WHO Prequalification of Diagnostics – Tips for Success AIDS 2012 Satellite Session 25 July 2012, Washington DC Gaby Vercauteren Diagnostics & Laboratory

WHO Prequalification of Diagnostics – Tips for Success

AIDS 2012 Satellite Session25 July 2012, Washington DC

Gaby VercauterenDiagnostics & Laboratory Technology

Department of Essential Medicines & Health Products

2 | AIDS2012 – WHO Satellite Session l 25 July 2012

Approach of PQDxApproach of PQDx

Through a rigorous process identify diagnostics that meet the quality standards

Harmonize the WHO prequalification process – More stringent dossier assessment of diagnostics – Inspection of the QMS at production site (ISO 13485/GMP)– Laboratory assessment of performance characteristics

Partnering with well known regulatory authorities and with key technical partners


Prequalification of Diagnostics Prequalification of Diagnostics

Application by Manufacturer

Meets Requirements

DossierAssessment

Manufacturing Site Inspection

Laboratory Evaluation

Product Prequalified

Post Market Surveillance


Prioritization of PQDx applicationsPrioritization of PQDx applications

Comment Current prioritization criterion

Ensure continuity of supply and quality of products procured

Already listed on UN procurement scheme and procured by UN organizations in significant levels

Focus on priority disease areas – highest historical procurement

Assist diagnosis of infection with HIV-1/ HIV-2 or with malaria

Point of Care tests, closer to the patient. Particular relevance for priority diseases

Rapid test format

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

Original product manufacturers

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


Applications to the PQDx ProgrammeApplications to the PQDx Programme

Relevant WHO documents:

1. Prequalification of diagnostics application form

2. Instructions for the completion of the application form

Application form + IFU + authorization letter must be submitted in hard copy and electronic copy to WHO/HSS/EHT/DLT

Application reviewed through the application checklist


What information is included in the application?What information is included in the application?

The application form provides summary information about the diagnostic product and the manufacturer

• Is it a priority diagnostic product?• Does the manufacturer claim to use a QMS approach to

manufacturing?• Do the instructions for use conform with WHO PQ requirements?


Tips for success - application formTips for success - application form

Submit a separate application for each product

List all manufacturing sites and key raw material suppliers

Ensure no discrepancies between data provided on the form and the IFU:

• Manufacturer contact details• Product name • Product code• Performance characteristics

Poor information and/or poor wording in IFU (GHTF/SG1/N43:2005 Labelling for Medical Devices criteria applied)




Meets Requirements

DossierAssessment






What is a product dossier? What is a product dossier?

Product dossier = the selection of records and documents from the technical documentation that shows how the diagnostic product was developed, designed and manufactured

WHO reviews the dossier with the purpose of– Assessing the product and how it performs– Assessing the product manufacture – Determining if the manufacturer's quality management system is of an

adequate to ensure consistent quality


WHO PQDx dossier requirementsWHO PQDx dossier requirements

Dossier must demonstrate that the in-vitro diagnostic medical device conforms to the Essential Principles of Safety and Performance of Medical Devices (GHTF/SG1/N41R9:2005)

Key Components

Product description

Design and manufacturing information

Product performance specifications & associated validation and verification studies

Labelling

Commercial history

Regulatory history

Quality management system


Tips for success – compilation of the product dossierTips for success – compilation of the product dossier

Read thoroughly the "Instructions for compilation of a product dossier" available at: http://www.who.int/diagnostics_laboratory/evaluations/PQDxInfo/en/index.html

Submit two hard copies and one electronic copy (CD or DVD only).

Dossier clarity. Product dossier should be clear and well organized.

Please be reminded that all the information submitted within the dossier is treated as CONFINDENTIAL.


Product dossier checklistProduct dossier checklist

Needs to be submitted together with the product dossier

Helps the manufacturer in correctly compiling the dossier

Helps the dossier assessor to identify dossier sections which correspond to a specific dossier requirement as all dossier sections must be cross-referenced to the cover sheet



Requirements applicable to the entire dossier

Dossier clarity (clear, well-organized, page numbers, bound/ring folder)

Layout in order as per instructions (differently formatted dossiers accepted if fully cross-referenced on checklist)

Language and units of measure used– English language unless arrangement prior to submission– Certified translations– Metric units of measure except for other internationally accepted units of

measurement



Regulatory versions of the product.• Clearly identify the regulatory version submitted for prequalification,

indicate the full name and product code. • All the information submitted in the dossier must relate to the

regulatory version undergoing prequalification.• The use of the same product code for different regulatory

versions is not acceptable under any circumstances!



Essential principles (EP) checklist. The entire checklist should be submitted, including identification of the product name and product code. EP checklist available at: http://www.ghtf.org/documents/sg1/sg1n41r92005.pdf. Guidance from TGA to assist in the completion of an EP Checklist. The reference for this is found at the following link: http://www.tga.gov.au/industry/devices-argmd.htm. Refer to section “Australian regulatory guidelines for medical devices (ARGMD) Part 1– Introduction”.

Product Design and Manufacturing process. Submit a design flowchart and a manufacturing process flowchart (in one or two separate flowcharts) specific to the product undergoing prequalification.



• Trueness of measurement. Where a reference standard or method is not available, a method comparison study can be submitted. In this case equivalency with an established product should be documented.

• Measuring range of the assay. In the case that the product undergoing prequalification is a qualitative assay, please provide information on how the assay performs at both spectrums of analyte concentrations, i.e. at high and low levels.

• Validation of assay cut-off. For qualitative assays, data supporting the distinction between reactive and nonreactive test results should be submitted.



Analytical Studies. • Clearly identify the full name and product code of the device used

to perform the studies. NOTE: the product used for the studies must be the same undergoing prequalification!

• Submit the full study report: study protocol, method of data analysis (no raw data) and conclusions.



Clinical evidence (clinical or diagnostic sensitivity and specificity).• Clinical evaluation – Manufacturer.

• Provide evidence for clinical/diagnostic sensitivity, including seroconversion sensitivity; clinical/ diagnostic specificity ; and positive and negative predictive values (PPV and NPVs respectively) for different populations (high and low prevalence).

• Studies should take into account different clinical stages associated with infection from these organisms; geographical distribution; and organism specific attributes such as genotypic differences, and micro-organism life cycle.

• Clinical evaluation - Independent study. Provide details of at least one well-designed independent performance evaluation for the product under assessment.


Tips for success – compilation of the product dossierTips for success – compilation of the product dossier Stability (excluding specimen stability).

Clearly identify the full name and product code of the device used to perform the studies. NOTE: the product used for the studies must be the same undergoing prequalification!

• Claimed shelf life and storage conditions. Clearly define the conditions for individual reagents in the kit and the assembled kit for both, when unopened.

• In-use stability of buffer and device. Provide information on the stability of the buffer and the device after first opening. Consider external factors such as heat and humidity. Evaluate on products near the end of shelf life, and low positive samples should be used to challenge the assay.

• Shipping Stability. These studies can be performed under real and/or simulated conditions and should include variable shipping conditions such as extreme temperature (heat and/or cold), humidity, light and/or pressure, etc.



Labels and instructions for use (IFU). • All labels and IFU should indicate the product code(s). • Please submit all the foil packs, boxing, cartons, etc. and the actual

instructions for use, as provided in the test kit box.

Regulatory history.• Provide in a certified copy any regulatory approval obtained in any of

the countries of supply of the product undergoing prequalification. Copies may be certified by the manufacturer or by a notary public. Submit translations of the approvals when applicable.



ISO 13485:2003 certification. Certified copies of the current ISO 13485:2003 certificate should be submitted. The copies may be certified by the manufacturer or by a notary public.

Fast-track. In order to attempt to fast-track the assessment and inspection processes, please submit the two previous inspection reports issued by the certification body, related to the ISO 13485:2003 certification.


Useful ISO referencesUseful ISO references

Relevant ISO standards

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

ISO/TR 10013:2001 Guidelines for quality management systemdocumentation

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

ISO 17511: In vitro diagnostic medical devices - Measurement of quantities in biological samples - Metrological traceability of values assigned to calibrators and control materials

ISO 14155:2003 parts I and II Clinical investigation of medical devices for human subjects

ISO 23640:2011 In vitro diagnostic medical devices - Evaluation of stability of in vitro diagnostic reagents


Useful GHTF referencesUseful GHTF references

Relevant GHTF guidance

GHTF/SG1-N63:2011 Summary Technical Documentation (STED) for Demonstrating Conformity to the Essential Principles of Safety and Performance of In Vitro Diagnostic Medical Devices

GHTF/SG1/N41R9:2005 Essential Principles of Safety and Performance of Medical Devices

GHTF/SG1/N70:2011 Labelling for Medical Devices

GHTF/SG2-N54R8:2006 Medical Devices Post Market Surveillance: Global Guidance for Adverse Event Reporting for Medical Devices

GHTF/SG2-N57R8:2006 Medical Devices Post Market Surveillance: Content of Field Safety Notices


Useful CSLI referencesUseful CSLI references

Relevant CSLI Standards

EP07-02 Interfering testing in clinical chemistry, 2nd edition

EP25-A Evaluation of Stability of IVDs

EP5-A2 Evaluation of Precision Performance of Quantitative Measurement Methods, 2nd edition




Meets Requirements

DossierAssessment






WHO PQDx inspection requirementsWHO PQDx inspection requirements

The manufacturer must demonstrate that the IVD is produced under a functional quality management system e.g. conforms to ISO 13485:2003

Key Components

Quality management system including documentation requirements

Management responsibilityincluding customer focus, quality policy

Resource managementincluding human resources, work environment

Product realizationincluding production and service provision, control of monitoring and measuring devices

Measurement, analysis and improvementincluding control of nonconforming product, improvement


WHO PQ Dx inspections requirementsWHO PQ Dx inspections requirements

AND ALSO

Dossier submission data – to confirm is true

QC and lot release

WHO related/end user issues - IFU- stability (transport, in use, to expiry dates),- training- complaints reporting mechanisms


Tips for success - be ISO 13485 compliantTips for success - be ISO 13485 compliant

Ensure the basics to avoid common nonconformities– document control; adequately descriptive SOPs – records, raw data poorly kept or non existent– inadequate human resources – lack of qualified technical staff

capable of investigating quality problems, with regulatory experience, with quality management system expertise

– infrastructure poor - impossible to clean– lack of adequate identification and traceability through production

processes– lack of adequate quality control over in-process product – no

acceptable quality level (AQL) defined


Tips for success - be ISO 13485 compliantTips for success - be ISO 13485 compliant

Other common nonconformities to avoid– lack of control of critical key suppliers especially of outsourced

parts of manufacturing process– not QA department driven and not independent of production

management– risk management – documentation, analysis poorly done– process validation poor / no schedule to repeat validation /poor

understanding of validation – version control – unclear identification of product (not using

unique codes: is product that was PQed the same one as offered for sale)


Tips for success - Lot (batch) release dataTips for success - Lot (batch) release data

Ensure robust and scientifically sound lot release practices– Adequate sampling procedures of tests for QA/QC– Specimen panels should be challenging enough to detect

failure or drift– Independence and adequately staffed QA/QC department

Reporting procedures on deviations from expected result – Ensure corrective and preventive action reporting and

rectification

Monitor on-going stability


Tips for success – WHO customer focusTips for success – WHO customer focus

Ensure risk management– End user – literacy, particular training needs– Environment – hot, humid, dusty – IFU content

• accurate with evidence of claimed sensitivity and specificity • easy to interpret – pictures, diagrams, simple language, ‘executive

summary’ for ready reference• controlled document – version clearly identified


Tips for success - confirmation of dossier submissionTips for success - confirmation of dossier submission

Ensure access to evidence– Confirmation of studies e.g. stability studies

• Raw data must be readily available• Detailed laboratory reports

Submit two lots for WHO laboratory evaluations – Demonstrate through batch manufacturing records that the lots

are significantly different– Send test kits from a typical lot, not small lots specifically made

for submission for WHO testing.


Tips for success - avoid critical nonconformitiesTips for success - avoid critical nonconformities

Evidence of falsification of information – relating to batch release QC – submission of information for WHO dossier review – submission to WHO laboratory evaluation – organogram/staff positions.

Lack of evidence (raw data) onsite to support significant numbers of claims made in dossier e.g. stability testing, performance claims




Meets Requirements

DossierAssessment






Tips for success - Laboratory evaluationTips for success - Laboratory evaluation

Ensure two representative production lots are submitted– Batch manufacturing records will be verified upon inspection

Ensure readiness for laboratory evaluation, if dossier assessment and inspection scheduling are underway

Demonstration of test procedure by manufacturer may precede the commencement of the evaluation


In conclusionIn conclusion

Please read carefully the instructions for compilation of the product dossier and the information for manufacturers regarding inspection

– Contact us early, if there is anything that is not clearly understood

– Via our email address: [email protected]

We are available for one-on-one sessions by teleconference or face-to-face meetings

Documents

WHO Prequalification of Diagnostics – Tips for Success AIDS 2012 Satellite Session 25 July 2012, Washington DC Gaby Vercauteren Diagnostics & Laboratory