who prequalification of in vitro diagnostics programme

WHO Prequalification of In Vitro Diagnostics

Programme

Copenhagen, Denmark 22-25 September 2014

1

> The aim of PQDx is to promote and facilitate access to safe, appropriate and affordable in vitro diagnostics of good quality in an equitable manner

> Focus is placed on IVDs for priority diseases and their suitability for use in resource-limited settings

> The findings of PQDx are used to provide independent technical information on safety, quality and performance of IVDs, principally to other UN agencies but also to WHO Member States and other interested organizations

> The PQDx status, in conjunction with other procurement criteria, is used by UN agencies, WHO Member States and other interested organizations to guide their procurement of IVDs

PQDx: aim, scope and impact


2

Joint UNICEF, UNFPA & WHO MEETING with manufacturers and suppliers

> PQDx undertakes a comprehensive assessment of individual IVDs through a standardized procedure aimed at determining if the product meets WHO prequalification requirements.

> The prequalification assessment process includes three components:

> Review of a product dossier;

> Laboratory evaluation of performance and operational characteristics; and

> Manufacturing site(s) inspection.

PQDx components


3


> Applications to PQDx are only accepted from the legal manufacturer of the product

> "Re-branding" arrangements

> WHO considers a "re-branded" product to be one that is manufactured under identical conditions at the same manufacturing site(s) as the original product. A “re-branded” product is identical in every aspect to the product manufactured by the original manufacturer, except that the product is labeled with the "re-branded" product name and purchaser identifier.

> WHO encourages joint applications by original equipment manufacturers and "re-branders".

> A condition for the prequalification assessment of a "re-branded" product is that the original product manufacturer and the "re-brander" explicitly consent to the public disclosure by WHO of this "re-branding" arrangement. Such disclosure will include the recommendation that the two products should not be used in combination within the same testing algorithm in the WHO prequalification public report.

Who can apply for PQDx?


4


WHO prequalification assessment


5


Dossier review Site inspection

Dossier incomplete

Laboratory evaluation

Prequalification decision

Dossier complete

Dossier screening

Priority product

Yes

No

Pre-submission form



6



Dossier incomplete



Dossier complete

Dossier screening

Priority product

Yes

No

Pre-submission form



7



Dossier incomplete



Dossier complete

Dossier screening

Priority product

Yes

No

Pre-submission form



8



Dossier incomplete



Dossier complete

Dossier screening

Priority product

Yes

No

Pre-submission form

> Final prequalification outcome depends on:

> Results of dossier assessment and acceptance of action plan

> Results of inspection(s) and acceptance of action plan

> No level 5 nonconformities outstanding for either dossier or for inspection

> Meeting the acceptance criteria for the laboratory evaluation

> WHO PQDx Public Report is posted on WHO website and product is added to the list of WHO prequalified products

> Product is then eligible for WHO and UN procurement

Prequalification: decision


9


Application


10

> Manufacturers can apply at any time

> Read the WHO PQDx_007 “Overview of the Prequalification of In Vitro Diagnostics”

> Complete the Pre-Submission Form (WHO PQDx_015), using the following guidance:

WHO PQDx_017 “Instructions for the Completion of the Prequalification of In Vitro Diagnostics Pre-submission Form.”

The Application Process


11


> Replaces the previously used Application Form

> Used to determine whether the application will be prioritized based on

> Prioritization criteria

> Programmatic suitability

> Used to determine whether the product is made by the original manufacturer (not rebranded)

> Used to determine the regulatory version of the device

The Pre-Submission Form


12



13


Prioritization Criteria

RationaleCriteria

Ensure continuity of supply and quality of products procured

Listed on the WHO procurement scheme and procured by UN organizations in significant levels

Focus on priority disease areas – highest historical procurement

Assist in the diagnosis and/or monitoring of infection with HIV-1/HIV-2, the diagnosis and/or monitoring of infection with hepatitis C, and diagnosis of infection with malaria parasites

Bringing testing closer to the community Rapid test format and/or technologies that can be used at or near to point-of-care (POC)

Ensure known supply chain; no duplication of effort, best possible prices

Original product manufacturers

Focus on unmet market / procurement needsFew other prequalified products exist in the product category such as CD4, VL

Focus on the needs of WHO disease programmes

Adult Male Circumcision Devices

Other criteria dependent on changing global health needs, the particular needs of WHO Member States, and the emergence of new and relevant diagnostic technologies.

> WHO will send a letter informing of the outcome of the prioritisation process

> The letter will provide further instruction for those applications that are prioritised

> First payment

> Whether the application will be eligible for an abbreviated assessment

> If for a full assessment, how and when to submit the product dossier

The Pre-Submission


14


Recurrent Issues


15


> Multiple products per application form

> Unclear name of product

> Unclear regulatory version of product undergoing PQ assessment

> Unclear/missing performance claims including lack of confidence intervals

> Unclear site(s) of manufacture and roles of different sites

> Misconception that this step constitutes part of the PQ process

Dossier


16

How and when to submit the dossier


17


> Required, on request by WHO, for applications undergoing full assessment

> Must be submitted according to WHO PQDx_018 “Instructions for Compilation of a Product Dossier”

> The first page should be the original signed Letter of Agreement

> The “Product Dossier Checklist” WHO PQDx_049 must be completed and used as a Table of Contents for the dossier documentation

> WHO has produced a Sample Product Dossier for a fictitious CD4 POC product to give an idea of the type of documentation to be submitted in a Product Dossier

Product Dossier Requirements


18


> Based on best international practice (ISO, EN, GHTF, IMDRF, CLSI…)

> Follows the content of the IMDRF MA IVD ToC(http://www.imdrf.org/docs/imdrf/final/technical/imdrf-tech-140630-rps-ivd-toc.pdf)

> Dossier must demonstrate that the IVD conforms to the Essential Principles of Safety and Performance of Medical Devices (GHTF/SG1/N41R9:2005)

> Looks into critical aspects for WHO Member States often not dealt with from a local prospective by SRAs

> stability, risk assessment, instructions for use, etc.

WHO Dossier Screening Process


19


Recurrent Issues - Dossier Screening Process


20


> No clear identification of the product being submitted to PQ in the dossier documentation

> Some sections not documented at all

> Full study reports not submitted or too summarised

> No certified copies of the certificates requested

WHO Dossier Technical Review Process


21


• Amendments

Reviewed

• Dossier Rated

• PQ Decision

Inspections


22

> Fully implemented quality management system (design & development, manufacturing including quality control, storage, distribution)

> Risk management to meet ISO 14971:2007

> Product stable to meet "harsh" conditions (hot, wet, dry, dusty)

> Products undergoing prequalification have to be in routine manufacturing

> Sufficient capacity to ensure reliable delivery

Requirements for Inspections


23


> Fully implemented quality management system (design & development, manufacturing including quality control, storage, distribution)

> Meets ISO 13485:2003 requirements (note: user requirements in areas of interest)

> Competence of personnel

> Work environment (determined and established)

> Quality control processes follow risk management results, quality control plan established, performance tested according to claims in instruction for use

> Storage conditions, temperature and humidity, validated for intermediates, components and kit, real time data required

Quality Management System


24


> Risk management to meet ISO 14971:2007

> Risk management for product realisation (design, manufacturing, storage, transportation), user and patient

> Risk management file

> Risk management plan

> Risk analysis

> Risk evaluation and control

> Residual risk acceptable?

Risk Management


25


> Product stable to meet "harsh" conditions (hot, wet, dry, dusty)

> Transportation studies (simulate "worst" conditions)

> Long term stability at limiting conditions

> In-use stability studies (open vial)

> Data to support all claims available on-site

> Note: product labelling (component, kit and shipping box)

Product Stability


26


> Transfer from R&D to production completed

> Established and evaluated suppliers

> Validated processes (acceptance ranges determined, in-process controls established)

> Trained personnel (requirements determined, training plan, records)

> Standard batch sizes

> Established "out-of-specification" process

> Batch manufacturing records established (include all manufacturing information, full traceability of material and equipment)

Routine Manufacturing


27


> WHO Guidance

> Overview of the prequalification of diagnostics assessment process

(PQDx_007)

> Information for manufacturers on prequalification inspection procedures for the sites of manufacture of diagnostics (PQDx_014)

> Abbreviated prequalification assessment (PQDx_173)

> International Guidance

> GHTF.SG4.(99)28 Guidelines for Regulatory Auditing of Quality Systems

of Medical Device Manufacturers - Part 1: General Requirements

(including supplements 1,2, 4 and 6). Note: 10.2.1 and 10.2.3 in this

document further describe audit team competency criteria

> GHTF/SG4/N30R20:2006 Guidelines for Regulatory Auditing of Quality

Systems of Medical Device Manufacturers - Part 2: Regulatory Auditing

Strategy

Guidance Documents


28


> International Guidance

> GHTF/SG4(pd1)/N33R16:2007 Guidelines for Regulatory Auditing of

Quality Systems of Medical Device Manufacturers - Part 3: Regulatory

Audit Reports

> GHTF/SG3/N17:2008 Quality Management System – Medical Devices –

Guidance on the Control of Products and Services Obtained from

Suppliers

> GHTF/SG3/N19:2012 Quality management system – Medical devices -Nonconformity Grading System for Regulatory Purposes and Information Exchange

> GHTF/SG3/N15R8:2005 Implementation of risk management principles

and activities within a Quality Management System.

Guidance Documents


29


> ISO 13485:2003 Medical devices - Quality management systems -Requirements for regulatory purposes

> ISO 14969:2004 Medical devices - Quality management systems -Guidance on the application of ISO 13485:2003

> ISO 19011:2011 Guidelines for quality and/or environmental management systems auditing.

> ISO 14971:2007 Medical devices - Application of risk management to medical devices

> Note: EN ISO 14971:2012 applies only to manufacturers placing devices on the market in Europe and contains useful annexes; the body of the standard is identical to ISO 14971:2007 ISO 9000:2005 Quality management systems - Fundamentals and vocabulary

International Standards


30


> ISO 15223-1:2012 Symbols to be used with medical device labels, labelling and information supplied—Part 1 General requirements

> ISO 2859-10:2006 Sampling procedures for inspection by attributes —Part 10: Introduction to the ISO 2859 series of standards for sampling for inspection by attributes

> …

International Standards


31



32

Stage 1

Plan

Stage 2

Inspection

2 rounds CAP

Ready for

Inspection

Compliant?

(<3 level 4 NC)

(Seek techn.

assistance)

Recommendation for PQ

N

Y

Y

N

Dossier Screening

Dossier Review

List of

questions

Compliant?

2 rounds CAP

Y

N

N

N

TerminateTerminate

Y

TerminateTerminate

Inspections process

> Application (Pre-submission form)

> Dossier review (QM documentation part)

> Inspection Cycle:

> Evaluation of readiness for inspection (stage 1)

> Desktop of additional documentation (Certificates, recent audit reports, quality

procedures, SOP, summary of sold product...)

> Stage 1 inspection (1 inspector day to inspect state of QMS implementation,

facility, competence of staff, critical suppliers incl. outsourced activities,

internal audit and management committment / review)

> Initial (Stage 2) Inspection

> Follow up (confirm implementation of CAP); onsite inspection, if required

> Surveillance (risk based, at least annual reporting required)

> Re-Inspection (risk based, after 3-5 years)

Onsite Inspections


33


Laboratory Evaluation


34

> WHO will send the evaluation protocol to the manufacturer

> Manufacturer is expected to review the protocol and inform WHO of any concerns

> Prepare two independent lots

> The WHO collaborating laboratory will write to the manufacturer and provide the shipping address

> The manufacturer will send specified number of tests within specified timeline

Processes for laboratory evaluation


35


> Manufacturer will demonstrate and train the lab technologists who will conduct the evaluation

> The WHO collaborating laboratory will conduct the evaluation in specified timeline and send the draft report to WHO

> WHO will review all the data and draft report

> WHO will send the draft report to the manufacturer who must respond with 1 month

Processes for laboratory evaluation cont'd


36


> After receiving comments from manufacturer, WHO will finalize the report and send the final report to the manufacturer

> Part of the report will be included in the public report for PQ

> The data will be included in the WHO summary report on performance and operational characteristics of HIV assays publication

> For Malaria RDT

> Laboratory evaluation (product testing) conducted by WHO/FIND is incorporated in the PQ reports

Processes for laboratory evaluation cont'd


37


Assays HIV serology HIV serology

(oral fluid)

Combined

HIV/Syphilis

serology

CD4

technologies

HIV viral

load/EID

Specimen

type

Plasma or

serum

Linked

plasma/serum

and oral fluid

Plasma or

serum

Whole blood Plasma/Dried

blood spots

Study type Retrospective Prospective clinic

settings

Retrospective Prospective

clinic settings

Retrospective/

Prospective

Panels type Characterized

panels

Consecutive

plasma + OF fresh

exudates

Characterized

panels

Consecutive

fresh whole

blood

Characterized

panels

HIV subtypes

Regional

distribution

African, Asia,

American,

European

African, Asia,

American,

European

African, Asia,

American,

European

At least two

regions

African, Asia,

American,

European

Seek ethical clearance for conducting the studies

Specimen panels used

Performance acceptance criteria for IVD assays

EIASensitivity

EIASpecificity

RDTSensitivity

RDTSpecificity

RDT (inter-

reader

variability)

Invalid

rate

HIV

serology

100% ≥ 98% ≥99% ≥ 98% ≤5% ≤5%

HCV

serology

100% ≥ 98% ≥98% ≥97% ≤5% ≤5%

HBsAg

serology

100% ≥ 98% 100% ≥98% ≤5% ≤5%

CD4 Precision

(Dedicated)

Precision

(POC)

Bias Carryover Failure rate

≤10% ≤15% ≤10% ≤2% ≤10%

> Characteristics of the technology (equipment/instrument)

– Including through-put, time to result, parameters available, power source,

portability , failure rate, portability, need for frequent maintenance,

instrument connectivity, amount of waste, results storage, turn around time

> Characteristics of the reagents

– Including stability/shelf life for storage and in-use stability

– Use of heat stable reagents (dry reagents)

– Ability to provide absolute and % CD4

Operational characteristics assessed

> Specimen preparation

– Stability of sample before testing (CD4)

– Specimen type & volume, number of steps, precision of measurement,

specimen stability after application to device

> Quality control

– Including internal QC (software and instrument), external QC

specimens, compatibility with known EQA schemes

> Regulatory, cost & other operational aspects

– Including national registration, cost of instrument and/or reagents,

connectivity & data management, maintenance, training, technical support

Operational characteristics assessed cont'd

Abbreviated WHO prequalification

assessment procedure


42

> Scenario 1

> Version submitted for PQ has been stringently assessed

> Scenario 2

> Version submitted for PQ has not been stringently assessed but a

regulatory version exists that has been

> Scenario 3

> Version submitted to PQ has not been stringently assessed

> Where stringent assessment has been conducted by founding member of GHTF

Categories of products submitted to PQ


43


Prequalification of IVDs Programme


44


Full prequalification assessment

Dossier reviewSite

inspection

Dossier incomplete



Dossier complete

Dossier screening

Priority product

Yes

No

Pre-submission form

Abbreviated prequalification assessment

Site inspection



Decision on abbreviated PQ

assessment

Priority product

Yes

No

Pre-submission form

Full PQ assessment

No

> If the regulatory version submitted for WHO PQ has undergone prior stringent regulatory review by a founding member of the GHTF

> Stringent regulatory review recognized as:

> CE; List A, Annex II

> FDA; PMA or BLA

> Health Canada; Class IV

> TGA; Class 4

> Japan; Minister's approval

Scenario 1


45


> An abbreviated PQ assessment procedure will be followed:

1. No dossier requested by WHO

2. Abbreviated WHO site inspection

> Information package requested to prepare for the inspection, including receipt of previous satisfactory audit report;

> Shorter duration, fewer inspectors; to verify WHO customer requirements;

> 1 inspector, 1 technical expert.

3. WHO laboratory evaluation of performance and operational characteristics to inform product selection

Scenario 1


46


> If the regulatory version submitted for WHO PQ is the rest of world regulatory version but the manufacturer has a "similar" product that has undergone prior stringent regulatory review

> Stringent regulatory review is recognized as:

> CE (List A, annex II), FDA (PMA or BLA), Health Canada (Class IV), TGA (Class 4), Japan (Minister's approval)

Scenario 2


47


> Procedure to be followed:

1. WHO pre-submission form reviewed

> Comparison of key differences between stringent regulatory version and ROW regulatory versions is made:

> Product description, intended use, test procedure, design, manufacturing

site, key suppliers, labelling, instructions of use, quality management

system, verification/validation studies, lot release criteria

> If substantial differences, usual full PQ assessment procedure is followed (no abbreviated assessment)

> If no substantial differences, abbreviated PQ assessment procedure is followed

Scenario 2


48


> Where no stringently assessed regulatory version exists

> Any regulatory review other than the following:

> CE; List A, Annex 2

> FDA; PMA or BLA

> Health Canada; Class IV

> TGA; Class 4

> Japan; Minister's approval

Scenario 3


49


> Usual PQ assessment procedure will be followed:

1. Dossier requested and reviewed by WHO

2. Site inspection

3. WHO laboratory evaluation of performance and operational characteristics to inform product selection

Scenario 3


50


Post PQ


51

> Post-market surveillance is a WHO post-qualification activity which includes reactive and proactive measures, through complaint reporting and post-shipment/pre-distribution lot testing.

> Post-qualification also includes mandatory manufacturer notification of changes to the product or the quality management system.

What happens after PQ


52


> As part of the life cycle of a prequalified IVD, changes to it, its regulatory or certification status and/or the QMS under which it is produced may become necessary

> Changes (“variations”) to prequalified products may be minor,administrative or substantial

> As part of its QMS, the manufacturer should have a system in place to design, validate and implement changes and to determine their significance

Changes to prequalified IVDs


53


> In order to meet the prequalification requirements, the manufacturer should establish, maintain and implement a procedure for categorizing and documenting any changes to the IVD, its regulatory or certification status and/or the QM

> The manufacturer should then assess the significance of any change

> To determine if a change requires notification to WHO, the manufacturer should evaluate the potential effect this change may have on the design, composition, safety, quality and/or performance of the IVD

Categorizing changes


54


Reporting criteria


55


> Changes notification form and guidance published

Guidance


56


> Contact us by email

Contact us


57


[email protected]

> Sign up to our mailing list

By emailing [email protected]

http://www.who.int/diagnostics_laboratory/evaluations/en/

> Check our website