Guidance

Target Product Profile: antibody tests to help determine if people have recent infection to SARS-CoV-2: Version 2

Updated 8 August 2023

Target Product Profile

Antibody tests to help determine if people have immunity to SARS-CoV-2

Issued by MHRA

Version Control

• 1.0 Initial document
• 2.0 Changes to specifications, changes to introduction

The purpose of a Target Product Profile “TPP”

Target product profiles (TPP) outline the desired ‘profile’ or characteristics of a target product that is aimed at a particular disease or diseases. TPPs state intended use, target populations and other desired attributes of products, including safety and performance-related characteristics. They provide a common foundation for the development of tests that contains sufficient detail to allow device developers and key stakeholders to understand the characteristics a test must have to be successful for the particular intended use. Included is a description of

(1) the preferred and

(2) the minimally acceptable profiles based on the intended use, setting of use, and intended user, with respect to the performance and operational characteristics expected of the target products.

TPPs for COVID-19

These product profiles have been developed to assist manufacturers to design and deliver tests that might be useful in support of Pillar 3 of the UK testing strategy. How closely a product matches the TPP will be helpful in procurement and regulatory decision making. Any deviation from existing standards must be fully justified. Production lead time will also factor into decision making.

Implementation of Pillar 3 of the testing strategy relies on availability of simple antibody tests that could tell people whether they have had the virus and are now immune. Such tests require taking a small blood sample and looking for the presence of the neutralising antibodies specific to SARS-CoV-2, the causative agent of COVID-19. When available these tests would be used in community settings and eventually in the home. They should thus be simple, robust and have a rapid time to test result.

Antibody tests for other purposes are not part of this profile and might include:

• to determine if a symptomatic individual has a reasonable likelihood of a current infection
• to determine if an at-risk individual with or without symptoms in an endemic setting has a reasonable likelihood of a current infection
• to aid in the diagnosis of a symptomatic individual with a SARS CoV-2 infection
• to monitor a local or sentinel population in order to obtain early indications of a COVID-19 outbreak.

It should be noted that for each of these intended use scenarios, a different TPP could apply. As such the contents of the TPPs in this document are restricted to those supporting use for Pillar 3. These TPPs are profiles based on our best information, but the science is rapidly evolving.

Clinical performance requirements

This is a specification of the clinically acceptable specifications for point of care and self-tests to be made and used in the UK during the current COVID-19 pandemic caused by SARS-CoV-2 virus. It sets out the clinical requirements based on the consensus of what is ‘minimally acceptable’ in the opinion of UK IVD industry, healthcare professionals and medical device regulators given the emergency situation. A test kit with other specifications than this may not be suitable to support Pillar 3 of the UK testing strategy.

The intended use of assays that match these profiles (or one that does not yet meet the specifications but looks promising) is to determine if an individual has previously been exposed to SARS-CoV-2 (and not other coronaviruses circulating in the population), and ultimately, if they are immune. As such, the test should detect IgG antibodies, specific to the virus and that are neutralising in their function. As these tests are intended to be used in a community or home setting, they need to be simple and thus a lateral flow is likely to provide this solution.

The criteria for clinical specificity is set deliberately high in a test intended to detect immunity where the result may be given in the absence of a confirmatory test or without a known past PCR (Polymerase chain reaction) positive result. In a test with low specificity, there is an unacceptable risk that a person is incorrectly told that they are immune. They may consequently be exposed to infection and be at risk of illness and may also pass that infection on to others that they come in contact with. This is particularly a concern in people from a high-risk group, or a group which is directly exposed to vulnerable persons.

These specification criteria are based on similar Target Product Profiles published by the World Health Organisation, PATH, and FIND for IVDs to other diseases. Each of these organisations has extensive experience with establishing TPPs for simple, rapid diagnostic tests.

Future developments

These profiles are subject to review and change, as we gain a greater knowledge of the virus, the disease and our needs for an effective response. They may need to be updated at short notice. For instance, if it is proven that immunity is temporary and the antibody clears after a few months, it might be necessary to measure and monitor the antibody level and therefore the feature of a qualitative test may change to that for a quantitative or semi-quantitative test.

Antibody tests may be more useful in specific populations depending on the prevalence of antibodies. More work is needed before we can include targets for predictive values based on seroprevalence.

As our knowledge and understanding of the disease changes and the UK clinical needs change, so will the specifications. A test that meets this version of the TPP may not meet future versions.

Other solutions

Ideally, products should be designed to achieve as many of the optimal characteristics as are feasible, while still satisfying the minimal criteria for all defined features. However, a test that does not yet meet all these profiles may still have a role in supporting the UK testing strategy.

Key

Acceptable:defines the minimum acceptable feature

Desired:highly desirable features of considerable benefit. As time is of the essence if omitting one of these features significantly accelerates development and production it should be considered.

Point of care test:an in vitro diagnostic medical device intended to be used by a healthcare professional outside of a laboratory in primary or secondary care environments

Near patient test:an in vitro diagnostic medical device that is not intended for self-testing but is intended to be used outside of a laboratory environment

Self-test:an in vitro diagnostic medical device intended to be used by a layperson

TPP COVID-19 Serology (antibody) point of care test/near patient test

Scope

Intended use

Desired: to determine if an individual is immune to SARS-CoV-2

Acceptable: to determine if an individual has previously been exposed to SARS-CoV-2

Evidence for each intended use must include that which supports the specificity of the immune response to SARS-CoV-2 (acceptable feature) and if claim is of immunity (desired feature), that the antibodies detected are protective.

Target population

Desired: people who need to know that they are immune to SARS CoV-2

Acceptable: people who may have recovered from suspected or confirmed SARS CoV-2 infection or may have previously developed an asymptomatic infection

Target user

Desired: the person trained in operating the test kit

Acceptable: health care professionals

Target use setting

Desired: clinics, pharmacies, workplaces and other non-laboratory settings

Acceptable: clinics, pharmacies, workplaces and other non-laboratory settings

Test design characteristics

Test format

Desired: a standardised kit that contains all materials required for the procedure in a self-contained kit that includes controls, reagents and accessories needed to perform the assay and blood collection (e.g. lancets, swabs)

Acceptable: a standardised kit that contains all materials required for the procedure in a self-contained kit that includes reagents. Accessories for specimen collection to be provided separately

Target analyte

Desired: IgG antibodies to SARS-CoV-2 virus

Acceptable: Total antibodies to SARS-CoV-2 virus

Assay design should use antigen known to be that which stimulates a specific response to the virus. The kinetics of the humoral response for COVID-19 are not yet fully understood but total antibody (IgA, IgM and IgG) may be useful.

Sample type

Desired: capillary whole blood from fingerstick sample OR venous blood, serum or plasma

Acceptable: capillary whole blood from fingerstick sample

Clinical sensitivity and specificity must be determined for each claimed specimen type and anticoagulant. Sample equivalence must be shown.

Result output

Qualitative

Internal control

Included. Procedural flow control detecting the capability of the assay. Controls that only detect migration of specimen are not considered sufficient.

Ease of use

Desired:

• One signal test PLUS control
• Easily interpreted by the intended user
• No need for additional equipment to read result (e.g. camera, etc.)
• Operator is able to record results without having to write them manually

Acceptable: * One signal test PLUS control * Easily interpreted by the intended user

Identification capability

Labelling of the device with the patient/donor identification must be feasible. For a lateral flow test, this means the cartridge must have sufficient space for patient ID (either manually added or via a patient label).

Pack size

Single or multiple test kits

Power requirements

None required

Need for calibration/spare parts

None

Performance characteristics

Clinical sensitivity

Greater than 98% (with 95% confidence intervals of 96-100%) on specimens collected 20 days or more after the appearance of first symptoms.

These statistics rely on testing of at least 200 confirmed positive cases. See annex

Clinical specificity

Greater than 98% (within 95% confidence intervals 96-100%)

These statistics rely on testing of at least 200 confirmed negative cases or from testing of specimens collected at least 6 months before the known appearance of the virus. See annex

Analytical specificity

Desired: no known cross-reactivity with other known coronavirus, common respiratory pathogens

Acceptable: minimal cross-reactivity with other known coronavirus, or common respiratory pathogens Refer to list in annex for relevant pathogens

Invalid rate

Desired: no more than 0.1%

Acceptable: no more than 1%

Test procedure characteristics

Number of steps to be performed by the operator

Desired: no more than 4 steps

Acceptable: no more than 5 steps

Steps to consider include: * lance fingertip * apply blood * apply buffer * read

Sample preparation

Desired: not required

Acceptable: no more than 15 minutes

Need to process sample prior to performing test

Need for operator to transfer a precise volume of sample or reagents

Desired: no

Acceptable: acceptable if robust transfer device is provided with the test device and if variation does not affect the test results

Requirement to add reagents e.g. sample diluent or buffer

Desired: no

Acceptable: reagent provided in a dropper bottle

Time to result

Desired: no more than 15 minutes

Acceptable: no more than 20 minutes

Result

Consists of easily reading and interpreting the results of the test and the control.

For a lateral flow test, this means that there will be two lines to read and interpret.

Biosafety

No biosafety should be needed in addition to personal protective equipment

Operational characteristics

Test kit storage conditions

5 – 30 ⁰C

80% relative humidity

Operating conditions

15 – 25 ⁰C

80% relative humidity

Kit reagent stability

At least 12 months at 5 – 30 ⁰C

No cold chain is required.

Accelerated stability testing is acceptable provided it is supported by real time stability studies.

In use stability

Desirable: more than 1 hour after opening of an individual pouch

Acceptable: more than 30 minutes after opening of an individual pouch

Reagents reconstitution (need to prepare the reagents prior to utilisation)

Desirable: all reagents provided and ready to use

Acceptable: all liquids, including water, already in kit

End point stability (time window during which signal remains valid)

Desirable: up to 1 hour

Acceptable: up to 30 minutes

In busy testing environments, the need for a stable end point is imperative.

Reader-to-reader variation

More than 95% of readers should detect true positive results near the limit of detection

Volume of sample

Desirable: single drop for fingerstick tests

Acceptable: no more than two drops for fingerstick tests

Disposal requirements

Desirable: none, device and accessories should be disposed in standard biological waste containers; no glassware or be biodegradable or combustible

Acceptable: none, device and accessories should be disposed in standard biological waste containers

Kit presentation (if not single format)

Desirable:

• No greater than 100 tests
• Test components individually packed
• Accessories not too small to be used with regular examination gloves
• Include all required components and accessories to perform the test

Acceptable:

• 5 test kits
• Test components individually packed
• Accessories not too small to be used with regular examination gloves

Training needs (time dedicated to training session for end users)

Desirable: none. Job aid included in test kit

Acceptable: minimal. Job aid included in test kit

Job aids are summaries of all the operational steps in performing the test, usually pictorial in content.

Other

Labelling and instructions for use:

• In accordance with relevant requirements of Annex 1 of the IVD Directive (98/79/EC)
• Simple interpretation by layperson with pictorials to aid sampling and results interpretation and what to do with the test if the control fails
• Clear reading time
• Instructions for interpretation of different ranges of intensity
• Clear warnings of limitations for use including expected performance characteristics
• Paper or electronic

Regulatory status

CE marked, or in process of meeting EU regulatory requirements for in vitro diagnostic medical devices

Design and manufacturing environment

Conforms to ISO 13485:2016

TPP COVID-19 Serology (antibody) self-test

Scope

Intended use

Desired: to determine if an individual is immune to SARS-CoV-2

Acceptable: to determine if an individual has previously been exposed to SARS-CoV-2

Evidence for each intended use must include that which supports the specificity of the immune response to SARS-CoV-2 (acceptable feature) and if claim is of immunity (desired feature), that the antibodies detected are protective.

Target population

Desired: people who need to know that they are immune to SARS CoV-2

Acceptable: people who may have recovered from suspected or confirmed SARS CoV-2 infection or may have previously developed an asymptomatic infection

Target user

A layperson with no knowledge of self-testing technology

Test design characteristics

Test format

A standardised kit that contains all materials required for the procedure in a self-contained kit that includes controls, reagents and accessories needed to perform the assay and blood collection (e.g. lancets, swabs)

Target analyte

Desired: IgG antibodies that neutralise SARS-CoV-2 virus

Acceptable: total antibodies to SARS-CoV-2 virus

Assay design should use antigen known to be that which stimulates a specific response to the virus.

Sample type

Capillary whole blood from fingerstick sample

Clinical sensitivity and specificity must be determined for each claimed specimen type and anticoagulant. Sample equivalence must be shown.

Result output

Qualitative

Internal control

Included. Procedural flow control detecting the capability of the assay

Controls that only detect migration of specimen are not considered sufficient

Pack size

Desired: no more than 2 tests/kit

Acceptable: single test kits

Power requirements

None required

Need for calibration/spare parts

None

Performance characteristics

Clinical sensitivity

Greater than 98% (with 95% confidence intervals of 96-100%) on specimens collected 20 days or more after the appearance of first symptoms.

These statistics rely on testing of at least 200 confirmed positive cases.

Clinical specificity

Greater than 98% (within 95% confidence intervals 96-100%)

These statistics rely on testing of at least 200 confirmed negative cases or from testing of specimens collected at least 6 months before the known appearance of the virus.

Analytical specificity

Desired: no known cross-reactivity with other known coronavirus, common respiratory pathogens

Acceptable: minimal cross-reactivity with other known coronavirus, or common respiratory pathogens

Refer to list in annex for relevant pathogens

Invalid rate

Desired: no more than 0.1%

Acceptable: no more than 1%

Test procedure characteristics

Number of steps to be performed by the operator

Desired: no more than 5 steps

Acceptable: no more than 6 steps

Steps to consider include:

• handwashing
• lance fingertip
• apply blood
• read
• apply plaster to fingerstick site

Sample preparation

Desired: not required

Acceptable: no more than 15 minutes

Need to process sample prior to performing test

Ease of use

Desired:

• one signal test PLUS control
• easily interpreted by the intended user
• no need for additional equipment to read result (e.g. camera, etc.)
• operator is able to record results without having to write them manually

Acceptable:

• one signal test PLUS control
• easily interpreted by the intended user

Need for operator to transfer a precise volume of sample or reagents

Desired: no

Acceptable: acceptable if robust transfer device is provided with the test device and if variation does not affect the test results

Requirement to add reagents e.g. sample diluent or buffer

Desired: no

Acceptable: reagent provided in a dropper bottle

Time to result

Desired: no more than 5 minutes

Acceptable: no more than 20 minutes

Result

Consists of easily reading and interpreting the results of the test and the control.

For a lateral flow test, this means that there will be two lines to read and interpret.

Biosafety

No biosafety should be required for self-testing or disposal of test / lancet

Operational characteristics

Test kit storage conditions

5 – 30 ⁰C

80% relative humidity

Operating conditions

Desired: 15 – 25 ⁰C

80% relative humidity

Acceptable: 15 – 25 ⁰C

70% relative humidity

Kit reagent stability

At least 12 months at 2 – 35 ⁰C

No cold chain is required.

Accelerated stability testing is acceptable provided it is supported by real time stability studies.

In use stability

Desirable: more than 1 hour after opening of an individual pouch

Acceptable: more than 30 minutes after opening of an individual pouch

Reagents reconstitution (need to prepare the reagents prior to utilisation)

Desirable: all reagents provided and ready to use

Acceptable: all liquids, including water, already in kit

End point stability (time window during which signal remains valid)

Desirable: up to 1 hour

Acceptable: up to 30 minutes

Reader-to-reader variation

More than 95% of people should detect true positive results near the limit of detection

Volume of sample

Desirable: single drop for fingerstick tests

Acceptable: no more than two drops for fingerstick tests

Disposal requirements

None, dispose in household waste

Kit presentation (if not single format)

Desirable:

• no greater than 2 tests
• test components individually packed
• accessories not too small to be used with regular examination gloves
• include all required components and accessories to perform the test

Acceptable:

• single test kit
• test components individually packed
• accessories not too small to be used with regular examination gloves

Training needs (time dedicated to training session for end users)

None: job aid included in test kit along with the FIU

Job aids are summaries of all the operational steps in performing the test, usually pictorial in content

Other

Labelling and instructions for use

• in accordance with relevant requirements of Annex 1 of the IVD Directive (98/79/EC)
• simple interpretation by layperson with pictorials to aid sampling and results interpretation and what to do with the test if the control fails
• clear reading time
• instructions for interpretation of different ranges of intensity
• clear warnings of limitations for use including expected performance characteristics
• paper

Regulatory status

CE marked

Design and manufacturing environment

Conforms to ISO 13485:2016

Annex: Assay validation

Establishing performance characteristics

The following aspects should be considered when designing and validating the assay:

1. When available, reference material should be used to establish performance, including seroconversion panels, quality control materials and proficiency testing materials

2. There is no currently agreed reference standard for establishing specimen immunity status. In the absence of such agreed position, it is recommended that a reference standard used for establishing truth is a composite standard, comprised of the following: “Appropriately timed specimens collected from symptomatic patients diagnosed in a laboratory with validated assays.” Technical documentation should include your rationale for your specimen characterisation and also any discrepant result analysis.

3. When establishing analytical specificity, the following should be considered:

• prepandemic samples
• other coronavirus, SARS-CoV-2
• hCOV 229E, OC43, HKU1, NL63 epitopes
• Adenovirus (e.g. C1 Ad. 71)
• Human metapneumovirus (hMPV)
• Parainfluenza virus 1 – 4
• Influenza A & B
• Enterovirus (e.g. EV68)
• Respiratory syncytial virus
• Rhinovirus
• Chlamydia pneumoniae
• Haemonphilus infuenzae
• Legionella pneumophila
• Mycobacterium tuberculosis
• Streptococcus pneumoniae
• Streptococcus pyogenes
• Bordetella pertussis
• Mycoplasma pneumoniae
• Pneumocystis jirovecii (PJP)

Other

MHRA guidance In vitro diagnostic medical devices: guidance on legislation.