Contains Nonbinding Recommendations
Replacement Reagent and 
Instrument Family Policy for In 
Vitro Diagnostic Devices
________________________________________________________________________________________________________________________________________________________________________________________
Guidance for Industry and
Food and Drug Administration Staff
Document issued on August 17, 2022. 
The draft of this document was issued on December 18, 2017.
This document supersedes Replacement Reagent and Instrument Family 
Policy; Guidance for Industry and FDA Staff issued on December 11, 2003.
For questions about this document, contact OHT7: Office of In Vitro Diagnostics at 301-796-
7692 and CDRH-OIR-Policy@fda.hhs.gov.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Devices and Radiological Health Contains Nonbinding Recommendations
Preface
Public Comment
 
You may submit electronic comments and suggestions at any time for Agency consideration to 
http://www.regulations.gov.  Submit written comments to the Dockets Management Staff, Food 
and Drug Administration, 5630 Fishers Lane, Room 1061, (HFA-305), Rockville, MD 20852. 
Identify all comments with the docket number FDA-2017-D-6765.  Comments may not be 
acted upon by the Agency until the document is next revised or updated. 
Additional Copies
Additional copies are available from the Internet.  You may also send an e-mail request to 
CDRH-Guidance@fda.hhs.gov to receive a copy of the guidance.  Please include the document 
number 950 and complete title of the guidance in the request. Contains Nonbinding Recommendations
Table of Contents
I.  Introduction ..................................................................................................................... 1
II.  Scope ................................................................................................................................ 2
III.  Replacement Reagent Policy ............................................................................................ 5
Assessment for changes to test system operating principles and changes to the 
indications for use...................................................................................................................6
Risk-based assessment...................................................................................................7
Design verification and/or validation activities.............................................................9
Documentation.............................................................................................................11
IV.  Instrument Family Policy ............................................................................................... 12
V.  Examples ........................................................................................................................ 13
VI.  Labeling .......................................................................................................................... 15
VII.  Clinical Laboratory Improvement Amendments (CLIA) Categorization ...................... 16
Appendix 1: Significant Terminology ........................................................................................ 17
Appendix 2  Flowchart aids for determinations regarding the Replacement Reagent and 
Instrument Family Policy ........................................................................................................... 18 Contains Nonbinding Recommendations
Replacement Reagent and Instrument 
Family Policy for In Vitro Diagnostic 
Devices
Guidance for Industry and Food and 
Drug Administration Staff
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) 
on this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  
You can use an alternative approach if it satisfies the requirements of the applicable statutes and 
regulations.  To discuss an alternative approach, contact the FDA staff or Office responsible for this 
guidance as listed on the title page.
I. Introduction
In 2003, FDA issued an updated guidance on the Replacement Reagent and Instrument Family Policy 
for in vitro diagnostic (IVD) devices.  The 2003 guidance described a mechanism for manufacturers to 
follow when applying an assay that was previously cleared based on performance characteristics when used 
with a specified instrument to an additional instrument that is either cleared or a member of an instrument 
family from which another instrument was previously cleared.  Through the approach described in the 2003 
guidance, manufacturers established sufficient control to maintain the level of safety and effectiveness 
demonstrated for the cleared device for these types of modified devices, when evaluated against predefined 
acceptance criteria using a proper validation protocol, without submission of a premarket notification 
(510(k)).  
For consistency of terminology with previous guidances and FDA-manufacturer communications, this 
updated guidance continues to use the terms Replacement Reagent and Instrument Family Policy.  
Within discussions in this guidance, generally the term assay is used instead of the term reagent to 
better represent typical scenarios, because most assays are currently comprised of multiple reagents.  
FDA believes this guidance is important for public health as FDA continues to promote more timely 
availability of a wider array of clinical laboratory tests for patient benefit.  This guidance is intended to 
update and provide clarity on the Replacement Reagent and Instrument Family Policy for manufacturers of 
IVD devices and FDA staff to promote consistent application of the concepts in this guidance.  This 
guidance also incorporates concepts and recommendations from FDAs guidances entitled Deciding When 
to Submit a 510(k) for a Change to an Existing Device,1Deciding When to Submit a 510(k) for a 
1 Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/deciding-when-submit-510k-
change-existing-device. 
1 Contains Nonbinding Recommendations
Software Change to an Existing Device,2 and The 510(k) Program: Evaluating Substantial Equivalence 
in Premarket Notifications [510(k)],3 and includes recommendations and information specifically 
regarding:
 Manufacturers preliminary considerations for determining whether this guidance is applicable 
(Section II) 
 The Replacement Reagent Policy (Section III) 
 The Instrument Family Policy (Section IV)
 Examples (Section V)
 Labeling  (Section VI) 
 Clinical Laboratory Improvement Amendments (CLIA) categorization when the manufacturer 
determines, taking into account the considerations described in this guidance, that a 510(k) is 
not needed (Section VII)
In addition, the guidance includes two Appendices.  Please refer to Appendix 1: Significant Terminology 
for the meaning of key terms used in this guidance.  Please refer to Appendix 2: Flowchart Aids for a 
series of flowcharts that are intended to supplement this guidance, but are not intended to be used alone.  
The flowcharts are provided as a visual aid only and are not intended to capture all appropriate 
considerations in determining whether the policies in this guidance may be applicable for your proposed 
modifications to certain IVD devices.  Refer to the corresponding text of this guidance when using the 
flowcharts.  
The contents of this document do not have the force and effect of law and are not meant to bind the public 
in any way, unless specifically incorporated into a contract.  This document is intended only to provide 
clarity to the public regarding existing requirements under the law.  FDA guidance documents, including 
this guidance, should be viewed only as recommendations, unless specific regulatory or statutory 
requirements are cited.  The use of the word should in Agency guidance means that something is suggested 
or recommended, but not required.
II.  Scope
This guidance pertains to IVD test systems regulated by CDRH and comprised of a cleared assay that is run 
on an automated laboratory instrument specified by the assay manufacturer.  Specifically, it addresses a 
manufacturers application of an assay that was previously cleared for use based on performance 
characteristics when used with a specified instrument to an additional instrument that was previously cleared, 
or that is a member of an instrument family from which another member has been previously cleared.  
This guidance is not intended to address the following:
 Modifications other than application of a cleared assay to an additional instrument4
2 Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/deciding-when-submit-510k-
software-change-existing-device. 
3 Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/510k-program-evaluating-
substantial-equivalence-premarket-notifications-510k. 
4 Additional information related to modifications of devices subject to 510(k) other than application of a cleared assay to an 
additional instrument is available in the following guidances:  
2 Contains Nonbinding Recommendations
 Class III devices5
 Devices indicated for use in support of blood banking practices
 Devices indicated for prescription or over-the-counter (OTC) home use
 CLIA-waived test systems
Section III.B includes discussion of situations in which principles within this guidance may be applicable to 
systems cleared for point of care (POC) use.
Special cases also exist where FDA has established final guidance for modifications to specific devices 
and/or specific requirements (e.g., special controls) that are identified in the classification regulation.  Some 
current device-specific guidances or Class II Special Controls Documents as discussed on FDAs 
webpage6 (Special Controls Documents) include a broad statement that the Replacement Reagent and 
Instrument Family Policy is not appropriate for the device type.7 This guidance modifies such statements 
so that the Replacement Reagent Policy and Instrument Family Policy described in this guidance may 
apply to such device types.8  Based on FDAs current understanding of, and experience with, currently 
classified device types, FDA believes that the recommendations presented in this guidance could provide 
alternative mitigation strategies that may allow for equivalent assurances of safety and effectiveness, such 
that the policy in this guidance could apply for certain IVD devices.  This guidance is not intended to 
supersede any other statements contained in device-specific guidances or Special Controls Documents, but 
may cover areas not addressed in such device-specific guidances or Special Controls Documents.  There 
may be additional considerations to take into account when determining the applicability of this guidance, 
and manufacturers should follow the logic scheme and recommendations herein, and must follow any 
applicable legal requirements, including special controls, to determine if this guidance could be applicable 
for certain changes to a particular test system.
Recommendations in this guidance are based on FDA experience with previously cleared test systems with 
established performance.  To date, the Replacement Reagent and Instrument Family Policy has largely been 
utilized for traditional laboratory analyzers.  Use of this guidance for other types of test systems or 
technologies may raise additional considerations.  If you have questions regarding how to apply this 
guidance to a particular technology, we recommend you contact the appropriate review division for your 
assay and instrument.  Manufacturers may use the pre-submission process to obtain feedback either when 
planning for the initial 510(k) submission (if future modifications to assay-instrument combinations can be 
anticipated) or after initial clearance.  Generally, pre-submissions are most appropriate for Replacement 
Reagent and Instrument Family Policy discussions of new and evolving technologies.  Information on the 
Deciding When to Submit a 510(k) for a Change to an Existing Device, available at https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/deciding-when-submit-510k-change-existing-device, and Deciding When to 
Submit a 510(k) for a Software Change to an Existing Device, available at https://www.fda.gov/regulatory-information/search-
fda-guidance-documents/deciding-when-submit-510k-software-change-existing-device. 
5 For modifications to test systems with assays classified as Class III, see the FDAs guidance document entitled Assay Migration 
Studies for In Vitro Diagnostic Devices, available at https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/assay-migration-studies-vitro-diagnostic-devices.   
6 https://www.fda.gov/medical-devices/guidance-documents-medical-devices-and-radiation-emitting-products/class-ii-special-
controls-documents.
7 For example, the Special Controls Document entitled Instrumentation for Clinical Multiplex Test Systems, available at 
https://www.fda.gov/medical-devices/guidance-documents-medical-devices-and-radiation-emitting-products/instrumentation-
clinical-multiplex-test-systems-class-ii-special-controls-guidance-industry-and-fda, states that the Replacement Reagent and 
Instrument Family Policy guidance document does not apply to instrumentation for clinical multiplex test systems.
8 Such modifications are made effective under this guidance document, even if the documents being so modified are not 
specifically updated to reflect the changes.
3 Contains Nonbinding Recommendations
pre-submission process can be found in FDAs guidance document entitled Requests for Feedback and 
Meetings for Medical Device Submissions: The Q-Submission Program.9
This guidance applies to a large spectrum of marketed class I reserved or class II-510(k) IVD test 
systems intended for use in CLIA-regulated laboratories performing testing with nonwaived tests.10 While 
most automated clinical instruments by themselves are classified as class I and exempt from submission of a 
510(k), assay/instrument systems are considered combination devices.  A 510(k) submission is required if 
the test system includes a claim that meets the definition for a class I reserved or class II device (see sections 
510(k), 510(l), and 513(a) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and 21 CFR 807.81 
and 860.3; see also the limitations to the exemption from premarket notification requirements found in 21 
CFR 862.9, 21 CFR 864.9, or 21 CFR 866.9, depending on the part in which the device is classified).  In its 
review of the 510(k) submission, CDRH subjects a combination device to the same procedure, including 
documentation requirements, that are applied to a single device.  When such a device is found to be 
substantially equivalent, it combines devices from different classes and is classified in the highest of the 
predicate device classifications, unless the combined devices are regulatable as separate articles, in which 
case the separately regulatable articles may be regulated in accordance with their separate classes.  
Indications of an assay for use with an additional instrument is a change of the type that indicates 
compatibility with a different type of device, component, or accessory that was not indicated as compatible 
previously and thus that change would likely be considered a change that could significantly affect the safety 
or effectiveness of the device and likely require submission of a new 510(k) under 21 CFR 807.81(a)(3)(i).11
This guidance addresses a manufacturers application of an assay that was previously cleared for use based 
on performance characteristics when used with a specified instrument to an additional instrument that was 
previously cleared, or that is a member of an instrument family from which another member has been 
previously cleared.  The following tables illustrate regulatory scenarios and corresponding applicable 
sections of the guidance.  In the tables below, Assay A and Instrument C were both reviewed within previous 
510(k)s and are part of separate previously cleared test systems, whereas neither Assay B nor Instrument D 
were previously cleared.
Test System Current Regulatory Status
Cleared Not previously 
cleared
Assay               A                 B
Instrument             C                 D
Assay and Instrument  Applicable Regulatory Policy in this Guidance
combinations
A+C See Section III (Replacement Reagent Policy)
9 Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/requests-feedback-and-meetings-
medical-device-submissions-q-submission-program. 
10 See 42 CFR 493.2.
11 For additional information about when to submit a new 510(k), see the guidance Deciding When to Submit a 510(k) for a 
Change to an Existing Device, available at https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/deciding-when-submit-510k-change-existing-device.
4 Contains Nonbinding Recommendations
A+D See Section IV (Instrument Family Policy) to help determine if D 
is an instrument family member of C.  Note: A+D is outside the 
scope of this guidance if D is not an instrument family member as 
described in Section IV.
B+C or B+D None (outside the scope of this guidance); 510(k) 
required (21 CFR 807.81(a)(2))
III. Replacement Reagent Policy
Generally, 510(k) clearance for test systems is based on assay performance characteristics demonstrated with 
an instrument (or instruments) specified by the assay manufacturer.  Once an assay has been cleared based on 
performance with a specified instrument, assay manufacturers may choose to modify the test system by 
applying the same cleared assay to additional laboratory instruments evaluated as part of previously cleared 
test systems.  Such assays are referred to as replacement reagents.  One common scenario is when the assay 
and instrument are both manufactured by the same manufacturer.  However, the Replacement Reagent Policy 
may also apply when the assay and instrument are each produced by separate manufacturers.  The assay 
manufacturer should assess capabilities and performance of the new combination of assay and instrument 
under the quality system requirements for the assay, to ensure acceptable performance of the test system.  
Additionally, the assay manufacturer is responsible for ensuring that the modified test system continues to 
meet design specifications.  FDA encourages communication between assay manufacturers and instrument 
manufacturers to ensure that any changes to the instrument do not impact the performance of the test system.  
Manufacturers planning to modify their test systems by applying a cleared assay to an additional instrument 
should determine whether a new 510(k) is needed, by completing the following steps: (i)  the manufacturer 
should confirm that the assay was previously cleared and the instrument was either previously cleared or is 
an instrument family member of an instrument that was previously cleared as described in Section IV (see 
Tables in Section II) and (ii) apply the considerations described within Sections III and IV of this guidance.  
Should a manufacturer determine, after applying the logic scheme and considering the issues described 
below (i.e., test system operating principles and changes to the indications for use, risk-based assessment, 
and verification and/or validation activities), that a new 510(k) is not needed and proceed with marketing the 
modified test system, the manufacturer must document, as part of the device master record, the design, 
production, or process changes made,12and should document the manufacturers assessment of whether a 
new 510(k) is required (510(k) assessment) (see Section III.D).
If the manufacturer determines that a new 510(k) is required, the manufacturer may also consider whether a 
Special or Abbreviated 510(k) may be appropriate.  (See FDAs guidance documents entitled The 
Abbreviated 510(k) Program13 and The Special 510(k) Program.14)
12 See 21 CFR 820.30(i), 21 CFR 820.70(b), and 21 CFR 820.181.  For additional information about documenting design, 
production, or process changes, see Appendix B of the guidance Deciding When to Submit a 510(k) for a Change to an 
Existing Device, available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/deciding-
when-submit-510k-change-existing-device.
13 Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/abbreviated-510k-program. 
14 Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/special-510k-program.
5 Contains Nonbinding Recommendations
Assessment for changes to test system operating principles and 
changes to the indications for use 
 
A1. Assay key components and fundamental test principles   
 
As noted, the first step in a manufacturer determining whether the Replacement Reagent Policy may be 
applicable in their specific situation is to confirm that the assay was previously cleared and the instrument 
was either previously cleared or is an instrument family member of an instrument that was previously 
cleared, as described in Section IV (see Tables in Section II). Further, the assay manufacturer should 
determine whether the use of the cleared assay on the additional instrument would require changes that alter 
assay key componentsor fundamental test principles.  Assay key components may includespecific antigen-
antibodyor enzyme-substratecomponents, conjugatesor signaling components, reaction surfaces,or 
components used in separationmethods. Fundamental test principles may include detectionmodes(e.g., ion 
selective electrode, colorimetric absorbance, fluorescence detection, turbidimetry,nephelometry),
measurement methods (e.g.,endpoints orratemeasurements,quantitative, semi-quantitative, or qualitative),
methodsforsignal processing, data acquisitionand interpretation, or assay-specific pre-analytical steps. If 
assay key components or fundamental test principlesneed to be modified in order to apply the assay to the 
additional instrument(s), anew 510(k) is likely requiredbecause such alterations could result inchanges to 
test system performance or interpretation of patient resultsthat could significantly affect safety and
effectiveness. A new 510(k) is also likely requiredforchanges to assay value assignmentmethodsor 
calibration schemesif they could significantly affect test system performanceor interpretation of patient 
results, and thus would belikely to affect the safety and effectiveness of the device.  
Examples of changes that are less likelyto affect performance or operating principles include modifications 
to outer cartridgesor reagent preservatives. However, the manufacturer should also conduct a risk-based 
assessment and design verification and/or validation activities to confirm (refer to Sections III.B and III.C for 
additional details).   
 
If application of a cleared assay to an additional instrument does not alter the assay key components or 
fundamental test principles, proceed to Section III.A2 below.  
 
A2. Instrument and software principles 
 
The assay manufacturer should confirm that the principles of analysis of the instrument with which the assay 
will be intended for use are comparable to those of the instrument with which assay performance was 
demonstrated in a cleared 510(k).  For example, the two instruments should have common detectionand 
measurement methods,control of reaction conditions,and signal processing.  The assay manufacturer should 
confirmthat basic capabilities of the additionalinstrumentrelevant to the assay were demonstrated in a 
cleared 510(k) (seeExample 2 in Section V).  If these conditions do not apply,a new 510(k) is likely 
required.
The Replacement ReagentPolicy applies only to opensystems.  For purposes of this guidance, an open 
system instrument has general purpose features intended for use with a wide array of assay types that share a 
similar methodology (e.g.,similar detection methods, similar processing and interpretive software).  An open 
system generally does not impose constraints (e.g., through softwareor labeling) for use with only specific 
typesof reagents(e.g., those produced by or for the instrument manufacturer),or for detection of only certain 
types of analytes.  If the same manufacturer has responsibility forthe quality systems for both the assay 
6 Contains Nonbinding Recommendations
and the instrument, in many cases the system can be considered open for that manufacturer, even if the 
system is not open for other manufacturers.
If software, such as for system integration, system constraints (noted above), signal processing, data 
acquisition, interpretation, or other calculations needed to produce clinical results, are modified in order to 
run the assay on the additional instrument, a new 510(k) is likely required because it is likely that such 
alterations could result in changes to test system performance that could significantly affect the safety or 
effectiveness of the test system. 
If application of a cleared assay to an additional instrument does not alter the instrument principles or 
software (including assay-specific software), proceed to Section III.A3 below. 
A3.  Changes to the Indications for Use
Examples of changes to the indications for use that would likely require a new 510(k) include (but are not 
limited to): change in output between qualitative, semi-quantitative, and quantitative results; change in 
clinical sample type (such as serum to cerebrospinal fluid (CSF), urine, or whole blood); or significant 
change in performance claims, such as a change in cut-off value, addition of a high sensitivity performance 
claim, or addition of POC use to a test system not previously cleared for such use.  For general information 
regarding when a change to indications would likely require the submission of a new 510(k), see Section 
V.A. of FDAs guidance entitled Deciding When to Submit a 510(k) for a Change to an Existing Device.15  
Risk-based assessment
The assay manufacturer should conduct a risk-based assessment for any modified test system.16 The risk-
based assessment should address analytical and clinical performance, indications for use, and any other 
factors that could affect the risk profile of the IVD.  When the risk-based assessment indicates that the 
performance17 of the modified test system could significantly change relative to the performance 
characteristics of the cleared test system, including performance claims in the labeling, a new 510(k) is 
likely required. A manufacturers risk-based assessment should identify any new or significantly modified 
existing risks, as applicable. For additional information concerning risk-based assessment, see FDAs 
guidance entitled Deciding When to Submit a 510(k) for a Change to an Existing Device.18 For IVD-
specific discussion, see Section V.D3. of that guidance. 
15 Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/deciding-when-submit-510k-
change-existing-device. 
16 Manufacturers should be aware that a risk analysis may be required as part of design validation (see 21 CFR 820.30(g)).
17 For IVDs, performance generally refers to the analytical and clinical specifications established as part of the most recent 
510(k) clearance.  Analytical performance refers to the documented ability of an IVD test or test system to measure or detect a 
target analyte or substance that the IVD is represented or purported to identify or measure.  Clinical performance refers to the 
documented ability of an IVD to identify, measure, monitor, or predict the presence or absence of, or the future development of, 
a clinical condition or predisposition, for which the device is intended.  See FDAs guidance entitled Deciding When to Submit 
a 510(k) for a Change to an Existing Device, available at https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/deciding-when-submit-510k-change-existing-device.
18 Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/deciding-when-submit-510k-
change-existing-device.  
7 Contains Nonbinding Recommendations
Changes to test system performance characteristics (e.g., precision, linearity or recovery, interference, 
assay traceability, detection limits, bias, or scatter observed in method comparison) from those indicated in 
the labeling for the cleared test system could have the potential to be significant and change the clinical 
performance of the device. In general, significant changes include those that could affect clinical 
interpretation or decision making. For example, if reference ranges or claimed cutoff concentrations for the 
intended use population(s) are expected to be altered as a result of the change in performance associated 
with the modified test system, this is considered a change to clinical performance, and a new 510(k) is 
likely required.   
Within each risk-based assessment, manufacturers should take into account the cleared indications for use 
and the various clinical and performance needs associated with such use(s).  In addition, manufacturers 
should also consider susceptibility to change of the specific assay technology.  For example, careful attention 
should be paid when a new combination of an instrument and assay includes modifications to reaction 
conditions, especially for technologies that include complex interactions of components (e.g., multiplex), are 
sensitive to small variations in assay parameters (e.g., temperature changes within antibody-antigen 
reactions), or where small differences in results have the potential to affect clinical decisions.  Changes that 
are significant for clinical decision making are likely to require a 510(k) since such changes could 
significantly affect the safety and effectiveness of the test system. 
In performing the risk-based assessment of the changed test system, manufacturers should consider whether 
a modification could cause possible effects that would lead a risk-based assessment to identify new risks or 
significantly modified existing risks that could significantly affect the safety or effectiveness of the device 
and thus a submission of a new 510(k) would likely be required.19  
In summary, if the risk-based assessment does not raise any of the issues noted above or otherwise identify 
new risks or significantly modified existing risks, the manufacturer should perform testing (i.e., verification 
and validation activities) to verify this initial assessment.  Section III.C further discusses this testing and its 
role in evaluating whether a change could significantly affect safety and effectiveness.
B1.  Additional Considerations for POC Test Systems 
Unlike many central laboratory test systems, many current POC test systems are designed for use with a 
manufacturers specified instrument(s), and are not designed for use with additional instruments (i.e., they 
are not open systems as described in Section A.2).  As noted, the Replacement Reagent Policy applies only 
for open test systems. However, in certain cases, particularly when the assay and instrument manufacturer 
are the same and the original and additional instrument(s) are closely related family members (see Section 
IV), the manufacturer could apply policies discussed in this guidance in combination with the 
recommendations in the guidance Deciding When to Submit a 510(k) for a Change to an Existing Device20
to determine whether a 510(k) may be required prior to marketing.  Please note these guidances are not 
intended to address all risk assessment (or testing) considerations for modifications of POC test systems. 
Therefore, we recommend that, after considering the policies described in these guidances, you contact the 
appropriate review division(s) if you need further clarity.  
19 See also example 32 of Appendix A in the guidance Deciding When to Submit a 510(k) for a Change to an Existing Device, 
available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/deciding-when-submit-510k-change-
existing-device, foran example of a manufacturerperforming a risk assessment for a material change to an assays reagent to 
identify any new risks or significantly modified existing risks and determining that it should submit a new 510(k).
20Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/deciding-when-submit-510k-
change-existing-device.
8 Contains Nonbinding Recommendations
An example of a change to an instrument used with an assay that likely does not constitute a significant 
change or modification to require a new 510(k) would be a change to the exterior of the instrument that does 
not affect reaction conditions or usability.  By contrast, some changes to an assays instrument could affect 
reaction conditions, processes followed by POC users (e.g., error reporting, calibration, sample or control 
handling), or susceptibility to environmental changes in POC use conditions, even when such changes do not 
alter the operating principles, and therefore may require submission of a new 510(k).
POC test systems may present a higher likelihood of preanalytical and use error than non-POC test systems, 
challenges related to the types of multi-tasking common to the POC environment, and challenges due to 
varying environmental conditions (e.g., temperature, movement, or vibrations).  Therefore, a manufacturer's 
risk assessment for a POC test system generally should include the risk impact of changes in user 
workflow.  Examples may include providing new information to the user or modifying the manner in 
which information is presented.  Changes to the layout of device controls may impact device use 
differently in different use scenarios and should be considered as part of the risk assessment for POC test 
systems. 
Design verification and/or validation activities
The assay manufacturer is responsible for verifying and/or validating the modified test system as part of 
design controls (see 21 CFR 820.30).  Verification and validation activities should be based upon the 
manufacturers quality processes, including its risk-based assessment for the specific device and changes 
involved.  
C1. Consideration of Protocols and Acceptance Criteria
For IVDs, accepted methods and performance criteria for evaluation of the specific device (e.g., protocols 
and criteria used to support the original 510(k), or a protocol and criteria established in the original 510(k) 
that described how anticipated changes would be evaluated) should generally be used to verify and validate 
the modification.  The assay manufacturer should develop a testing protocol and pre-specified acceptance 
criteria for each assay prior to testing.  Protocols should be sufficiently robust and challenging to ensure that 
any significant changes to the performance of the new combination of instrument and assay (relative to the 
performance of the cleared instrument-assay system) will be identified.  The acceptance criteria should be 
clinically justified and ensure that all performance claims in the labeling for the cleared test system will 
continue to be met.  If verification or validation test methods or acceptance criteria other than those 
discussed above are necessary to evaluate the change, it is likely that the change could significantly affect 
safety or effectiveness and that submission of a new 510(k) is required. 
For example, if the following types of protocols were included in the cleared 510(k) for the assay, the 
manufacturer should consider them for inclusion in testing protocols for the new combination of instrument 
and assay: 
 Testing in accordance with CLSI (Clinical and Laboratory Standards Institute) guidelines 
EP-17 to support a specified Limit of Blank, Limit of Detection, and Limit of Quantitation.
 Testing in accordance with CLSI guidelines EP-05 to support precision at limits of the 
claimed measuring range, and at medical decision points. 
 Linearity across the assay measuring interval in accordance with CLSI guidelines EP-06, or, if 
9 Contains Nonbinding Recommendations
appropriate, recovery to standard materials or methods. 
 Method comparison studies in accordance with CLSI guidelines EP-09. Generally, this is a 
comparison of results obtained with the additional instrument to those obtained with the 
instrument in the cleared 510(k) (or the instrument or method used as comparator in that 
510(k)).21Sample types (e.g., matrix), measurand value range, and comparator methods 
should be consistent with the original 510(k). If comparison to a well-known reference 
method(s) or material(s) was needed to support the original 510(k) (e.g., because of known 
lack of standardization among cleared assays), we recommend incorporating the same 
material(s) or method(s) to ensure similar performance for the new combination of assay 
and instrument. 
Similarly, where relevant, manufacturers should include the following within verification and validation 
activities for the new combination of assay and instrument: 
 Interference studies in accordance with CLSI guidelines EP-07, as needed for the particular 
reagents, or detection methods.
 Carry-over or cross-contamination studies.
 Matrix equivalence studies in accordance with CLSI guidelines EP-35. 
 On-board stability for reagent, calibrator, and sample.
 Hook-effect studies. 
The bullets above are examples of common types of testing, and are not meant as a comprehensive list.  The 
assay manufacturer should determine appropriate testing based on a risk-based assessment for the specific 
device and changes involved.  If an updated, FDA-recognized standard or guideline has been published since 
the time of assay clearance, FDA recommends that the manufacturer follow this; however, using the same 
standard or guideline that was followed to support the cleared 510(k) may also be appropriate.
In some cases, the manufacturer might determine, based on the change to the specific combination of 
assay and instrument, that some of the study types included in the original 510(k) are not needed.  In 
such cases, the manufacturer should clearly document the risk-based justification for this (see Section 
III.D).  These types of determinations may be more common when the assay manufacturer is the same 
as the instrument manufacturer, and the assay is being applied to that manufacturers new or additional 
instrument family member. 
In general, FDA anticipates that in order to demonstrate that assay performance characteristics are the 
same as those represented in the assay labeling, test protocol sample sizes should be similar.  However, 
a manufacturer could determine that performance characteristics in the assay labeling can be 
statistically supported based on testing with a smaller sample size.  In such cases, the manufacturer 
should document the statistical rationale.
If a manufacturer determines that the new test system necessitates a different verification and/or validation 
21 In cases where a direct method comparison is not feasible, such as when the original, cleared instrument (Analyzer A) is no 
longer available, other approaches may sometimes be appropriate.  For example, in some cases it may be acceptable to compare 
results obtained with the additional instrument (Analyzer C) to those of another legally marketed instrument (Analyzer 
B).  Using the results of comparison studies of B vs. A and C vs. B and the precision of A, B, and C, the differences between C 
and A can be evaluated.  Alternatively, in some cases, a recognized reference method (R) might be used.  In this case, using the 
results of comparison studies of A vs. R and C vs. R and the precision of A, R, and C, it may be possible to evaluate the 
differences between C and A.
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scheme (e.g., new types of studies not included in the cleared 510(k) are needed to demonstrate performance, 
or non-standard verification or validation test methods are necessary to produce the expected results), a new 
510(k) is likely required.
For most IVD assays, analytical validation, including method comparison, may be sufficient to validate that 
performance does not change when the assay is applied to an additional similar instrument.  However, in 
some cases, analytical validation alone may not be adequate to assess the impact of the change, and 
assessment of critical clinical performance parameters, such as clinical sensitivity and specificity, may be 
needed (see Section V, example 6).  If a clinical study is necessary to answer safety and effectiveness 
questions relating to a particular modification to a test system, a new 510(k) is likely required.  In contrast, 
use of de-identified clinical samples for standard testing to verify analytical performance may not in itself 
normally necessitate a new 510(k).
C2. Manufacturers Assessment of Results
Should the results of verification and validation using standard methods and performance criteria established 
for the evaluation of the specific device indicate that (a) the performance of the modified test system is 
within the criteria, (b) the performance of the modified test system has not significantly changed relative to 
claims in the labeling for the cleared test system, and (c) otherwise, no new risks or significantly modified 
existing risks are noted, then it is unlikely that the application of the assay to the additional instrument could 
significantly affect safety or effectiveness, and a new 510(k) is likely not required.
If the results of routine verification and validation produce any unexpected issues or otherwise prove 
inadequate to verify and/or validate the modified test system, it is likely that the modification could 
significantly affect the test systems safety and effectiveness, and a new 510(k) is likely required.  This might 
be the case, for example, when pre-specified acceptance criteria are not met (e.g., when changes are made 
to widen pre-specified acceptance criteria).
Should a manufacturer determine, after applying the logic scheme and considering the issues described 
above (i.e., changes to test system operating principles and to the indications for use, risk-based assessment, 
and design verification and/or validation activities), that a new 510(k) is not needed, and proceed with the 
change to the test system, the manufacturer should make sure to document the changes to the test system and 
the manufacturers 510(k) assessment (see Section III.D).  
Documentation
Among other requirements, FDAs quality system regulation (QS regulation) requires manufacturers of 
finished devices to review and approve changes to device design and production (21 CFR 820.30 and 
820.70) and to document changes and approvals in the device master record (21 CFR 820.181).  An 
appropriately designated individual (or individuals) should sign and date documentation for internal analyses 
and activities.  The manufacturer must keep records, and these records must be made available to an FDA 
investigator (see section 704(e) of the FD&C Act; see also 21 CFR part 820 subpart M (Records)).  
Documentation should include comparison between the old and new assay-instrument combination, risk-
based assessment, detailed protocols, acceptance criteria, and results.  If the manufacturer determined that 
some of the types of testing included in the initial 510(k) were not needed, the risk-based rationale should be 
included within the documentation. 
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IV.  Instrument Family Policy
The Instrument Family Policy specifically addresses modifications made to an instrument by its original 
manufacturer, to produce a new version of the instrument (i.e., a new instrument family member).  
Instruments within a family are the same in terms of the hardware and software components related to the 
test reaction and interpretation.  Further, the term instrument family, as used in this guidance, means a group 
of one or more instruments produced by, or for, the same manufacturer, having the same general architecture, 
design, tolerance limits, and capabilities, such as detection methods, signal range and intensity, and reaction 
conditions.  Examples of the types of differences between instrument family members include improvements 
to some features of the user interface, ability for higher sample throughput due to pre-analytical features, or 
increased data storage.  Instruments within a family share a common device classification regulation and 
product code.  A manufacturer may choose to use separate design history files (DHF) (see 21 CFR 820.30(j)) 
for individual instrument family members (and cross-reference the other DHFs as needed) or use a single 
DHF for both the original instrument as well as a modified instrument.  In either case, the design information 
within the DHF for each instrument should demonstrate that each instrument can be considered an 
instrument family member (as defined above), rather than an instrument that is not an instrument family 
member. 
The instrument manufacturer should perform testing to confirm that instrument features, including software, 
are within the claimed tolerance limits or specifications (see also FDAs guidance entitled General 
Principles of Software Validation).22  The manufacturer should also maintain documentation of the 
relationship between the proposed instrument family member and an instrument family member (or 
members) cleared by FDA, including a description of the technological similarities and differences between 
the instruments, including software differences.  
An assay manufacturer planning to apply its assay to an additional instrument family member should follow 
the logic scheme and consider the issues in Section III to determine if a new 510(k) is needed.  Similar to any 
instruments to which the Replacement Reagent Policy is applied, the new instrument family member should 
yield no significant difference in results for a given sample, using the same assay. 
The manufacturer might determine that application of an assay to a new instrument family member does not 
call for the entire range of testing that was performed to support the 510(k) for the initial assay clearance.  
For example, if the change to an instrument is known to involve only post-analytic data storage, it is unlikely 
that interference characteristics would be affected, and the manufacturer might determine that interference 
testing is not needed.  Knowledge of differences between family member instruments is important for this 
type of determination based on risk assessment.  Therefore, a determination regarding reduced testing can 
most easily be made when the assay and instrument manufacturer are the same.  A manufacturer should fully 
document the risk-based rationale for this type of determination.  It would not be sufficient to meet the 
recommendations in this guidance, for example, for an assay manufacturer to simply document that testing 
was not performed because the instrument is an instrument family member.  If there are multiple instruments 
within an instrument family, manufacturers should assess assay performance with the new instrument family 
members relative to an instrument whose performance was demonstrated in a cleared 510(k) in order to 
ensure comparability for successive changes to instruments within the instrument family.  (Also see 
discussion of method comparison studies in particular, including footnote 19 in Section III.C.1.)
22 Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/general-principles-software-
validation. 
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If the new instrument does not fall within the instrument family definition, and was not reviewed within a 
previously cleared 510(k), in general, the application of the new instrument to the test system could 
significantly affect the safety or effectiveness of the test system, and a new 510(k) is likely required.  
V.  Examples
1  Scope; Replacement Reagent Policy applies to cleared assays only.
Rheumatoid factor immunological test systems (RF assays) are Class II devices, regulated under 21 CFR 
866.5775, and subject to 510(k).  The First RF Immunoassay manufactured by manufacturer 1 was 
previously cleared for use with the ABC Immunofluorescence Instrument.  The manufacturer of the 
Second RF Immunoassay, manufacturer 2, now plans to apply its assay to the cleared ABC 
Immunofluorescence Instrument.  
Scenario A  The Second RF Immunoassay was cleared based on performance with the cleared XYZ 
Immunofluorescence Instrument, which has similar capabilities as the ABC Immunofluorescence 
Instrument.  Manufacturer 2 assessed the considerations described in Section III above, and performed a 
risk-based assessment and design verification and validation activities.  The risk-based assessment did not 
identify any new risks or significantly modified existing risks, the design verification and validation 
activities did not produce any unexpected issues of safety or effectiveness, and the Second RF 
Immunoassay performance was the same on the ABC Immunofluorescence Instrument as on the XYZ 
Immunofluorescence Instrument.  Therefore, manufacturer 2 determined that a new 510(k) was not needed 
to market the Second RF Immunoassay for use with the ABC Immunofluorescence Instrument, and 
documented the change and 510(k) assessment to the file.
Scenario B  There is no previously cleared 510(k) for the Second RF Immunoassay.  Although other 
assays for RF have been cleared for use on the ABC Immunofluorescence Instrument, manufacturer 2 is 
required to submit a 510(k) and obtain clearance before marketing the Second RF Immunoassay (sections 
510(k) and 513(f)(1) of the FD&C Act; 21 CFR 807.81(a)(2)).  
2  Test system operating principles; Demonstrated instrument capabilities
Enzyme immunoassays to quantitatively measure multiple endogenous clinical chemistry analytes were 
cleared based on performance using the Open System Instrument.  For this cleared test system, results are 
based on absorbance measurements.
Scenario A  A therapeutic drug monitoring (TDM) Assay cleared to quantitatively measure a therapeutic 
drug in serum and plasma is based on absorbance measurements with a manufacturer-specified instrument.  
The TDM Assay manufacturer investigated the Open System Instrument, and determined it has 
capabilities needed to accurately measure results with its assay.  These capabilities were demonstrated 
during clearance of the multiple endogenous chemistry analytes assays.  No changes need to be made to 
the TDM Assay or to the Open System Instrument in order to use this assay with this instrument.  
Furthermore, based on the risk-based assessment, the TDM Assay manufacturer determined that using the 
TDM Assay with the Open System Instrument does not significantly modify existing risks or create risks 
that were not previously identified for this assay, and performance is expected to be the same.  The 
manufacturer performed testing which verified this expectation.  Based on this, the manufacturer 
determined that a new 510(k) was not needed to market the TDM Assay to run on the Open System 
Instrument and documented the change and 510(k) assessment to the file. 
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Scenario B  A qualitative urine assay to detect multiple clinical chemistry analytes was previously cleared 
for use with an instrument specified by the assay manufacturer.  The qualitative urine assay manufacturer 
now plans to market its assay for use with the Open System Instrument.  However, to date, assays cleared 
for use with the Open System Instrument have all been quantitative.  Use of the Open System Instrument 
for qualitative assays calls for alternative instrument calibration schemes and software, and performance of 
the instrument with qualitative assays has not yet been demonstrated.  Therefore, the qualitative assay 
manufacturer submits a new 510(k) for use of its assay with the Open System Instrument.  
3  Test system operating principles: Optics and software changes
Assay A was cleared for use on Instrument A, which contains assay-specific software.  The manufacturer 
now plans to also market its assay on the previously cleared Instrument B.  However, there are differences 
in signal processing between these instruments due to differences in light source and other optics 
components.  It is expected that these changes to test system operating principles are likely to affect assay 
performance.  In order to run the assay on Instrument B, the manufacturer needs to significantly modify 
its software to address the differences.  The manufacturer submits a new 510(k).
4   Risk-based assessment and change to indication23  
The CVD cholesterol assay was cleared for quantitative measurements of high-density lipoprotein (HDL) 
and low-density lipoprotein (LDL) in venous blood samples based on performance with a laboratory 
instrument specified by the manufacturer.  The instrument is intended for use in centralized laboratories.  
The test uses a sample volume of 65 uL. 
Scenario A  The manufacturer plans to apply the assay to additional cleared instruments, similar in 
methodology to the one used to support initial CVD clearance.  The reagent volumes used by the 
additional instruments vary from 50 to 75 uL.  The reagents to sample ratio is unchanged.  The 
manufacturers risk-based assessment did not identify any new risks or significantly modified existing 
risks and indicated that the performance is expected to remain the same.  In addition, the same type of 
testing conducted to support the 510(k) verified there was no change to performance caused by the 
additional instruments.  Based on this, the manufacturer determined that a new 510(k) was not needed, and 
documented the change and 510(k) assessment to the file. 
Scenario B  The assay manufacturer plans to market the assay with a miniaturized POC instrument for 
fingerstick samples.  The modified test system uses a sample size of 10 uL.  This modification represents a 
change to the sample type (venous to fingerstick) and volume which could significantly change the clinical 
performance claims and reference range relative to the claims in the labeling of the cleared test system.  In 
addition, this modification represents a change in the intended user and use environment (from central 
laboratory to POC), as well as in operating principles (e.g., miniaturizing the instrument changed the basic 
capabilities and specifications of the instrument) relative to the cleared test system.  For each of the 
reasons above, the manufacturer submits a new 510(k) for use of the assay on the miniaturized POC 
instrument. 
23 Note that a change in the instrument for use with an assay, as described in the scenarios above, may also constitute a change 
in indication, but as discussed in this guidance, whether such change requires a new 510(k) depends on whether the change 
could significantly affect the safety or effectiveness of the cleared test system.
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5  Design verification and/or validation activities
The EZPZ troponin assay was cleared for use at central (core) laboratories with the SAFT clinical 
chemistry instrument.  Clinical performance of the assay from the prospective clinical study performed 
using the EZPZ assay-SAFT instrument combination (sensitivity, specificity, positive predictive value, and 
negative predictive value) is described in the labeling.
Scenario A  The assay manufacturer plans to apply the assay to the SAFR instrument, which is similar in 
technology to the SAFT instrument, but is designed and manufactured differently (e.g., different sample 
processing internal layout, different sample workflow, etc.).  The assay manufacturer performs a risk-
based assessment, which does not identify any new risks or significantly modified existing risks, but 
design validation and verification activities using the manufacturers established analytical and clinical 
protocols demonstrated unexpected assay performance that does not meet the acceptance criteria 
established at the time of the initial 510(k) clearance.  These differences raise questions about whether the 
change in analytical performance may affect clinical performance.  The manufacturer plans to address 
these issues using different protocols and/or acceptance criteria from those used in the initial 510(k) and 
thus submits a new 510(k) for the combination of the EZPZ troponin assay with the SAFR instrument.
Scenario B  The assay manufacturer plans to apply the assay to the SAFTS instrument, an instrument  
family member of the SAFT instrument.  The changes to the system (relative to the one using SAFT) 
include a small change in the shape of the outer instrument box and minor differences in the user interface.  
The assay manufacturer performs a risk-based assessment, which does not identify any new risks or 
significantly modified existing risks and indicates that no other features of the SAFT instrument are 
affected by these changes.  Testing using the manufacturers established protocols demonstrates assay 
performance is not affected by the change.  Based on this, the manufacturer determines that a new 510(k) 
is not needed to market the EZPZ troponin assay to run on the SAFTS instrument, and the manufacturer 
documents the change and 510(k) assessment to the file.
VI.  Labeling 
Labeling for IVDs must comply with 21 CFR parts 801 and 809 and any applicable device-specific 
requirements (e.g., special controls, restrictions, or limitations found in a clearance with limitations24).  
Package inserts for a new assay-instrument combination within the scope of the Replacement Reagent Policy 
or Instrument Family Policy should include any new procedural steps relevant for use of the assay with the 
additional instrument.25  Some manufacturers choose to include settings for new combinations of an assay 
and an instrument in an application sheet.  In these cases, FDA recommends that the package insert refer to 
the application sheet, and vice versa, to ensure users are aware of all relevant information.  Assay package 
inserts or accompanying application sheets should clearly state which instruments have been tested for use 
with the assays.  For instrument modifications, operator manuals should include any updated specifications 
and instructions.  The addition of a new combination of assay and instrument within the scope of this 
guidance should not significantly affect assay labeling, including performance claims.  
24 FDA has the authority to issue a substantially equivalent (SE) with limitations letter under section 513(i)(1)(E) of the 
FD&C Act if FDA determines and states in writing that there is a reasonable likelihood that the device will be used for an 
intended use not identified in the proposed labeling for the device and such use could cause harm.
25 This refers only to small changes in procedural steps.  Significant changes may require a 510(k).
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VII. Clinical Laboratory Improvement Amendments (CLIA) 
Categorization
FDA categorizes IVD test systems according to their CLIA complexity (42 CFR 493.17) and enters the 
categorizations in the CLIA database following clearance or approval.  See the FDAs guidance document 
entitled Administrative Procedures for CLIA Categorization.26  For modifications relating to application 
of cleared assays to additional instruments, assay manufacturers should submit CLIA categorization requests 
to FDA in order for the test system to be incorporated in the CLIA database.  A CLIA categorization request 
for application of an assay to an additional instrument using the Replacement Reagent Policy or Instrument 
Family Policy should include: 
 A signed cover page, with contact information, clearly designating the request For CLIA 
Categorization Only and we recommend including a statement that the manufacturer has followed 
the logic scheme and considered the issues in this guidance.
 Specification of which instruments (cleared or family member) and cleared assays are being 
combined, including reference to all related assay and instrument 510(k) numbers.  This information 
can be most clearly represented in table format, especially if multiple assays or instruments are 
involved.
 The package insert (and application sheet, if applicable) for the new test system specifying the 
additional instruments.  Inclusion of the 510(k)-cleared package insert is also recommended to help 
streamline the categorization process.
Additionally, for systems with new instrument family members (i.e., instruments that are not part of a 
previously cleared 510(k) and were not previously categorized), the manufacturer should include the 
Operator Manual (or excerpts including the instrument name, intended use, manufacturer or distributor, 
changes to the cleared instrument, and any procedural changes).
In addition, if the assay manufacturer is different from the instrument manufacturer and is applying its assay 
to a new instrument family member (i.e., that was not part of a test system reviewed within a cleared 
510(k)), the assay manufacturer should also include information (e.g., confirmation from the instrument 
manufacturer) to support that the instrument is an instrument family member as defined in this guidance.
FDA will assign a discrete CLIA Record (CR) number to this submission, notify the sponsor of the 
tracking number, and attempt to notify the sponsor of the categorization within 30 days of the request.  
Following notification to the sponsor, FDA posts the categorization(s) in the public CLIA database.  
Categorization in response to a CLIA categorization request is not a substantial equivalence determination, 
and is not meant to indicate FDA review of the manufacturers internal assessments and testing.  A 
modified instrument (including family member) or new assay-instrument combination categorized in 
response to a CLIA categorization request based on the Replacement Reagent Policy or Instrument Family 
Policy, and without a 510(k) clearance for the modification, should not be used as a predicate device for a 
new 510(k).27  
26 Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/administrative-procedures-clia-
categorization.
27 If there is sufficient scientific rationale, method comparison studies can utilize devices other than the predicate as a 
comparator within a method comparison study to support a new 510(k). 
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Appendix 1: Significant Terminology
The following significant terminology is provided in this appendix to clarify the meaning of terms used in 
this guidance for purposes of this guidance only.  In some instances, existing definitions or descriptors 
from the medical device regulations have been used or referenced.
Instrument A device that produces an analytical result from an applied clinical sample by reading a 
generated signal and modifying or translating the signal into a result.  The instrument 
may also control pre-analytic and/or post-analytic components including: mechanisms 
for sampling and processing specimens, and software for interpretation and storage.
Assay A set of all reagents and instructions needed for measurement or detection of the 
analyte.
Design history file DHF means a compilation of records which describes the design history of a finished 
(DHF) device.  The DHF shall contain or reference the records necessary to demonstrate that 
the design was developed in accordance with the approved design plan and the 
requirements of 21 CFR part 820.
Instrument  A group of two or more instruments produced by (or for) the same manufacturer, 
family having the same general architecture, design, tolerance limits, and capabilities, such as 
detection methods, signal range and intensity, and reaction conditions.  Instruments 
within a family are the same in terms of the hardware and software components related 
to the test reaction and interpretation, and share a common device classification 
regulation and product code.  Examples of the types of differences between instrument 
family members include improvements to some features of the user interface, ability 
for higher sample throughput due to pre-analytical features, or increased data storage.  
Labeling accompanying an in vitro diagnostic product with instructions for 
Package insert
performing and interpreting the assay and any other required information.  See 21 
CFR parts 801 and 809, as applicable (e.g., 21 CFR 809.10(b)), and any applicable 
device-specific requirements (e.g., special controls, restrictions, or limitations found 
in a clearance with limitations).
Other forms of labeling noted in this guidance include: 
Operator manual which accompanies the instrument and contains its description, 
claimed specifications, and instructions. 
Application sheet which contains settings for applying the manufacturers assay 
to a specified instrument.  Note: When an assay manufacturer makes available 
an application sheet for a specific instrument(s), this implies adequate 
performance for the assay on the instrument(s).
A substance or component of an assay that allows a target analyte to be detected or 
Reagent
measured. An assay typically includes multiple reagents.  
Replacement reagent refers to a previously cleared reagent that is being applied to an 
Replacement 
reagent additional instrument.  IVD manufacturers should refer to the considerations described 
in Section III of this guidance, including test system operating principles, risk-based 
assessment, and design verification and/or validation activities, to help determine 
whether reagent application to the additional instrument calls for a new 510(k).
All test components required to perform an in vitro diagnostic test, including but not 
Test system
limited to, instruments, software, assay reagents, calibrators, and controls.
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Appendix 2  Flowchart aids for determinations regarding the 
Replacement Reagent and Instrument Family Policy  
The flowcharts in this Appendix are intended to supplement the guidance.  For ease of use, the logic flow 
has been broken down into smaller sections that include: 
 Overall Flowchart, which identifies the overall steps for consideration in the manufacturers 
determination to apply a previously cleared assay to an additional instrument (Figure 1).
 Flowchart A, which focuses on the initial considerations the manufacturer should address (Figure 
2).
 Flowchart B, which focuses on the risk-based assessment and design verification and/or validation 
activities (Figure 3).
Sections within Figures 2 and 3 refer to corresponding sections within this guidance.  Manufacturers 
should not use the flowcharts alone in making determinations regarding the need for a new 510(k).  In 
addition, when using the flowcharts, the reader should interpret Submit 510(k) to mean a new 510(k) is 
likely required.  Manufacturers internal documentation means a new 510(k) is not likely to be required, 
and that the manufacturer must document, as part of the device master record, the design, production, or 
process changes made,28 and should document the manufacturers 510(k) assessment with appropriate 
documentation. 
As previously stated, if you have questions regarding how to apply this guidance to a particular technology, 
we recommend you contact the appropriate review division for your assay and instrument.
28 See 21 CFR 820.30(i), 21 CFR 820.70(b), and 21 CFR 820.181.
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