. ‘‘Assessment of the Clinical Accuracy of trols). The device is exempt from the Laboratory Tests Using Receiver Operating premarket notification procedures in Characteristic (ROC) Plots; Tentative Guide- subpart E of part 807 of this chapter line,’’ NCCLS Document KGP10–T, December subject to the limitations in § 864.9. If 1993. the device is not labeled or otherwise 3. ‘‘Review Criteria for Assessment of In represented as sterile, it is exempt Vitro Diagnostic Devices for Direct Detec- from the current good manufacturing tion of Mycobacterium spp,’’ FDA, July 6, practice requirements of the quality 1993, and its ‘‘Attachment 1,’’ February 28, 1994. system regulation in part 820 of this 4. ‘‘Draft Review Criteria for Nucleic Acid chapter, with the exception of § 820.180, Amplification-Based In Vitro Diagnostic De- with respect to general requirements vices for Direct Detection of Infectious concerning records, and § 820.198, with Microorganisms,’’ FDA, July 6, 1993. respect to complaint files. 5. The Center for Biologics Evaluation and Research, FDA, ‘‘Points to Consider in the [45 FR 60592, Sept. 12, 1980, as amended at 54 Manufacture and Clinical Evaluation of In FR 25045, June 12, 1989; 62 FR 62260, Nov. 21, Vitro Tests to Detect Antibodies to the 1997; 66 FR 38789, July 25, 2001] Human Immunodeficiency Virus, Type I’’ (54 FR 48943, November 28, 1989). § 864.4020 Analyte specific reagents. (3) Class III (premarket approval), (a) Identification. Analyte specific re- when: agents (ASR’s) are antibodies, both (i) The analyte is intended as a com- polyclonal and monoclonal, specific re- ponent in a test intended for use in the ceptor proteins, ligands, nucleic acid diagnosis of a contagious condition sequences, and similar reagents which, that is highly likely to result in a fatal through specific binding or chemical outcome and prompt, accurate diag- reaction with substances in a speci- nosis offers the opportunity to miti- men, are intended for use in a diag- gate the public health impact of the nostic application for identification condition (e.g., human immuno- and quantification of an individual deficiency virus (HIV/AIDS)or tuber- chemical substance or ligand in bio- culosis (TB)); or logical specimens. ASR’s that other- (ii) The analyte is intended as a com- wise fall within this definition are not ponent in a test intended for use in within the scope of subpart E of this donor screening for conditions for part when they are sold to: which FDA has recommended or re- (1) In vitro diagnostic manufacturers; quired testing in order to safeguard the or blood supply or establish the safe use

275

VerDate Sep<11>2014 17:19 Sep 28, 2020 Jkt 250077 PO 00000 Frm 00285 Fmt 8010 Sfmt 8010 Q:\21\21V8.TXT PC31 kpayne on VMOFRWIN702 with $$_JOB § 864.4400 21 CFR Ch. I (4–1–20 Edition)

of blood and blood products (e.g., tests erythrocyte mean corpuscular volume, for hepatitis or tests for identifying the mean corpuscular hemoglobin, or blood groups). the mean corpuscular hemoglobin con- (c) Date of 510(k), or date of PMA or centration). These devices may use ei- notice of completion of a product develop- ther an electronic particle counting ment protocol is required. (1) method or an optical counting method. Preamendments ASR’s; No effective (b) Classification. Class II (perform- date has been established for the re- ance standards). quirement for premarket approval for [45 FR 60593, Sept. 12, 1980] the device described in paragraph (b)(3) of this section. See § 864.3. § 864.5220 Automated differential cell (2) For postamendments ASR’s; No- counter. vember 23, 1998. (a) Identification. An automated dif- (d) Restrictions. Restrictions on the ferential cell counter is a device used sale, distribution and use of ASR’s are to identify one or more of the formed set forth in § 809.30 of this chapter. elements of the blood. The device may [62 FR 62260, Nov. 21, 1997] also have the capability to flag, count, or classify immature or abnormal § 864.4400 Enzyme preparations. hematopoietic cells of the blood, bone (a) Identification. Enzyme prepara- marrow, or other body fluids. These de- tions are products that are used in the vices may combine an electronic par- histopathology laboratory for the fol- ticle counting method, optical method, lowing purposes: or a flow cytometric method utilizing (1) To disaggregate tissues and cells monoclonal CD (cluster designation) already in established cultures for markers. The device includes accessory preparation into subsequent cultures CD markers. (e.g., trypsin); (b) Classification. Class II (special (2) To disaggregate fluid specimens controls). The special control for this for cytological examination (e.g., device is the FDA document entitled papain for gastric lavage or trypsin for ‘‘Class II Special Controls Guidance sputum liquefaction); Document: Premarket Notifications for (3) To aid in the selective staining of Automated Differential Cell Counters tissue specimens (e.g., diastase for gly- for Immature or Abnormal Blood Cells; cogen determination). Final Guidance for Industry and FDA.’’ (b) Classification. Class I (general con- [67 FR 1607, Jan. 14, 2002] trols). This device is exempt from the premarket notification procedures in § 864.5240 Automated blood cell dilut- subpart E of part 807 of this chapter ing apparatus. subject to the limitations in § 864.9. (a) Identification. An automated blood [45 FR 60592, Sept. 12, 1980, as amended at 54 cell diluting apparatus is a fully auto- FR 25045, June 12, 1989; 66 FR 38789, July 25, mated or semi-automated device used 2001] to make appropriate dilutions of a blood sample for further testing. Subpart F—Automated and Semi- (b) Classification. Class I (general con- Automated Hematology Devices trols). The device is exempt from the premarket notification procedures in § 864.5200 Automated cell counter. subpart E of part 807 of this chapter (a) Identification. An automated cell subject to § 864.9. counter is a fully-automated or semi- [45 FR 60596, Sept. 12, 1980, as amended at 65 automated device used to count red FR 2310, Jan. 14, 2000] blood cells, white blood cells, or blood platelets using a sample of the pa- § 864.5260 Automated cell-locating de- tient’s peripheral blood (blood circu- vice. lating in one of the body’s extremities, (a) Identification. An automated cell- such as the arm). These devices may locating device is a device used to lo- also measure hemoglobin or hemato- cate blood cells on a peripheral blood crit and may also calculate or measure smear, allowing the operator to iden- one or more of the red cell indices (the tify and classify each cell according to

276

VerDate Sep<11>2014 17:19 Sep 28, 2020 Jkt 250077 PO 00000 Frm 00286 Fmt 8010 Sfmt 8010 Q:\21\21V8.TXT PC31 kpayne on VMOFRWIN702 with $$_JOB Food and Drug Administration, HHS § 864.5680

type. (Peripheral blood is blood circu- semiautomated instrument and its as- lating in one of the body’s extremities, sociated reagents and controls. The such as the arm.) system is used to perform a series of (b) Classification. Class II (perform- coagulation studies and coagulation ance standards). factor assays. [45 FR 60597, Sept. 12, 1980] (b) Classification. Class II (special controls). A control intended for use § 864.5300 Red cell indices device. with a multipurpose system for in vitro coagulation studies is exempt from the (a) Identification. A red cell indices device, usually part of a larger system, premarket notification procedures in calculates or directly measures the subpart E of part 807 of this chapter erythrocyte mean corpuscular volume subject to the limitations in § 864.9. (MCV), the mean corpuscular hemo- [45 FR 60599, Sept. 12, 1980, as amended at 84 globin (MCH), and the mean corpus- FR 71799, Dec. 30, 2019] cular hemoglobin concentration (MCHC). The red cell indices are used § 864.5600 Automated hematocrit infor the differential diagnosis of strument. anemias. (a) Identification. An automated hem- (b) Classification. Class II (perform- atocrit instrument is a fully auto- ance standards). mated or semi-automated device which may or may not be part of a larger sys- [45 FR 60597, Sept. 12, 1980] tem. This device measures the packed § 864.5350 Microsedimentation cen- red cell volume of a blood sample to trifuge. distinguish normal from abnormal (a) Identification. A microsedimenta- states, such as anemia and tion centrifuge is a device used to sedi- erythrocytosis (an increase in the num- ment red cells for the microsedimenta- ber of red cells). tion rate test. (b) Classification. Class II (perform- (b) Classification. Class I (general con- ance standards). trols). This device is exempt from the [45 FR 60600, Sept. 12, 1980] premarket notification procedures in subpart E of part 807 of this chapter § 864.5620 Automated hemoglobin sys- subject to the limitations in § 864.9. tem. [45 FR 60598, Sept. 12, 1980, as amended at 59 (a) Identification. An automated he- FR 63007, Dec. 7, 1994; 66 FR 38789, July 25, moglobin system is a fully automated 2001] or semi-automated device which may or may not be part of a larger system. § 864.5400 Coagulation instrument. The generic type of device consists of (a) Identification. A coagulation in- the reagents, calibrators, controls, and strument is an automated or semiauto- instrumentation used to determine the mated device used to determine the hemoglobin content of human blood. onset of clot formation for in vitro co- (b) Classification. Class II (perform- agulation studies. ance standards). (b) Classification. Class II (special [45 FR 60601, Sept. 12, 1980] controls). A fibrometer or coagulation timer intended for use with a coagula- § 864.5680 Automated heparin ana- tion instrument is exempt from the lyzer. premarket notification procedures in (a) Identification. An automated hep- subpart E of part 807 of this chapter arin analyzer is a device used to deter- subject to the limitations in § 864.9. mine the heparin level in a blood sam- [45 FR 60598, Sept. 12, 1980, as amended at 84 ple by mixing the sample with prot- FR 71799, Dec. 30, 2019] amine (a heparin-neutralizing substance) and determining § 864.5425 Multipurpose system for in photometrically the onset of air-acti- vitro coagulation studies. vated clotting. The analyzer also deter- (a) Identification. A multipurpose sys- mines the amount of protamine nec- tem for in vitro coagulation studies is essary to neutralize the heparin in the a device consisting of one automated or patient’s circulation.

277

VerDate Sep<11>2014 17:19 Sep 28, 2020 Jkt 250077 PO 00000 Frm 00287 Fmt 8010 Sfmt 8010 Q:\21\21V8.TXT PC31 kpayne on VMOFRWIN702 with $$_JOB § 864.5700 21 CFR Ch. I (4–1–20 Edition)

(b) Classification. Class II (special § 864.5950 Blood volume measuring de- controls). vice. [45 FR 60601, Sept. 12, 1980, as amended at 52 (a) Identification. A blood volume FR 17733, May 11, 1987; 58 FR 51571, Oct. 4, measuring device is a manual, semi- 1993] automated, or automated system that is used to calculate the red cell mass, § 864.5700 Automated platelet aggrega- plasma volume, and total blood vol- tion system. ume. (a) Identification. An automated (b) Classification. Class II (perform- platelet aggregation system is a device ance standards). used to determine changes in platelet [45 FR 60603, Sept. 12, 1980] shape and platelet aggregation following the addition of an aggregating Subpart G—Manual Hematology reagent to a platelet-rich plasma. Devices (b) Classification. Class II (performance standards). § 864.6100 Bleeding time device. [45 FR 60602, Sept. 12, 1980] (a) Identification. A bleeding time device is a device, usually employing two § 864.5800 Automated sedimentation spring-loaded blades, that produces two rate device. small incisions in the patient’s skin. (a) Identification. An automated sedi- The length of time required for the bleeding to stop is a measure of the ef- mentation rate device is an instrument fectiveness of the coagulation system, that measures automatically the primarily the platelets. erythrocyte sedimentation rate in (b) Classification. Class II (special whole blood. Because an increased sedi- controls). The device is exempt from mentation rate indicates tissue dam- the premarket notification procedures age or inflammation, the erythrocyte in subpart E of part 807 of this chapter sedimentation rate device is useful in subject to § 864.9. monitoring treatment of a disease. (b) Classification. Class I (general con- [45 FR 60604, Sept. 12, 1980, as amended at 63 FR 59225, Nov. 3, 1998] trols). This device is exempt from the premarket notification procedures in § 864.6150 Capillary blood collection subpart E of part 807 of this chapter tube. subject to the limitations in § 864.9. (a) Identification. A capillary blood [45 FR 60602, Sept. 12, 1980, as amended at 54 collection tube is a plain or FR 25045, June 12, 1989; 66 FR 38790, July 25, heparinized glass tube of very small di- 2001] ameter used to collect blood by capillary action. § 864.5850 Automated slide spinner. (b) Classification. Class I (general con- (a) Identification. An automated slide trols). The device is exempt from the spinner is a device that prepares auto- premarket notification procedures in subpart E of part 807 of this chapter matically a blood film on a microscope subject to § 864.9. slide using a small amount of peripheral blood (blood circulating in one of [45 FR 60604, Sept. 12, 1980, as amended at 54 the body’s extremities, such as the FR 25045, June 12, 1989; 65 FR 2310, Jan. 14, arm). 2000] (b) Classification. Class I (general con- § 864.6160 Manual blood cell counting trols). This device is exempt from the device. premarket notification procedures in (a) Identification. A manual blood cell subpart E of part 807 of this chapter counting device is a device used to subject to the limitations in § 864.9. count red blood cells, white blood cells, [45 FR 60603, Sept. 12, 1980, as amended at 54 or blood platelets. FR 25045, June 12, 1989; 66 FR 38790, July 25, (b) Classification. Class I (general con- 2001] trols). This device is exempt from the premarket notification procedures in

278

VerDate Sep<11>2014 17:19 Sep 28, 2020 Jkt 250077 PO 00000 Frm 00288 Fmt 8010 Sfmt 8010 Q:\21\21V8.TXT PC31 kpayne on VMOFRWIN702 with $$_JOB Food and Drug Administration, HHS § 864.7010

subpart E of part 807 of this chapter subpart E of part 807 of this chapter subject to the limitations in § 864.9. subject to the limitations in § 864.9. [45 FR 60605, Sept. 12, 1980, as amended at 54 [45 FR 60607, Sept. 12, 1980, as amended at 54 FR 25045, June 12, 1989; 66 FR 38790, July 25, FR 25045, June 12, 1989; 66 FR 38790, July 25, 2001] 2001]

§ 864.6400 Hematocrit measuring de- § 864.6650 Platelet adhesion test. vice. (a) Identification. A platelet adhesion (a) Identification. A hematocrit meas- test is a device used to determine in uring device is a system consisting of vitro platelet function. instruments, tubes, racks, and a sealer (b) Classification. Class II (perform- and a holder. The device is used to ance standards). measure the packed red cell volume in blood to determine whether the pa- [45 FR 60608, Sept. 12, 1980] tient’s total red cell volume is normal or abnormal. Abnormal states include § 864.6675 Platelet aggregometer. anemia (an abnormally low total red (a) Identification. A platelet cell volume) and erythrocytosis (an ab- aggregometer is a device, used to de- normally high total red cell mass). The termine changes in platelet shape and packed red cell volume is produced by platelet aggregation following the ad- centrifuging a given volume of blood. dition of an aggregating reagent to a (b) Classification. Class II (special platelet rich plasma. controls). The device is exempt from (b) Classification. Class II (perform- the premarket notification procedures ance standards). in subpart E of part 807 of this chapter [45 FR 60608, Sept. 12, 1980] subject to § 864.9. [45 FR 60606, Sept. 12, 1980, as amended at 63 § 864.6700 Erythrocyte sedimentation FR 59225, Nov. 3, 1998] rate test. (a) Identification. An erythrocyte § 864.6550 Occult blood test. sedimentation rate test is a device that (a) Identification. An occult blood test measures the length of time required is a device used to detect occult blood for the red cells in a blood sample to in urine or feces. (Occult blood is blood fall a specified distance or a device present in such small quantities that it that measures the degree of sedimenta- can be detected only by chemical tests tion taking place in a given length of of suspected material, or by micro- time. An increased rate indicates tis- scopic or spectroscopic examination.) sue damage or inflammation. (b) Classification. Class II (special (b) Classification. Class I (general con- controls). A control intended for use trols). This device is exempt from the with an occult blood test is exempt premarket notification procedures in from the premarket notification proce- subpart E of part 807 of this chapter dures in subpart E of part 807 of this subject to the limitations in § 864.9. chapter subject to the limitations in [45 FR 60608, Sept. 12, 1980, as amended at 54 § 864.9. FR 25045, June 12, 1989; 66 FR 38790, July 25, [45 FR 60606, Sept. 12, 1980, as amended at 84 2001] FR 71799, Dec. 30, 2019] Subpart H—Hematology Kits and § 864.6600 Osmotic fragility test. Packages (a) Identification. An osmotic fragility test is a device used to determine the § 864.7010 Flow cytometric test system resistance of red blood cells to hemol- for hematopoietic neoplasms. ysis (destruction) in varying con- (a) Identification. A flow cytometric centrations of hypotonic saline solu- test for hematopoietic neoplasms is a tions. device that consists of reagents for (b) Classification. Class I (general con- immunophenotyping of human cells in trols). This device is exempt from the relation to the level of expression, premarket notification procedures in antigen density, and distribution of

279

VerDate Sep<11>2014 17:19 Sep 28, 2020 Jkt 250077 PO 00000 Frm 00289 Fmt 8010 Sfmt 8010 Q:\21\21V8.TXT PC31 kpayne on VMOFRWIN702 with $$_JOB § 864.7010 21 CFR Ch. I (4–1–20 Edition)

specific cellular markers. These re- markers to a predicate device or data agents are used as an aid in the dif- collected through a clinical study dem- ferential diagnosis or monitoring of onstrating clinical validity using well- hematologically abnormal patients characterized clinical specimens. Sam- having or suspected of having ples must be representative of the in- hematopoietic neoplasms. The results tended use population of the device in- should be interpreted by a pathologist cluding hematologic neoplasms and the or equivalent professional in conjunc- specific sample types for which the test tion with other clinical and laboratory is indicated for use. findings. (B) If applicable, device performance (b) Classification. Class II (special data from a clinical study dem- controls). The special controls for this onstrating clinical validity for param- device are: eters not established in a predicate de- (1) Premarket notification submis- vice of this generic type using well- sions must include the following infor- characterized prospectively obtained mation: clinical specimens including all hem- (i) The indications for use must indi- atologic neoplasms and the specific cate the clinical hematopoietic neo- sample types for which the device is in- plasms for which the assay was de- dicated for use. signed and validated, for example, (C) Device precision data using clin- chronic leukemia or lymphoma. ical samples to evaluate the within-lot, (ii) A detailed device description in- between-lot, within-run, between run, cluding the following: site-to-site and total variation using a (A) A detailed description of all test minimum of three sites, of which at components, all required reagents, and least two sites must be external sites. all instrumentation and equipment, in- Results shall be reported as the stand- cluding illustrations or photographs of ard deviation and percentage coeffi- nonstandard equipment or methods. cient of variation for each level tested. (B) Detailed documentation of the (D) Reproducibility data generated device software including, but not lim- using a minimum of three lots of re- ited to, standalone software applica- agents to evaluate mean fluorescence tions and hardware-based devices that intensity and variability of the recov- incorporate software. ery of the different markers and/or cell (C) A detailed description of method- populations. ology and assay procedure. (E) Data from specimen and reagent (D) A description of appropriate in- carryover testing performed using well- ternal and external quality control ma- established methods (e.g., CLSI H26– terials that are recommended or pro- A2). vided. The description must identify (F) Specimen and prepared sample those control elements that are incor- stability data established for each porated into the testing procedure, if specimen matrix in the anticoagulant applicable. combinations and storage/use condi- (E) Detailed specifications for sample tions that will be indicated. collection, processing, and storage. (G) A study testing anticoagulant (F) Detailed specification of the cri- equivalency in all claimed specimen teria for test results interpretation and type/anticoagulant combinations using reporting including pre-established clinical specimens that are representa- templates. tive of the intended use population of (G) If applicable, based on the output the device. of the results, a description of the spe- (H) Analytic sensitivity data using a cific number of events to collect, result dilution panel created from clinical outputs, and analytical sensitivity of samples. the assay that will be reported. (I) Analytical specificity data, in- (iii) Information that demonstrates cluding interference and cross-con- the performance characteristics of the tamination. test, including: (J) Device stability data, including (A) Device performance data from ei- real-time stability of reagents under ther a method comparison study com- various storage times and tempera- paring the specific lymphocyte cell tures.

280

VerDate Sep<11>2014 17:19 Sep 28, 2020 Jkt 250077 PO 00000 Frm 00290 Fmt 8010 Sfmt 8010 Q:\21\21V8.TXT PC31 kpayne on VMOFRWIN702 with $$_JOB Food and Drug Administration, HHS § 864.7100

(K) For devices that include the indications described in paragraph polyclonal antibodies, Fluorescence (b)(1)(i) of this section. Minus One (FMO) studies to evaluate [82 FR 61165, Dec. 27, 2017] non-specific binding for all polyclonal antibodies. Each FMO tube is compared § 864.7040 Adenosine triphosphate re- to reagent reference to demonstrate lease assay. that no additional population appears (a) Identification. An adenosine when one marker is absent. Pre-speci- triphosphate release assay is a device fied acceptance criteria must be pro- that measures the release of adenosine vided and followed. triphosphate (ATP) from platelets fol- (L) For devices indicated for use as a lowing aggregation. This measurement semi-quantitative test, linearity data is made on platelet-rich plasma using a using a dilution panel created from photometer and a luminescent firefly clinical samples. extract. Simultaneous measurements (M) For devices indicated for use as a of platelet aggregation and ATP re- semi-quantitative test, clinically rel- lease are used to evaluate platelet evant analytical sensitivity data, in- function disorders. cluding limit of blank, limit of detec- (b) Classification. Class I (general con- tion, and limit of quantification. trols). The device is exempt from the (iv) Identification of risk mitigation premarket notification procedures in elements used by the device, including subpart E of part 807 of this chapter a detailed description of all additional subject to the limitations in § 864.9. procedures, methods, and practices in- [45 FR 60609, Sept. 12, 1980, as amended at 84 corporated into the instructions for use FR 71799, Dec. 30, 2019] that mitigate risks associated with testing the device. § 864.7060 Antithrombin III assay. (2) The 21 CFR 809.10 compliant label- (a) Identification. An antithrombin III ing must include the following: assay is a device that is used to deter- (i) The intended use statement in the mine the plasma level of antithrombin 21 CFR 809.10(a)(2) and (b)(2) compliant III (a substance which acts with the labeling must include a statement that anticoagulant heparin to prevent co- the results should be interpreted by a agulation). This determination is used pathologist or equivalent professional to monitor the administration of hep- in conjunction with other clinical and arin in the treatment of thrombosis. laboratory findings. The intended use The determination may also be used in statement must also include informa- the diagnosis of thrombophilia (a con- tion on what the device detects and genital deficiency of antithrombin III). measures, whether the device is quali- (b) Classification. Class II (perform- tative, semi-quantitative, and/or quan- ance standards). titative, the clinical indications for which the device is to be used, and the [45 FR 60609, Sept. 12, 1980] specific population(s) for which the device is intended. § 864.7100 Red blood cell enzyme assay. (ii) A detailed description of the performance studies conducted to comply (a) Identification. Red blood cell en- with paragraph (b)(1)(iii) of this section zyme assay is a device used to measure and a summary of the results. the activity in red blood cells of clini- (3) As part of the risk management cally important enzymatic reactions and their products, such as pyruvate activities performed under 21 CFR kinase or 2,3-diphosphoglycerate. A red 820.30 design controls, product labeling blood cell enzyme assay is used to de- and instruction manuals must include termine the enzyme defects responsible clear examples of all expected for a patient’s hereditary hemolytic phenotypic patterns and gating strate- anemia. gies using well-defined clinical samples (b) Classification. Class II (perform- representative of both abnormal and ance standards). normal cellular populations. These samples must be selected based upon [45 FR 60610, Sept. 12, 1980]

281

VerDate Sep<11>2014 17:19 Sep 28, 2020 Jkt 250077 PO 00000 Frm 00291 Fmt 8010 Sfmt 8010 Q:\21\21V8.TXT PC31 kpayne on VMOFRWIN702 with $$_JOB § 864.7140 21 CFR Ch. I (4–1–20 Edition)

§ 864.7140 Activated whole blood clot- ments which include polymerase chain ting time tests. reaction (PCR) primers, hybridization (a) Identification. An activated whole matrices, thermal cyclers, imagers, blood clotting time tests is a device, and software packages. The detection used to monitor heparin therapy for of the Factor V Leiden mutation aids the treatment of venous thrombosis or in the diagnosis of patients with sus- pulmonary embolism by measuring the pected thrombophilia. coagulation time of whole blood. (b) Classification. Class II (special (b) Classification. Class II (perform- controls). The special control is FDA’s ance standards). guidance entitled ‘‘Class II Special [45 FR 60611, Sept. 12, 1980] Controls Guidance Document: Factor V Leiden DNA Mutation Detection Sys- § 864.7250 Erythropoietin assay. tems.’’ (See § 864.1(d) for the avail- (a) Identification. A erythropoietin ability of this guidance document.) assay is a device that measures the [69 FR 12273, Mar. 16, 2004] concentration of erythropoietin (an enzyme that regulates the production of § 864.7290 Factor deficiency test. red blood cells) in serum or urine. This assay provides diagnostic information (a) Identification. A factor deficiency for the evaluation of erythrocytosis test is a device used to diagnose spe- (increased total red cell mass) and ane- cific coagulation defects, to monitor mia. certain types of therapy, to detect co- (b) Classification. Class II. The special agulation inhibitors, and to detect a control for this device is FDA’s ‘‘Docu- carrier state (a person carrying both a ment for Special Controls for Erythro- recessive gene for a coagulation factor poietin Assay Premarket Notification deficiency such as hemophilia and the (510(k)s).’’ corresponding normal gene). [45 FR 60612, Sept. 12, 1980, as amended at 52 (b) Classification. Class II (perform- FR 17733, May 11, 1987; 65 FR 17144, Mar. 31, ance standards). 2000] [45 FR 60613, Sept. 12, 1980] § 864.7275 Euglobulin lysis time tests. (a) Identification. A euglobulin lysis § 864.7300 Fibrin monomer paracoagulation test. time test is a device that measures the length of time required for the lysis (a) Identification. A fibrin monomer (dissolution) of a clot formed from paracoagulation test is a device used to fibrinogen in the euglobulin fraction detect fibrin monomer in the diagnosis (that fraction of the plasma responsible of disseminated intravascular coagula- for the formation of plasmin, a clot tion (nonlocalized clotting within a lysing enzyme). This test evaluates blood vessel) or in the differential diag- natural fibrinolysis (destruction of a nosis between disseminated blood clot after bleeding has been ar- intravascular coagulation and primary rested). The test also will detect accel- fibrinolysis (dissolution of the fibrin in erated fibrinolysis. a blood clot). (b) Class II (special Classification. (b) Classification. Class II (special controls). The device is exempt from controls). The device is exempt from the premarket notification procedures the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9. in subpart E of part 807 of this chapter subject to the limitations in § 864.9. The [45 FR 60612, Sept. 12, 1980, as amended at 84 special control for this device is FDA’s FR 71799, Dec. 30, 2019] ‘‘In Vitro Diagnostic Fibrin Monomer § 864.7280 Factor V Leiden DNA muta- Paracoagulation Test.’’ See § 864.1(d) tion detection systems. for information on obtaining this docu- (a) Identification. Factor V Leiden ment. deoxyribonucleic acid (DNA) mutation [45 FR 60614, Sept. 12, 1980, as amended at 52 detection systems are devices that con- FR 17733, May 11, 1987; 65 FR 17144, Mar. 31, sist of different reagents and instru- 2000, 84 FR 71799, Dec. 30, 2019]

282

VerDate Sep<11>2014 17:19 Sep 28, 2020 Jkt 250077 PO 00000 Frm 00292 Fmt 8010 Sfmt 8010 Q:\21\21V8.TXT PC31 kpayne on VMOFRWIN702 with $$_JOB Food and Drug Administration, HHS § 864.7415

§ 864.7320 Fibrinogen/fibrin degrada- methemoglobin reduction, catalase in- tion products assay. hibition, and ultraviolet kinetics. (a) Identification. A fibrinogen/fibrin (b) Classification. Class II (perform- degradation products assay is a device ance standards). used to detect and measure fibrinogen [45 FR 60616, Sept. 12, 1980] degradation products and fibrin degradation products (protein fragments § 864.7375 Glutathione reductase produced by the enzymatic action of assay. plasmin on fibrinogen and fibrin) as an aid in detecting the presence and de- (a) Identification. A glutathione re- gree of intravascular coagulation and ductase assay is a device used to deter- fibrinolysis (the dissolution of the mine the activity of the enzyme gluta- fibrin in a blood clot) and in moni- thione reductase in serum, plasma, or toring therapy for disseminated erythrocytes by such techniques as flu- intravascular coagulation (nonlocal- orescence and photometry. The results ized clotting in the blood vessels). of this assay are used in the diagnosis (b) Classification. Class II (perform- of liver disease, glutathione reductase ance standards). deficiency, or riboflavin deficiency. (b) Classification. Class II (special [45 FR 60615, Sept. 12, 1980] controls). The device is exempt from § 864.7340 Fibrinogen determination the premarket notification procedures system. in subpart E of part 807 of this chapter (a) Identification. A fibrinogen deter- subject to the limitations in § 864.9. mination system is a device that con- [45 FR 60616, Sept. 12, 1980, as amended at 84 sists of the instruments, reagents, FR 71799, Dec. 30, 2019] standards, and controls used to determine the fibrinogen levels in dissemi- § 864.7400 Hemoglobin A2 assay. nated intravascular coagulation (non- (a) Identification. A hemoglobin A2 localized clotting within the blood ves- assay is a device used to determine the sels) and primary fibrinolysis (the dis- hemoglobin A content of human blood. solution of fibrin in a blood clot). 2 The measurement of hemoglobin A is (b) Classification. Class II (special 2 used in the diagnosis of the controls). A control or fibrinogen thalassemias (hereditary hemolytic standard intended for use with a anemias characterized by decreased fibrinogen determination system is exempt from the premarket notification synthesis of one or more types of he- procedures in subpart E of part 807 of moglobin polypeptide chains). this chapter subject to the limitations (b) Classification. Class II (perform- in § 864.9. ance standards). [45 FR 60615, Sept. 12, 1980, as amended at 84 [45 FR 60617, Sept. 12, 1980] FR 71799, Dec. 30, 2019] § 864.7415 Abnormal hemoglobin assay. § 864.7360 Erythrocytic glucose-6-phos- (a) Identification. An abnormal hemo- phate dehydrogenase assay. globin assay is a device consisting of (a) Identification. An erythrocytic the reagents, apparatus, instrumenta- glucose-6-phosphate dehydrogenase tion, and controls necessary to isolate assay is a device used to measure the and identify abnormal genetically de- activity of the enzyme glucose-6-phos- termined hemoglobin types. phate dehydrogenase or of glucose-6- (b) Classification. Class II (special phosphate dehydrogenase isoenzymes. controls). A control intended for use The results of this assay are used in with an abnormal hemoglobin assay is the diagnosis and treatment of exempt from the premarket notifica- nonspherocytic congenital hemolytic tion procedures in subpart E of part 807 anemia or drug-induced hemolytic ane- of this chapter subject to the limita- mia associated with a glucose-6-phos- tions in § 864.9. phate dehydrogenase deficiency. This generic device includes assays based on [45 FR 60618, Sept. 12, 1980, as amended at 84 fluorescence, electrophoresis, FR 71799, Dec. 30, 2019]

283

VerDate Sep<11>2014 17:19 Sep 28, 2020 Jkt 250077 PO 00000 Frm 00293 Fmt 8010 Sfmt 8010 Q:\21\21V8.TXT PC31 kpayne on VMOFRWIN702 with $$_JOB § 864.7425 21 CFR Ch. I (4–1–20 Edition)

§ 864.7425 Carboxyhemoglobin assay. part 807 of this chapter subject to the limitations in § 864.9. (a) Identification. A carboxyhemoglobin assay is a device [45 FR 60620, Sept. 12, 1980, as amended at 84 used to determine the FR 71799, Dec. 30, 2019] carboxyhemoglobin (the compound § 864.7470 Glycosylated hemoglobin formed when hemoglobin is exposed to assay. carbon monoxide) content of human (a) Identification. A glycosylated he- blood as an aid in the diagnosis of car- moglobin assay is a device used to bon monoxide poisoning. This measure- measure the glycosylated hemoglobins ment may be made using methods such (A1a, A1b, and A1c) in a patient’s blood as spectroscopy, colorimetry, by a column chromatographic proce- spectrophotometry, and gasometry. dure. Measurement of glycosylated he- (b) Classification. Class II (perform- moglobin is used to assess the level of ance standards). control of a patient’s diabetes and to determine the proper insulin dosage for [45 FR 60619, Sept. 12, 1980] a patient. Elevated levels of § 864.7440 Electrophoretic hemoglobin glycosylated hemoglobin indicate un- analysis system. controlled diabetes in a patient. (b) Classification. Class II (perform- (a) Identification. An electrophoretic ance standards). hemoglobin analysis system is a device that electrophoretically separates and [45 FR 60621, Sept. 12, 1980] identifies normal and abnormal hemo- § 864.7490 Sulfhemoglobin assay. globin types as an aid in the diagnosis of anemia or erythrocytosis (increased (a) Identification. A sulfhemoglobin assay is a device consisting of the re- total red cell mass) due to a hemo- agents, calibrators, controls, and in- globin abnormality. strumentation used to determine the (b) Classification. Class II (perform- sulfhemoglobin (a compound of sulfur ance standards). and hemoglobin) content of human [45 FR 60620, Sept. 12, 1980] blood as an aid in the diagnosis of sulfhemoglobinemia (presence of § 864.7455 Fetal hemoglobin assay. sulfhemoglobin in the blood due to drug administration or exposure to a (a) Identification. A fetal hemoglobin poison). This measurement may be assay is a device that is used to deter- made using methods such as spectros- mine the presence and distribution of copy, colorimetry, spectrophotometry, fetal hemoglobin (hemoglobin F) in red or gasometry. cells or to measure the amount of fetal (b) Classification. Class II (perform- hemoglobin present. The assay may be ance standards). used to detect fetal red cells in the ma- ternal circulation or to detect the ele- [45 FR 60621, Sept. 12, 1980] vated levels of fetal hemoglobin exhib- § 864.7500 Whole blood hemoglobin as- ited in cases of hemoglobin abnormali- says. ties such as thalassemia (a hereditary (a) Identification. A whole blood he- hemolytic anemia characterized by a moglobin assay is a device consisting decreased synthesis of one or more or reagents, calibrators, controls, or types of hemoglobin polypeptide photometric or spectrophotometric in- chains). The hemoglobin determination strumentation used to measure the he- may be made by methods such as elec- moglobin content of whole blood for trophoresis, alkali denaturation, col- the detection of anemia. This generic umn chromatography, or radial device category does not include auto- immunodiffusion. mated hemoglobin systems. (b) Classification. Class II (special (b) Classification. Class II (special controls). A fetal hemoglobin stain in- controls). An acid hematin intended for tended for use with a fetal hemoglobin use with whole blood hemoglobin as- assay is exempt from the premarket says is exempt from the premarket no- notification procedures in subpart E of tification procedures in subpart E of

284

VerDate Sep<11>2014 17:19 Sep 28, 2020 Jkt 250077 PO 00000 Frm 00294 Fmt 8010 Sfmt 8010 Q:\21\21V8.TXT PC31 kpayne on VMOFRWIN702 with $$_JOB Food and Drug Administration, HHS § 864.7735

part 807 of this chapter subject to the activity as evidenced by staining. The limitations in § 864.9. results of this test are used in the dif- [45 FR 60622, Sept. 12, 1980, as amended at 84 ferential diagnosis of the leukemias. FR 71799, Dec. 30, 2019] (b) Classification. Class I (general controls). This device is exempt from the § 864.7525 Heparin assay. premarket notification procedures in (a) Identification. A heparin assay is a subpart E of part 807 of this chapter device used to determine the level of subject to the limitations in § 864.9. the anticoagulant heparin in the pa- [45 FR 60624, Sept. 12, 1980, as amended at 59 tient’s circulation. These assays are FR 63007, Dec. 7, 1994; 66 FR 38790, July 25, quantitative clotting time procedures 2001] using the effect of heparin on activated coagulation factor X (Stuart factor) or § 864.7695 Platelet factor 4 procedures based on the neutralization radioimmunoassay. of heparin by protamine sulfate (a protein that neutralizes heparin). (a) Identification. A platelet factor 4 (b) Classification. Class II (perform- radioimmunoassay is a device used to ance standards). measure the level of platelet factor 4, a protein released during platelet activa- [45 FR 60623, Sept. 12, 1980] tion by radioimmunoassay. This device § 864.7660 Leukocyte alkaline phos- measures platelet activiation, which phatase test. may indicate a coagulation disorder, such as myocardial infarction or coro- (a) Identification. A leukocyte alkaline phosphatase test is a device used nary artery disease. to identify the enzyme leukocyte alka- (b) Classification. Class II (perform- line phosphatase in neutrophilic ance standards). granulocytes (granular leukocytes [45 FR 60625, Sept. 12, 1980; 46 FR 14890, Mar. stainable by neutral dyes). The 3, 1981] cytochemical identification of alkaline phosphatase depends on the formation § 864.7720 Prothrombin consumption of blue granules in cells containing al- test. kaline phosphatase. The results of this (a) Identification. A prothrombin con- test are used to differentiate chronic sumption tests is a device that meas- granulocytic leukemia (a malignant ures the patient’s capacity to generate disease characterized by excessive thromboplastin in the coagulation overgrowth of granulocytes in the bone marrow) and reactions that resemble process. The test also is an indirect in- true leukemia, such as those occuring dicator of qualitative or quantitative in severe infections and polycythemia platelet abnormalities. It is a screen- (increased total red cell mass). ing test for thrombocytopenia (de- (b) Classification. Class I (general con- creased number of blood platelets) and trols). This device is exempt from the hemophilia A and B. premarket notification procedures in (b) Classification. Class II (special subpart E of part 807 of this chapter controls). The device is exempt from subject to the limitations in § 864.9. the premarket notification procedures [45 FR 60623, Sept. 12, 1980, as amended at 59 in subpart E of part 807 of this chapter FR 63007, Dec. 7, 1994; 66 FR 38790, July 25, subject to the limitations in § 864.9. 2001] [45 FR 60625, Sept. 12, 1980, as amended at 84 § 864.7675 Leukocyte peroxidase test. FR 71800, Dec. 30, 2019] (a) Identification. A leukocyte peroxi- § 864.7735 Prothrombin-proconvertin dase test is a device used to distinguish test and thrombotest. certain myeloid cells derived from the (a) Identification. The prothrombin- bone marrow, i.e., neutrophils, proconvertin test and thrombotest are eosinophils, and monocytes, from lymphoid cells of the lymphatic system devices used in the regulation of cou- and erythroid cells of the red blood cell marin therapy (administration of a series on the basis of their peroxidase

285

VerDate Sep<11>2014 17:19 Sep 28, 2020 Jkt 250077 PO 00000 Frm 00295 Fmt 8010 Sfmt 8010 Q:\21\21V8.TXT PC31 kpayne on VMOFRWIN702 with $$_JOB § 864.7750 21 CFR Ch. I (4–1–20 Edition)

coumarin anticoagulant such as so- tect and identify coagulation factor de- dium warfarin in the treatment of ve- ficiencies and coagulation inhibitors. nous thrombosis and pulmonary embo- (b) Classification. Class I (general con- lism) and as a diagnostic test in controls). This device is exempt from the junction with, or in place of, the Quick premarket notification procedures in prothrombin time test to detect coagu- subpart E of part 807 of this chapter lation disorders. subject to the limitations in § 864.9. (b) Classification. Class II (special [45 FR 60628, Sept. 12, 1980, as amended at 59 controls). The device is exempt from FR 63007, Dec. 7, 1994; 66 FR 38790, July 25, the premarket notification procedures 2001] in subpart E of part 807 of this chapter subject to the limitations in § 864.9. § 864.7925 Partial thromboplastin time tests. [45 FR 60626, Sept. 12, 1980, as amended at 84 FR 71800, Dec. 30, 2019] (a) Identification. A partial thromboplastin time test is a device used for § 864.7750 Prothrombin time test. primary screening for coagulation ab- (a) Identification. A prothrombin time normalities, for evaluation of the ef- test is a device used as a general fect of therapy on procoagulant dis- screening procedure for the detection orders, and as an assay for coagulation of possible clotting factor deficiencies factor deficiencies of the intrinsic co- in the extrinsic coagulation pathway, agulation pathway. which involves the reaction between (b) Classification. Class II (perform- coagulation factors III and VII, and to ance standards). monitor patients receiving coumarin [45 FR 60629, Sept. 12, 1980] therapy (the administration of one of the coumarin anticoagulants in the Subpart I—Hematology Reagents treatment of venous thrombosis or pulmonary embolism). § 864.8100 Bothrops atrox reagent. (b) Classification. Class II (perform- (a) Identification. A Bothrops atrox ance standards). reagent is a device made from snake [45 FR 60626, Sept. 12, 1980] venom and used to determine blood fibrinogen levels to aid in the evalua- § 864.7825 Sickle cell test. tion of disseminated intravascular co- (a) Identification. A sickle cell test is agulation (nonlocalized clotting in the a device used to determine the sickle blood vessels) in patients receiving cell hemoglobin content of human heparin therapy (the administration of blood to detect sickle cell trait or sick- the anticoagulant heparin in the treat- le cell diseases. ment of thrombosis) or as an aid in the (b) Classification. Class II (perform- classification of dysfibrinogenemia ance standards). (presence in the plasma of functionally defective fibrinogen). [45 FR 60627, Sept. 12, 1980] (b) Classification. Class II (performance standards). § 864.7875 Thrombin time test. [45 FR 60629, Sept. 12, 1980] (a) Identification. A thrombin time test is a device used to measure § 864.8150 Calibrator for cell indices. fibrinogen concentration and detect fibrin or fibrinogen split products for (a) Identification. A calibrator for cell the evaluation of bleeding disorders. indices is a device that approximates (b) Classification. Class II (perform- whole blood or certain blood cells and ance standards). that is used to set an instrument intended to measure mean cell volume [45 FR 60628, Sept. 12, 1980] (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemo- § 864.7900 Thromboplastin generation globin concentration (MCHC), or other test. cell indices. It is a suspension of par- (a) Identification. A thromboplastin ticles or cells whose size, shape, con- generation test is a device used to de- centration, and other characteristics

286

VerDate Sep<11>2014 17:19 Sep 28, 2020 Jkt 250077 PO 00000 Frm 00296 Fmt 8010 Sfmt 8010 Q:\21\21V8.TXT PC31 kpayne on VMOFRWIN702 with $$_JOB Food and Drug Administration, HHS § 864.8625

have been precisely and accurately de- tion, and other characteristics have termined. been precisely and accurately deter- (b) Classification. Class II (special mined. controls). The device is exempt from (b) Classification. Class II (special the premarket notification procedures controls). The device is exempt from in subpart E of part 807 of this chapter the premarket notification procedures subject to the limitations in § 864.9. in subpart E of part 807 of this chapter subject to the limitations in § 864.9. [45 FR 60631, Sept. 12, 1980, as amended at 84 FR 71800, Dec. 30, 2019] [45 FR 60634, Sept. 12, 1980, as amended at 84 FR 71800, Dec. 30, 2019] § 864.8165 Calibrator for hemoglobin or hematocrit measurement. § 864.8200 Blood cell diluent. (a) Identification. A calibrator for he- (a) Identification. A blood cell diluent moglobin or hematocrit measurement is a device used to dilute blood for fur- is a device that approximates whole ther testing, such as blood cell count- blood, red blood cells, or a hemoglobin ing. derivative and that is used to set in- (b) Classification. Class I (general con- struments intended to measure hemo- trols). This device is exempt from the globin, the hematocrit, or both. It is a premarket notification procedures in material whose characteristics have subpart E of part 807 of this chapter been precisely and accurately deter- subject to the limitations in § 864.9. mined. [45 FR 60635, Sept. 12, 1980, as amended at 54 (b) Classification. Class II (special FR 25045, June 12, 1989; 66 FR 38790, July 25, controls). The device is exempt from 2001] the premarket notification procedures in subpart E of part 807 of this chapter § 864.8500 Lymphocyte separation me- subject to the limitations in § 864.9. dium. [45 FR 60632, Sept. 12, 1980, as amended at 84 (a) Identification. A lymphocyte sepa- FR 71800, Dec. 30, 2019] ration medium is a device used to isolate lymphocytes from whole blood. § 864.8175 Calibrator for platelet (b) Classification. Class I (general con- counting. trols). This device is exempt from the (a) Identification. A calibrator for premarket notification procedures in platelet counting is a device that re- subpart E of part 807 of this chapter sembles platelets in plasma or whole subject to the limitations in § 864.9. blood and that is used to set a platelet [45 FR 60636, Sept. 12, 1980, as amended at 59 counting instrument. It is a suspension FR 63007, Dec. 7, 1994; 66 FR 38790, July 25, of particles or cells whose size, shape 2001] concentration, and other characteristics have been precisely and accurately § 864.8540 Red cell lysing reagent. determined. (a) Identification. A red cell lysing re- (b) Classification. Class II (special agent is a device used to lyse (destroy) controls). The device is exempt from red blood cells for hemoglobin deter- the premarket notification procedures minations or aid in the counting of in subpart E of part 807 of this chapter white blood cells. subject to the limitations in § 864.9. (b) Classification. Class I (general con- [45 FR 60633, Sept. 12, 1980, as amended at 84 trols). This device is exempt from the FR 71800, Dec. 30, 2019] premarket notification procedures in subpart E of part 807 of this chapter § 864.8185 Calibrator for red cell and subject to the limitations in § 864.9. white cell counting. [45 FR 60636, Sept. 12, 1980, as amended at 54 (a) Identification. A calibrator for red FR 25045, June 12, 1989; 66 FR 38790, July 25, cell and white cell counting is a device 2001] that resembles red or white blood cells and that is used to set instruments in- § 864.8625 Hematology quality control tended to count red cells, white cells, mixture. or both. It is a suspension of particles (a) Identification. A hematology qual- or cells whose size, shape, concentra- ity control mixture is a device used to

287

VerDate Sep<11>2014 17:19 Sep 28, 2020 Jkt 250077 PO 00000 Frm 00297 Fmt 8010 Sfmt 8010 Q:\21\21V8.TXT PC31 kpayne on VMOFRWIN702 with $$_JOB § 864.8950 21 CFR Ch. I (4–1–20 Edition)

ascertain the accuracy and precision of blood and blood components is a device manual, semiautomated, and auto- intended for medical purposes that is mated determinations of cell param- an empty plastic bag or plastic or glass eters such as white cell count (WBC), bottle used to collect, store, or transfer red cell count (RBC), platelet count blood and blood components for further (PLT), hemoglobin, hematocrit (HCT), processing. mean corpuscular volume (MCV), mean (b) Classification. Class II (perform- corpuscular hemoglobin (MCH), and ance standards). mean corpuscular hemoglobin concentration (MCHC). [45 FR 60638, Sept. 12, 1980] (b) Classification. Class II (special controls). Except when intended for use § 864.9125 Vacuum-assisted blood collection system. in blood components, the device is exempt from the premarket notification (a) Identification. A vacuum-assisted procedures in subpart E of part 807 of blood collection system is a device in- this chapter subject to the limitations tended for medical purposes that uses a in § 864.9. vacuum to draw blood for subsequent reinfusion. [45 FR 60637, Sept. 12, 1980, as amended at 84 FR 71800, Dec. 30, 2019] (b) Classification. Class I (general controls). The manual device is exempt § 864.8950 Russell viper venom rea- from the premarket notification proce- gent. dures in subpart E of part 807 of this (a) Identification. Russell viper venom chapter subject to § 864.9. reagent is a device used to determine [45 FR 60639, Sept. 12, 1980, as amended at 65 the cause of an increase in the pro- FR 2310, Jan. 14, 2000] thrombin time. (b) Classification. Class I (general con- § 864.9145 Processing system for fro- trols). zen blood. [45 FR 60637, Sept. 12, 1980] (a) Identification. A processing system for frozen blood is a device used to Subpart J—Products Used In Es- glycerolize red blood cells prior to tablishments That Manufac- freezing to minimize hemolysis (disrup- ture Blood and Blood Prod- tion of the red cell membrane accom- panied by the release of hemoglobin) ucts due to freezing and thawing of red § 864.9050 Blood bank supplies. blood cells and to deglycerolize and wash thawed cells for subsequent re- (a) Identification. Blood bank supplies infusion. are general purpose devices intended (b) Classification. Class II (perform- for in vitro use in blood banking. This ance standards). generic type of device includes products such as blood bank pipettes, blood [45 FR 60639, Sept. 12, 1980] grouping slides, blood typing tubes, blood typing racks, and cold packs for § 864.9160 Blood group substances of antisera reagents. The device does not nonhuman origin for in vitro diag- include articles that are licensed by nostic use. the Center for Biologics Evaluation (a) Identification. Blood group sub- and Research of the Food and Drug Ad- stances of nonhuman origin for in vitro ministration. diagnostic use are materials, such as (b) Classification. Class I (general con- blood group specific substances pre- trols). pared from nonhuman sources (e.g., [45 FR 60638, Sept. 12, 1980, as amended at 53 pigs, cows, and horses) used to detect, FR 11253, Apr. 6, 1988] identify, or neutralize antibodies to various human blood group antigens. § 864.9100 Empty container for the col- This generic type of device does not in- lection and processing of blood and clude materials that are licensed by blood components. the Center for Biologics Evaluation (a) Identification. An empty container and Research of the Food and Drug Ad- for the collection and processing of ministration.

288

VerDate Sep<11>2014 17:19 Sep 28, 2020 Jkt 250077 PO 00000 Frm 00298 Fmt 8010 Sfmt 8010 Q:\21\21V8.TXT PC31 kpayne on VMOFRWIN702 with $$_JOB Food and Drug Administration, HHS § 864.9205

(b) Classification. Class II (special (e.g., electrical safety, electromagnetic controls). The device is exempt from compatibility, or wireless coexistence). the premarket notification procedures [83 FR 23217, June 18, 2018] in subpart E of part 807 of this chapter subject to § 864.9. § 864.9175 Automated blood grouping [45 FR 60640, Sept. 12, 1980, as amended at 53 and antibody test system. FR 11253, Apr. 6, 1988; 63 FR 59225, Nov. 3, (a) Identification. An automated blood 1998] grouping and antibody test system is a device used to group erythrocytes (red § 864.9165 Blood establishment com- blood cells) and to detect antibodies to puter software and accessories. blood group antigens. (a) Identification. Blood establishment (b) Classification. Class II (perform- computer software (BECS) is a device ance standards). used in the manufacture of blood and blood components to assist in the pre- [45 FR 60641, Sept. 12, 1980] vention of disease in humans by identi- § 864.9185 Blood grouping view box. fying ineligible donors, by preventing the release of unsuitable blood and (a) Identification. A blood grouping blood components for transfusion or for view box is a device with a glass or further manufacturing into products plastic viewing surface, which may be for human treatment or diagnosis, by illuminated and heated, that is used to performing compatibility testing be- view cell reactions in antigen-antibody tween donor and recipient, or by per- testing. forming positive identification of pa- (b) Classification. Class I (general con- tients and blood components at the trols). The device is exempt from the point of transfusion to prevent trans- premarket notification procedures in fusion reactions. This generic type of subpart E of part 807 of this chapter device may include a BECS accessory, subject to § 864.9. a device intended for use with BECS to [45 FR 60641, Sept. 12, 1980, as amended at 65 augment the performance of the BECS FR 2310, Jan. 14, 2000] or to expand or modify its indications for use. § 864.9195 Blood mixing devices and (b) Classification. Class II (special blood weighing devices. controls). The special controls for (a) Identification. A blood mixing de- these devices are: vice is a device intended for medical (1) Software performance and func- purposes that is used to mix blood or tional requirements including detailed blood components by agitation. A design specifications (e.g., algorithms blood weighing device is a device in- or control characteristics, alarms, de- tended for medical purposes that is vice limitations, and safety require- used to weigh blood or blood compo- ments). nents as they are collected. (2) Verification and validation test- (b) Classification. Class I (general con- ing and hazard analysis must be per- trols). The manual device is exempt formed. from the premarket notification proce- (3) Labeling must include: dures in subpart E of part 807 of this (i) Software limitations; chapter subject to § 864.9. (ii) Unresolved anomalies, annotated [45 FR 60642, Sept. 12, 1980, as amended at 65 with an explanation of the impact on FR 2310, Jan. 14, 2000] safety or effectiveness; (iii) Revision history; and § 864.9205 Blood and plasma warming (iv) Hardware and peripheral speci- device. fications. (a) Nonelectromagnetic blood or plasma (4) Traceability matrix must be per- warming device—(1) Identification. A formed. nonelectromagnetic blood and plasma (5) Performance testing to ensure the warming device is a device that warms safety and effectiveness of the system blood or plasma, by means other than must be performed, including when electromagnetic radiation, prior to ad- adding new functional requirements ministration.

289

VerDate Sep<11>2014 17:19 Sep 28, 2020 Jkt 250077 PO 00000 Frm 00299 Fmt 8010 Sfmt 8010 Q:\21\21V8.TXT PC31 kpayne on VMOFRWIN702 with $$_JOB § 864.9225 21 CFR Ch. I (4–1–20 Edition)

(2) Classification. Class II (perform- erating by Centrifugal or Filtration ance standards). Separation Principle.’’ (b) Electromagnetic blood and plasma [72 FR 67644, Nov. 30, 2007] warming device—(1) Identification. An electromagnetic blood and plasma § 864.9275 Blood bank centrifuge for in warming device is a device that em- vitro diagnostic use. ploys electromagnetic radiation (a) Identification. A blood bank cen- (radiowaves or microwaves) to warm a trifuge for in vitro diagnostic use is a bag or bottle of blood or plasma prior device used only to separate blood cells to administration. for further diagnostic testing. (2) Classfication. Class III (premarket (b) Classification. Class I (general con- approval). trols). The device is exempt from the (c) Date PMA or notice of completion of premarket notification procedures in a PDP is required. No effective date has subpart E of part 807 of this chapter been established of the requirement for subject to § 864.9. premarket approval for the device described in paragraph (b)(1). See § 864.3. [45 FR 60645, Sept. 12, 1980, as amended at 65 FR 2310, Jan. 14, 2000] [45 FR 60642, Sept. 12, 1980, as amended at 52 FR 17733, May 11, 1987] § 864.9285 Automated cell-washing centrifuge for immuno-hematology. § 864.9225 Cell-freezing apparatus and (a) Identification. An automated cell- reagents for in vitro diagnostic use. washing centrifuge for immuno-hema- (a) Identification. Cell-freezing appa- tology is a device used to separate and ratus and reagents for in vitro diag- prepare cells and sera for further in nostic use are devices used to freeze vitro diagnostic testing. human red blood cells for in vitro diag- (b) Classification. Class II (perform- nostic use. ance standards). (b) Classification. Class I (general con- [45 FR 60646, Sept. 12, 1980] trols). The device is exempt from the premarket notification procedures in § 864.9300 Automated Coombs test sys- subpart E of part 807 of this chapter tems. subject to § 864.9. (a) Identification. An automated [45 FR 60643, Sept. 12, 1980, as amended at 65 Coombs test system is a device used to FR 2310, Jan. 14, 2000] detect and identify antibodies in patient sera or antibodies bound to red § 864.9245 Automated blood cell sepa- cells. The Coombs test is used for the rator. diagnosis of hemolytic disease of the (a) Identification. An automated blood newborn, and autoimmune hemolytic cell separator is a device that uses a anemia. The test is also used in centrifugal or filtration separation crossmatching and in investigating principle to automatically withdraw transfusion reactions and drug-induced whole blood from a donor, separate the red cell sensitization. whole blood into blood components, (b) Classification. Class II (perform- collect one or more of the blood compo- ance standards). nents, and return to the donor the re- [45 FR 60646, Sept. 12, 1980] mainder of the whole blood and blood components. The automated blood cell § 864.9320 Copper sulfate solution for separator device is intended for routine specific gravity determinations. collection of blood and blood compo- (a) Identification. A copper sulfate so- nents for transfusion or further manu- lution for specific gravity determina- facturing use. tions is a device used to determine (b) Classification. Class II (special whether the hemoglobin content of a controls). The special control for this potential donor’s blood meets the re- device is a guidance for industry and quired level (12.5 grams per 100 milli- FDA staff entitled ‘‘Class II Special liters of blood for women and 13.5 Controls Guidance Document: Auto- grams per 100 milliliters of blood for mated Blood Cell Separator Device Op- men).

290

VerDate Sep<11>2014 17:19 Sep 28, 2020 Jkt 250077 PO 00000 Frm 00300 Fmt 8010 Sfmt 8010 Q:\21\21V8.TXT PC31 kpayne on VMOFRWIN702 with $$_JOB Food and Drug Administration, HHS § 864.9750

(b) Classification. Class I (general con- § 864.9600 Potentiating media for in trols). The device is exempt from the vitro diagnostic use. premarket notification procedures in (a) Identification. Potentiating media subpart E of part 807 of this chapter for in vitro diagnostic use are media, subject to § 864.9. such as bovine albumin, that are used [45 FR 60647, Sept. 12, 1980, as amended at 65 to suspend red cells and to enhance cell FR 2310, Jan. 14, 2000] reactions for antigen-antibody testing. (b) Classification. Class II (special § 864.9400 Stabilized enzyme solution. controls). The device is exempt from (a) Identification. A stabilized enzyme the premarket notification procedures solution is a reagent intended for med- in subpart E of part 807 of this chapter ical purposes that is used to enhance subject to § 864.9. the reactivity of red blood cells with [45 FR 60649, Sept. 12, 1980, as amended at 63 certain antibodies, including anti- FR 59226, Nov. 3, 1998] bodies that are not detectable by other techniques. These enzyme solutions in- § 864.9650 Quality control kit for blood clude papain, bromelin, ficin, and banking reagents. trypsin. (a) Identification. A quality control (b) Classification. Class II (special kit for blood banking reagents is a de- controls). The device is exempt from vice that consists of sera, cells, buffers, the premarket notification procedures and antibodies used to determine the in subpart E of part 807 of this chapter specificity, potency, and reactivity of subject to the limitations in § 864.9. the cells and reagents used for blood banking. [45 FR 60647, Sept. 12, 1980, as amended at 84 (b) Classification. Class II (perform- FR 71800, Dec. 30, 2019] ance standards). § 864.9550 Lectins and protectins. [45 FR 60649, Sept. 12, 1980] (a) Identification. Lectins and § 864.9700 Blood storage refrigerator protectins are proteins derived from and blood storage freezer. plants and lower animals that cause (a) Identification. A blood storage re- cell agglutination in the presence of frigerator and a blood storage freezer certain antigens. These substances are are devices intended for medical pur- used to detect blood group antigens for poses that are used to preserve blood in vitro diagnostic purposes. and blood products by storing them at (b) Classification. Class II (special cold or freezing temperatures. controls). The device is exempt from (b) Classification. Class II (special the premarket notification procedures controls). The device is exempt from in subpart E of part 807 of this chapter the premarket notification procedures subject to § 864.9. in subpart E of part 807 of this chapter [45 FR 60648, Sept. 12, 1980, as amended at 63 subject to § 864.9. FR 59226, Nov. 3, 1998] [45 FR 60650, Sept. 12, 1980, as amended at 63 FR 59226, Nov. 3, 1998] § 864.9575 Environmental chamber for storage of platelet concentrate. § 864.9750 Heat-sealing device. (a) Identification. An environmental (a) Identification. A heat-sealing de- chamber for storage of platelet con- vice is a device intended for medical centrate is a device used to hold plate- purposes that uses heat to seal plastic let-rich plasma within a preselected bags containing blood or blood compo- temperature range. nents. (b) Classification. Class II (special (b) Classification. Class I (general con- controls). The device is exempt from trols). The device is exempt from the the premarket notification procedures premarket notification procedures in in subpart E of part 807 of this chapter subpart E of part 807 of this chapter subject to § 864.9. subject to § 864.9. [45 FR 60648, Sept. 12, 1980, as amended at 63 [45 FR 60650, Sept. 12, 1980, as amended at 65 FR 59226, Nov. 3, 1998] FR 2311, Jan. 14, 2000]

291

VerDate Sep<11>2014 17:19 Sep 28, 2020 Jkt 250077 PO 00000 Frm 00301 Fmt 8010 Sfmt 8010 Q:\21\21V8.TXT PC31 kpayne on VMOFRWIN702 with $$_JOB § 864.9875 21 CFR Ch. I (4–1–20 Edition)

§ 864.9875 Transfer set. 866.1645 Fully automated short-term incu- bation cycle antimicrobial susceptibility (a) Identification. A transfer set is a system. device intended for medical purposes 866.1700 Culture medium for antimicrobial that consists of a piece of tubing with susceptibility tests. suitable adaptors used to transfer blood or plasma from one container to Subpart C—Microbiology Devices another. 866.2050 Staphylococcal typing (b) Classification. Class II (perform- bacteriophage. ance standards). 866.2120 Anaerobic chamber. 866.2160 Coagulase plasma. [45 FR 60651, Sept. 12, 1980] 866.2170 Automated colony counter. 866.2180 Manual colony counter. Subpart K—Products Used In Es- 866.2190 Automated image assessment sys- tablishments That Manufac- tem for microbial colonies on solid culture media. ture Human Cells, Tissues, and 866.2300 Multipurpose culture medium. Cellular and Tissue-Based 866.2320 Differential culture medium. Products (HCT/Ps) 866.2330 Enriched culture medium. 866.2350 Microbiological assay culture me- § 864.9900 Cord blood processing sys- dium. tem and storage container. 866.2360 Selective culture medium. (a) Identification. A cord blood proc- 866.2390 Transport culture medium. 866.2410 Culture medium for pathogenic essing system and storage container is Neisseria spp. a device intended for use in the proc- 866.2420 Oxidase screening test for gonor- essing and the storage of cord blood. rhea. This device is a functionally closed 866.2440 Automated medium dispensing and processing system that includes con- stacking device. tainers, other soft goods, and a cen- 866.2450 Supplement for culture media. trifugation system for cord blood con- 866.2480 Quality control kit for culture centration, and a final container for media. 866.2500 Microtiter diluting and dispensing the cryopreservation and the storage of device. a cord blood product. 866.2540 Microbiological incubator. (b) Classification. Class II (special 866.2560 Microbial growth monitor. controls). The special control for this 866.2580 Gas-generating device. device is FDA’s guidance document en- 866.2600 Wood’s fluorescent lamp. titled ‘‘Class II Special Controls Guid- 866.2660 Microorganism differentiation and ance Document: Cord Blood Processing identification device. System and Storage Container.’’ For 866.2680 Streptococcus spp. nucleic acid- based assay. the availability of this guidance docu- 866.2850 Automated zone reader. ment, see § 864.1(d). 866.2900 Microbiological specimen collection [72 FR 4638, Feb. 1, 2007] and transport device. Subpart D—Serological Reagents PART 866—IMMUNOLOGY AND MICROBIOLOGY DEVICES 866.3010 Acinetobacter calcoaceticus serological reagents. 866.3020 Adenovirus serological reagents. Subpart A—General Provisions 866.3035 Arizona spp. serological reagents. Sec. 866.3040 Aspergillus spp. serological reagents. 866.1 Scope. 866.3045 In vitro diagnostic device for Bacil- 866.3 Effective dates of requirement for pre- lus spp. detection. market approval. 866.3050 Beta-glucan serological assays. 866.9 Limitations of exemptions from sec- 866.3060 Blastomyces dermatitidis serological tion 510(k) of the Federal Food, Drug, reagents. and Cosmetic Act (the act). 866.3065 Bordetella spp. serological reagents. 866.3085 Brucella spp. serological reagents. Subpart B—Diagnostic Devices 866.3110 Campylobacter fetus serological reagents. 866.1620 Antimicrobial susceptibility test 866.3120 Chlamydia serological reagents. disc. 866.3125 Citrobacter spp. serological reagents. 866.1640 Antimicrobial susceptibility test 866.3130 Clostridium difficile toxin gene am- powder. plification assay.

292

VerDate Sep<11>2014 17:19 Sep 28, 2020 Jkt 250077 PO 00000 Frm 00302 Fmt 8010 Sfmt 8010 Q:\21\21V8.TXT PC31 kpayne on VMOFRWIN702 with $$_JOB