WHO Prequalification: Sample product dossier for a quantitative nucleic acid-based testing technology to measure HIV-1 RNA SIMU HIV-1 Quant Test PQDx 9876-543-22 THE Manufacturing Company
Disclaimer This Product Dossier is entirely fictitious and has been produced for illustrative purposes only. Each manufacturer must determine what should be submitted to fulfil World Health Organization prequalification assessment requirements.
WHO Sample product dossier for SIMU HIV-1 QUANT WHO prequalification: sample product dossier for a quantitative nucleic acid-based testing technology to measure HIV-1 RNA ISBN 978-92-4-151225-1
© World Health Organization 2017 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. WHO prequalification: sample product dossier for a quantitative nucleic acid-based testing technology to measure HIV-1 RNA. Geneva: World Health Organization; 2017. Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data. CIP data are available at http://apps.who.int/iris. Sales, rights and licensing. To purchase WHO publications, see http://apps.who.int/bookorders. To submit requests for commercial use and queries on rights and licensing, see http://www.who.int/about/licensing. Third-party materials. If you wish to reuse material from this work that is attributed to a third party, such as tables, figures or images, it is your responsibility to determine whether permission is needed for that reuse and to obtain permission from the copyright holder. The risk of claims resulting from infringement of any third-party-owned component in the work rests solely with the user. General disclaimers. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of WHO concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by WHO to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use.
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WHO Sample product dossier for SIMU HIV-1 QUANT
Table of contents
Table of contents TABLE OF CONTENTS ..................................................................................................... IV ABBREVIATIONS ........................................................................................................... VII ACKNOWLEDGEMENTS ................................................................................................ VIII Part I – Introductory information 1 1.1 1.1 1.2 1.3
1
INTRODUCTION ............................................................................................. 1 Purpose of the sample product dossier .....................................................................1 Content of the sample product dossier .....................................................................1 Completeness of the sample product dossier ............................................................1 Format of the sample product dossier ......................................................................1
2 3 3.1
INTENDED AUDIENCE ..................................................................................... 2 THE PRODUCT DOSSIER .................................................................................. 2 WHO product dossier elements ................................................................................2
Part II - The WHO sample product dossier 4 5 5.1 1.4
3
WHO PRODUCT DOSSIER CHECKLIST............................................................... 3 THE PRODUCT .............................................................................................. 12 Regulatory versions of this product ........................................................................12 Product description including variants (configurations) and accessories .................. 15 1.4.1 Product description.................................................................................... 15 1.4.2 Intended use .............................................................................................. 17 1.4.3 Intended testing population ...................................................................... 17 1.4.4 Intended users ........................................................................................... 17 1.4.5 Photographs of kit...................................................................................... 17 1.4.6 A general description of the principle of the test method or instrument principles of operation ............................................................ 18 1.4.7 A description of the components of the test (e.g. reagents, assay controls and calibrators) and the reactive ingredients of relevant components (e.g., antibodies, antigens, nucleic acid primers .................. 20 1.4.8 A description of the specimen collection and transport materials provided with the product or descriptions of specifications recommended for use. .............................................................................. 20 1.4.9 For Instruments of automated assays: a description of the appropriate assay characteristics or dedicated assays.............................. 21 1.4.10 For automated assays: a description of the appropriate instrumentation characteristics or dedicated instrumentation. ............... 21 Page iv
WHO Sample product dossier for SIMU HIV-1 QUANT 1.4.11
Table of contents
1.5 1.6
If applicable, a description of any software to be used with the product....................................................................................................... 21 1.4.12 If applicable, a description or complete list of the various configurations or variants of product that will be made available............ 21 1.4.13 If applicable, a description of the accessories, and other products that are intended to be used in combination with the diagnostic. ........... 21 Essential principles check list ..................................................................................22 Risk analysis and control summary .........................................................................22 1.6.1 Risk analysis policy ..................................................................................... 22 1.6.2 Risk categories ........................................................................................... 22 1.6.3 Instrument ................................................................................................. 24 1.6.4 Risk/Benefit................................................................................................ 25
6 6.0 6.1 6.1.1 6.1.2 6.1.3 6.1.4 6.3
DESIGN AND MANUFACTURING INFORMATION ........................................... 26 Design control ........................................................................................................26 Product design .......................................................................................................28 Design overview.....................................................................................................28 Formulation and composition.................................................................................30 Biological safety .....................................................................................................31 Documentation of design changes ..........................................................................31 Manufacturing process...........................................................................................32 6.3.1 Overview of manufacture .......................................................................... 32 6.3.2 Sites of manufacture .................................................................................. 34 6.3.3 Key suppliers .............................................................................................. 34
7 7.0 7.1 7.2 7.3 7.4
PRODUCT PERFORMANCE SPECIFICATIONS AND ASSOCIATED VALIDATION AND VERIFICATION STUDIES ................................................................................ 37 Overview of testing procedures ..............................................................................38 Analytical studies ...................................................................................................39 7.1.1 Specimen types .......................................................................................... 39 7.1.2 Analytical performance characteristics ..................................................... 41 Stability (excluding specimen stability) ...................................................................59 7.2.1 Claimed shelf-life (including transport challenge) ..................................... 59 7.2.2 In-use stability ............................................................................................ 62 Robustness studies ................................................................................................64 7.3.1 Cross-contamination .................................................................................. 64 7.3.2 Whole system failure ................................................................................. 65 Clinical evidence (clinical sensitivity and specificity) ................................................66 7.4.1 Clinical Evaluation by manufacturer .......................................................... 66
8 8.1 8.2 8.3
LABELLING ................................................................................................... 69 Labelling ................................................................................................................69 8.1.1 Instrument labelling ................................................................................... 69 8.1.2 Test Cartridge pouch packaging and labelling (Figure XXY) ....................... 69 Instructions for Use ................................................................................................69 Instrument manual ................................................................................................70
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WHO Sample product dossier for SIMU HIV-1 QUANT
Table of contents
9 9.1
COMMERCIAL HISTORY ................................................................................ 71 Countries of supply ................................................................................................71 9.1.1 List of countries where product is currently supplied ............................... 71 9.1.2 Minimum and maximum price in 2015...................................................... 71 9.1.3 Training and support network ................................................................... 71 Adverse events and field safety corrective actions ..................................................71 9.2.1 Table of adverse event reports .................................................................. 71
9.2
10 11 11.1 11.2
REGULATORY HISTORY ................................................................................. 72 QUALITY MANAGEMENT SYSTEM................................................................. 73 Quality manual ......................................................................................................73 11.1.1 Quality management system documents .................................................. 73 11.1.2 Quality management system procedures.................................................. 73 Quality management system certification ...............................................................73
ANNEX I: ESSENTIAL PRINCIPLES CHECKLIST ................................................................... 74 ANNEX II: RISK MANAGEMENT POLICY........................................................................... 95 ANNEX III: RESIDUAL RISK STATEMENT .......................................................................... 97 ANNEX IV: DESIGN INPUTS FMEA ................................................................................... 98 ANNEX V: USER AND PATIENT FMEA ............................................................................ 104 ANNEX VI: INPUT REQUIREMENTS FOR THE HIV-1 QUANT TEST ................................... 106 ANNEX VII: THE MANUFACTURING COMPANY QUALITY MANUAL ........................ 113
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WHO Sample product dossier for SIMU HIV-1 QUANT
Abbreviations
Abbreviations CAPA cDNA CE CI CLSI DHF DMR EDTA FDA FMEA GHTF HTLV IFU IMDRF ISO IU IVD LoD NAT OEM PCR QA QC QMS qPCR R&D RT SD SOP VL WHO corrective and preventive action complementary DNA Conformité Européenne (European Conformity) confidence interval Clinical and Laboratory Standards Institute design history file device master record ethylenediaminetetraacetic acid US Food and Drug Administration failure mode and effects analysis Global Harmonization Task Force human T-cell lymphotropic virus instructions for use International Medical Devices Regulators Forum International Organization for Standardization international units in vitro diagnostic medical device limit of detection nucleic acid-based testing technology original equipment manufacturer polymerase chain reaction quality assurance quality control quality management system quantitative PCR research and development reverse transcriptase standard deviation standard operating procedure viral load World Health Organization
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WHO Sample product dossier for SIMU HIV-1 QUANT
Acknowledgements
Acknowledgements The sample dossier WHO Prequalification: Sample product dossier for a Quantitative HIV-1 nucleic acid-based testing technology was developed with support from the Bill & Melinda Gates Foundation and UNITAID. The draft document was prepared in collaboration with Dr C Hill, Encinitas, USA and Dr J Saldanha, Immucor, Norcross, USA; Ms D Healy, and Ms R Meurant, WHO, Geneva, Switzerland and with input and expertise from Dr E Cowan, MA, USA; Dr F Gruszka, Paris, France; Dr M Lanigan, Geneva, Switzerland; and Ms M Perez Gonzalez, WHO, Geneva, Switzerland. This document was produced under the coordination and supervision of Ms D Healy, Ms R Meurant and Ms I Prat, Prequalification team – Diagnostic Assessment, WHO, Geneva, Switzerland.
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WHO Sample product dossier for SIMU HIV-1 QUANT
Introduction
Part I – Introductory information
1 Introduction 1.1 Purpose of the sample product dossier The purpose of this sample product dossier is to provide manufacturers with an example of a product dossier required for WHO prequalification of an in vitro diagnostic medical device (IVD). The product dossier should contain evidence submitted by the manufacturer to demonstrate to WHO that the IVD is of acceptable quality, is safe and performs optimally when used as intended by the manufacturer. Evidence will take the form for example, of results of testing, certifications, standard operating procedures (SOPs), systems and any other documentation necessary to support quality, safety and performance. As such, this sample product dossier contains the results of testing, extracts of SOPs and other information that may be of relevance in support of an application for prequalification of a simple, rapid molecular diagnostic test for HIV-1 infection.
1.1 Content of the sample product dossier This dossier is based on a fictitious IVD, the SIMU Quantitative HIV-1 NAT assay and its fictitious manufacturer, THE Manufacturing Company. As the product and its manufacturer do not exist, any related aspects that have been described within the sample product dossier are purely for the purposes of demonstrating the type of information that may be included in a product dossier submitted to WHO Prequalification.
1.2 Completeness of the sample product dossier Because of its invented nature, the information provided is an example only and does not necessarily contain the full level of detail that may be required to fulfil WHO Prequalification requirements. At times the information is presented in summary format. Additionally, the abbreviation “XXX” is used extensively to describe materials that do not exist, but again is incorporated to provide an example of the type of information that may be required. Further instructions are also provided in blue coloured boxes to indicate where additional information may be expected. This sample product dossier can never be considered to represent all the evidence that may be needed to meet WHO Prequalification requirements. Alternative approaches to the studies presented in this sample dossier may also be acceptable. Each manufacturer is responsible for identifying the type and volume of evidence that will be sufficient to support its submission. WHO Prequalification staff is available to assist manufacturers at any point in the prequalification process. Staff may be contacted by email at diagnostics@who.int.
1.3 Format of the sample product dossier The format of this sample product dossier, including the section numbering system, follows that contained in WHO document PQDx_018 “Instructions for Compilation of a Product Dossier” which can be found on the WHO Prequalification of IVDs website http://www.who.int/diagnostics_laboratory/en/
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WHO Sample product dossier for SIMU HIV-1 QUANT
The Product Dossier
2 Intended Audience This document has been created to assist manufacturers applying to WHO prequalification who are submitting a product dossier for a quantitative nucleic acid-based testing technology measuring HIV1 RNA.
3 The Product Dossier 3.1 WHO product dossier elements For the purposes of WHO Prequalification, the product dossier is a selection of records and documents compiled by a manufacturer from their existing records and documents to provide evidence that the IVD submitted for WHO prequalification assessment conforms to the Essential Principles of Safety and Performance of Medical Devices, available at (http://www.imdrf.org/docs/ghtf/final/sg1/technical-docs/ghtf-sg1-n68-2012-safety-performancemedical-devices-121102.pdf) and meets WHO requirements. During the WHO review of a product dossier, WHO will take into account the information that was previously submitted in the WHO document PQDx_015 “Prequalification of Diagnostics – Presubmission form”, available on the WHO Prequalification – Diagnostic Assessment website. Therefore, manufacturers should ensure that the content of the product dossier is consistent with the information submitted with the pre-submission form and that WHO be promptly notified of any changes in the information submitted with the respective pre-submission form by email at the email address diagnostics@who.int. Furthermore, WHO prequalification will communicate to the manufacturer any issues identified in the pre-submission form that needs to be addressed in the product dossier submission. WHO sample product dossier starts on next page
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WHO Sample product dossier for SIMU HIV-1 QUANT
WHO Product Dossier Checklist
Part II - The WHO sample product dossier
4 WHO Product Dossier Checklist The attached product dossier contains information in support of the previously submitted Prequalification of Diagnostics – Pre-submission form (WHO document PQDx_015) for the following product: PQDx Number: Product Name: Manufacturer Name: PQDx SIMU HIV-1 Quant System
THE Manufacturing Company
PRODUCT DOSSIER CHECKLIST WHO require manufacturers to complete the WHO document PQDx_049 1 Product Dossier Checklist as part of the product dossier submission Dossier Content Requirement Provided Yes/No Location: Volume/Section Page number – Page number (illustrative)
Letter of Agreement The Letter of Agreement is attached to the front page of the dossier and supports attestation of payment The information concerning the product is the same on the Letter of Agreement and the Prequalification Dossier 4. Dossier Format 4.1. Product Dossier Submission Format One printed copy and one electronic copy of product dossier submitted A signed document attesting that the content of the electronic version is an exact duplicate of the printed copy was submitted Dossier is clearly presented (bound or in a clearly marked set of ringbinders) 4.2. Layout and Order Proper formatting of 1 of 2, 2 of 2, etc., used The submission is clearly divided into sections as described and all pages are numbered Table of contents included This checklist is attached to the front of the submission and used as a cross-reference 1
Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes Yes Yes/No Yes Yes Yes/No Entire dossier Entire dossier Entire dossier
WHO document PQDx_049 Product dossier checklist is available at http://www.who.int/diagnostics_laboratory/evaluations/140701_pqdx_049_dossier_checklist_v2.pdf?ua=1
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WHO Sample product dossier for SIMU HIV-1 QUANT Dossier Content Requirement The physical pages of the dossier and the page numbers correspond There are appropriately named tab identifiers Standard A4 paper is used for all submissions Font sizes are easily legible 4.2.1. Electronic Copy Requirements The electronic copy is in PDF form with no password required The electronic copy is organized in the same format as the printed copy The name of the file is descriptive and doesn’t contain any of the noted special characters 4.3. Language and Units of Measurement English language and units of measure used Any translations must have been carried out by a certified translator 5. Product 5.1. Regulatory versions of this product All regulatory versions of the product are identified and the version being submitted for assessment is indicated For all submissions, the regulatory version to which it relates is identified 5.2. Product description including variants (configurations) and accessories The intended use of the diagnostic, testing population, user, and setting of use for the diagnostic is included Photographs of all kit components, both packaged and individual, are included A description of the principle of the assay method/instrument principles of operation are provided A description of the components and reactive ingredients are included A description of the specimen collection and transport materials are provided A description of the appropriate assay and instrumentation characteristics are included If applicable, there are descriptions of software to be used with the product, a list of variants/configurations of the product, and a description of accessories are included 5.3. Essential principles checklist A checklist in the form of a table that lists all relevant material is included 5.4. Risk analysis and control summary There is a summary report of the risks identified during the risk analysis process A description of how risks have been controlled to an acceptable level Provided Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes Yes/No Yes/No Yes Yes Yes Yes Yes Yes Yes Yes/No
WHO Product Dossier Checklist Location:
Page 12
Page 15 Page 17 Page 17 Page 18 Page 20 Page 20 Page 21 Page 21
Yes Yes/No Yes Yes/No Yes/No
Page 21 and Annex I
Pages 22–25 and Annex II
Page 4
WHO Sample product dossier for SIMU HIV-1 QUANT Dossier Content Requirement A signed conclusion with evidence that the remaining risks are acceptable is presented There is evidence that the risk analysis is part of the manufacturer’s risk management plan When applicable, specific standards/guidelines recommended by the WHO are identified 6. Design and manufacturing information 6.1. Product design 6.1.1. Design Overview Information to provide a general understanding on design is provided There is a flowchart of the design process A general description of the critical assay ingredients for use with the product is provided If applicable, a controlling site is identified 6.1.2. Formulation and composition For each of the ingredients, formulation/composition information is provided Sources of IVD component materials are identified 6.1.3. Biological safety There is a table, including all required information, listing all biological components included in the product If applicable, a determination of the residual risk of transmission/infection to the user is provided There is information on how users of the device are informed of any residual risk 6.1.4. Documentation of design changes Records of each design change for the product submitted, with all pertinent information, is included 6.2. Manufacturing process 6.2.1. Overview of manufacture A flow chart of the entire manufacturing process is included A site master file, with a diagram of the floor plan, is provided If applicable, certified copies of quality management system certificates are annexed to the dossier There are details of each major step in the manufacturing process (e.g. as flow charts) There is an overview of verification, validation, and quality control activities for all stages of design and manufacture Batch release criteria for the product are included 6.2.2. Sites of manufacture All critical manufacturing sites for all stages of manufacture are listed and information on each site Provided Yes/No Yes/No Yes/No Yes Yes Yes Yes/No Yes/No Yes/No Yes/No Yes Yes/No Yes/No Yes Yes/No Yes/No Yes/No Yes Yes/No Yes Yes/No Yes/No Yes Yes/No Yes/No Yes/No Yes Yes/No Yes/No
WHO Product Dossier Checklist Location: Annex III
Pages Error! Bookmark not defined.–34 Page 28 Page 28
Page 30
Page 31
Page 31
Page 32
Annex XXX
Page 34, verification reports AXXXX and BXXXX
Page 5
WHO Sample product dossier for SIMU HIV-1 QUANT Dossier Content Requirement 6.2.3. Key suppliers All key suppliers are listed with all required information If applicable, certified copies of the key suppliers’ certificates are annexed to the dossier 7. Product performance specifications and associated validation and verification studies with the following information provided for each section • The complete study protocol • The methods of data analysis • The complete study report (signed and dated), including the study conclusion. 7.1. Analytical studies 7.1.1. Specimen types The different specimen types that may be used with the product are identified Studies to support each specimen type are included The studies and required information to support stability, storage and where applicable transport condition claims for each specimen type are included 7.1.2. Analytical Performance Characteristics 7.1.2.1. Accuracy of Measurement 7.1.2.1.1. Trueness of Measurement Studies to establish trueness of measurement are provided 7.1.2.1.2. Precision of Measurement 7.1.2.1.2.1. Repeatability Studies and information needed to establish within-run variability are included If applicable, studies to establish repeatability undertaken by nonlaboratory personnel should be provided 7.1.2.1.2.2 Reproducibility Studies and information to establish variability between-days, runs, sites, lots, operators and instruments are included The use of specimens that represent the full range of expected analyte concentration are included If applicable, provide studies to establish reproduciblity undertaken by non-laboratory personnel 7.1.2.2. Analytical sensitivity Provided Yes/No Yes/No Yes/No Yes/No
WHO Product Dossier Checklist Location: Page 34
Pages 37 and following
Yes/No Yes/No Yes/No Yes/No Yes/No Pages 39–xx
Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Page 46 and Annex X (Results of analytical sensitivity Study)
Studies required to establish analytical sensitivity are included If applicable, the relevant parameters and detail on their derivation is provided
Yes/No Yes/No
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WHO Sample product dossier for SIMU HIV-1 QUANT Dossier Content Requirement 7.1.2.3. Analytical Specificity Provided Yes/No
WHO Product Dossier Checklist Location: Page 51 (Cross-reaction with unrelated medical conditions) and XXX (Exogenous interfering substances)
Studies to evaluate the effects of potentially interfering and crossreacting substances/agents on the assay are included The studies provided consider common infectious agents and related treatments for patients in resource limited settings in WHO Member States including those in Africa and Asia. 7.1.2.4. Metrological Traceability of Calibrators and Control Material Values There is detailed information about the traceability of values assigned to calibrators and control materials supplied with the assay (if applicable) and those used in the manufacturing process. 7.1.2.5. Measuring range of the assay
Yes/No
Yes/No Yes/No
Yes/No
Pages 57-xx and Annexes X (Linearity study), XXX (Limit of detection study) and X (Method correlation study)
Studies that define the measuring range of the assay are included and a description of how they were established 7.1.2.6. Validation of Assay Cut-off Studies on how the assay cut-off is determined are included 7.1.2.7. Validation of Assay Procedure-reading time Studies on how the reading time was determined are included 7.2. Stability (excluding specimen stability) When applicable, the manufacturer has looked to internationally accepted methods for determining stability of IVDs and followed WHO recommendations for stability 7.2.1. Claimed shelf-life including transportation challenge
Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No
Yes/No
Pages 59–xxx and Annex XX (Study protocol SHST XXX); Full study report Annex XXX
Transportation challenge studies are conducted on at least three different lots manufactured under conditions equivalent to routine production conditions Transportation challenge studies are conducted under simulated conditions that reflect the anticipated transport and environmental conditions to the countries of supply, along with justification All lots are moved into real-time stability studies The study protocol specifies acceptance criteria and testing intervals Accelerated studies/extrapolated data are acceptable for initial shelf-life claim, but have been/will be followed up with real-time stability studies If applicable, the method used for accelerated studies is identified The shelf-life is derived from the lot with the shortest real-time stability data Yes/No Yes/No
Yes/No Yes/No
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WHO Sample product dossier for SIMU HIV-1 QUANT Dossier Content Requirement The results and conclusions must clearly demonstrate that the product will be effective at the end of its claimed shelf-life after being subjected to the stressed conditions 7.2.2. In-use stability Provided Yes/No
WHO Product Dossier Checklist Location:
Yes/No
Page 62Error! Bookmark not defined. and Annex XXX (In-use stability study)
Studies are provided for the in-use stability of each assay component For each component, testing is conducted on at least one lot The studies reflect routine use of the device (open vial stability and/or on-board stability and/or multiple access of reagent bottles) The study protocol specifies acceptance criteria and testing intervals If applicable, supporting data for calibration stability claims is provided Conclusions clearly identify the claimed in-use stability 7.3. Robustness studies
Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Pages 64–xx and Annexes X (Cross-contamination study) and X (whole system failure study)
There is a summary of all evidence for the robustness study(ies) The test environment and its relation to the intended environment are stated There is a discussion of what tests were considered for the device and why they were/were not performed There is a discussion to support why the evidence presented is sufficient to support the application If a performance study has been conducted in different sections of the product dossier that includes human factors/usability end points, reference to the studies and endpoints should be made 7.4. Clinical Evidence (Clinical or Diagnostic Sensitivity and Specificity) 7.4.1. Clinical evaluation - manufacturer
Yes/No Yes/No Yes/No Yes/No Yes/No
Yes/No Yes/No Pages 66–xx and Annexes XX (Clinical specificity study) and X (Clinical sensitivity study)
All performance claims are supported by well-designed performance evaluations that have been carried out or coordinated by the manufacturer and these studies are included with all relevant information 7.4.2. Clinical evaluation - independent study There are details of at least one well-designed independent performance evaluation for the product under assessment If applicable, publication details of the independent study(ies) is included 8. Labelling The product dossier contains a complete set of labelling associated with the product
Yes/No
Yes/No Yes/No Yes/No Yes/No Yes/No Page 69
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WHO Sample product dossier for SIMU HIV-1 QUANT Dossier Content Requirement 8.1. Labels Copies of all outer and component labels for the assay are included and contain all required information 8.2. Instructions for use A copy of the current instructions for use are included and these instructions include all relevant information 8.3. Instrument manual If applicable, there is a copy of the instrument manual/associated operator manuals included 8.4. Any other instructional materials provided to the user If applicable, any other instructional material copies are provided 9. Commercial History 9.1. Countries of Supply There is a list of all countries in which the product under assessment is currently supplied and the year when supply started For each country, detailed information about the training and support network is provided The minimum and maximum global price of supply for the product for the last financial year are included (quote in US dollar) 9.2. Adverse events and field safety corrective actions A list of all adverse events within the last five years with details of the corrective and preventive action taken is provided A list of all events within the last five years that required field safety corrective action is provided 10. Regulatory history If applicable, include a list of National Regulatory Authorities that have provided current regulatory approval for the supply of the IVD under assessment and the type of regulatory approval obtained Current evidence of the regulatory approval, such as certified copies, must be included If applicable, details regarding any situations in which the product was rejected or approval was withdrawn by a National Regulatory Authority or the application was withdrawn by the manufacturer Information relating to the export-only regulatory approvals are clearly identifiable 11. Quality Management System 11.1. Quality manual system documents and procedures There is a copy of the current version of the manufacturer’s quality manual with all required information An organizational chart for the manufacturer is provided A complete list of all valid quality management systems documents is included Documented procedure/s for the control of design and development changes are included Provided Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No
WHO Product Dossier Checklist Location: Page 69
Page 69 and Annex XX
Page 71 and Annex XX
Page 71
Page 72 and Annex XX
Yes/No Yes/No
Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Pages 73–xx and Annex VIII (Quality manual)
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WHO Sample product dossier for SIMU HIV-1 QUANT Dossier Content Requirement Documented procedure/s relevant to risk management planning and implementation are included Documented procedure/s relevant to control of non-conforming goods are included Documented procedure/s relevant to the control of the key suppliers are included 11.2. Quality Management System Documents If applicable, certified copies of ISO 13485 certificates provided clearly demonstrate that the manufacture of the product under assessment is within the scope of the certification The two previous inspection reports issued by the certification body are included Essential Principles Checklist This checklist is filled in as per the description and examples provided in the instructions Provided Yes/No Yes/No Yes/No Yes/No Yes/No
WHO Product Dossier Checklist Location:
Yes/No Yes/No Yes/No Annex I, page 74
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WHO Sample product dossier for SIMU HIV-1 QUANT Manufacturer Declaration:
WHO Product Dossier Checklist
The undersigned authorized contact person for the Manufacturer makes the following declarations on behalf of the Manufacturer and, in signing this product dossier checklist form, declares that he/she has the authority to bind the Manufacturer. I declare that: • • • • • I am authorized to represent the manufacturer specified in this prequalification product dossier (the "Manufacturer") for the purposes of WHO Prequalification of Diagnostics of the product specified in this product dossier (the "Product"). All the information provided in this product dossier is current and correct. This product dossier contains all the information as is prescribed in WHO Publication PQDx 018 “Instructions for compilation of a Product Dossier”. The Manufacturer will notify WHO of all changes and variations to the Product prior to implementation of the changes. The Manufacturer will notify WHO of any changes to the regulatory approval status for the Product, such as suspension or withdrawal of regulatory approval, in all countries of manufacture and supply.
Name of the Authorized Contact Person for the Manufacturer: Alan Bloggs Signature of the Authorized Contact Person for the Manufacturer: Alan Bloggs Date: 01 September 2016 Please Note: The Checklist submitted to WHO must be signed and dated.
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WHO Sample product dossier for SIMU HIV-1 QUANT
The Product
5 The Product 5.1 Regulatory versions of the product The SIMU HIV-1 Quant Test is comprised of two components: the SIMU HIV-1 Quant Test Cartridge and the SIMU Instrument. SIMU HIV-1 Quant Test Cartridge: The regulatory version submitted to WHO is the rest of world version. The test kit is not sold in Europe. SIMU Instrument: There is only one regulatory version of the SIMU Instrument. This version has Conformité Européene/ European Conformity (CE )marking. The test kit is available in the following configurations Table 5-1: Test kit configuration and accessories Configuration 25 Test Cartridge kit Product code M123 Contents/Component description 25 x individual waterproof pouch containing a Test Cartridge and desiccant 25 x IFU 100 x individual waterproof pouch containing a Test Cartridge and desiccant 100 x IFU 1 x 2.5 ml bottle
100 Test Cartridge kit
M124
SIMU Positive Controls (Non-infectious HIV-1 Armored RNA in defibrinated human plasma) SIMU Negative Controls (HIV-1 negative defibrinated human plasma) SIMU Instrument
CONTP 1234
CONTN 4321
1 x 2.5 ml bottle
X01111
1x SIMU Instrument 1 x backpack 1 x battery 1 x power cord 1 x printer 1 x instrument manual
The Test Cartridge kit is shipped to distributors in secondary packaging as described in Section 8 Labelling of this dossier.
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WHO Sample product dossier for SIMU HIV-1 QUANT
The Product
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WHO Sample product dossier for SIMU HIV-1 QUANT
The Product
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WHO Sample product dossier for SIMU HIV-1 QUANT
The Product
5.2 Product description including variants (configurations) and accessories 5.2.1 Product description The SIMU HIV-1 Quant Test is a nucleic acid-based testing technology utilizing specific nucleic acid target capture, specimen processing and real-time quantitative reverse transcription PCR (RT qPCR) amplification and fluorescence detection in a small, self-contained Test Cartridge. The SIMU HIV-1 Quant Test Cartridge consists of a solid plastic body with a Test Cartridge cap that covers the Specimen Port (Figure 5-2). Each Test Cartridge is completely self-contained and prefilled with all reagents needed for the test. The cartridge is used together with the SIMU Instrument (Figure 5-4). Specifications for the Instrument are outlined in Table 5-3. The Instrument is a small and easily portable by handle or backpack. The Instrument is fully automated after insertion of the Test Cartridge and operates with a rechargeable battery. All operations are controlled on the Instrument and results may be read on the Instrument screen or output to a computer or printer. The Instrument reads one Test Cartridge at a time, but multiple Instruments may be combined together to increase throughput. The Instrument is classified as an in vitro diagnostic medical device. The SIMU HIV-1 Quant Test is capable of processing small volumes (50 µL) of plasma. The appropriate volume of plasma is applied directly into the SIMU HIV-1 Quant Test Cartridge. Plasma is added directly into the SIMU HIV-1 Quant Test Cartridge via the Specimen Port using precision pipetting. The amount of specimen volume delivered into the Specimen Port may be visualized through the Specimen Detection Port window on the Test Cartridge. Specimen is added until it reaches the gradation mark in the Specimen detection port window. Once specimen is introduced, the cap to the port is closed and the Test Cartridge is loaded into the SIMU Instrument. The Test Cartridge consists of several internal chambers including both liquid reagents and a buffer reservoir connected by microfluidic channels. Air and liquid movement through the Test Cartridge is regulated by the Instrument using valves within the cartridge. Once the Test Cartridge is loaded into the Instrument and the test run is initiated, the specimen is delivered into the reaction chamber where the HIV RNA is extracted. All excess specimen and liquid waste produced during the test is sealed within the Test Cartridge to reduce the possibility of contamination. Once the Test Cartridge is used, it cannot be opened or reused. The real-time RT qPCR reaction takes place in the reactor chamber of the Test Cartridge. Fluorescent signal generated from the specimen and the specimen processing control is detected and interpreted by the system software. The results appear on the Instrument screen and also as output to a computer or printer. The entire time to result after initiation of the test run is 45 minutes.
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WHO Sample product dossier for SIMU HIV-1 QUANT Figure 5-2. Diagrams of the SIMU HIV-1 Quant Test Cartridge Top: external view; Bottom: cutaway showing internal components.
The Product
Specifications of the SIMU Instrument are given below in Table 5-3 Table 5-3: Specifications of the SIMU Instrument
Device dimensions/weight Detection test Languages Memory Software Operating conditions (°C, humidity, altitude) Storage conditions Rated voltage Alternative charging options Built-in voltage surge protection
Depth 12 cm; Width 23 cm; Height 35 cm; Weight 8.5 kg Fluorimeter English, French, Portuguese, Spanish 2 GB RAM, 100 GB Flash Storage Version 10.6.8 12-45 °C, 5-95 % Relative Humidity, up to 3500 metres 2-55 °C 100-240 volts, 50-60 Hertz May be run off 24 v DC power (e.g., solar panels or batteries) External uninterruptible power source and battery back-up Page 16
WHO Sample product dossier for SIMU HIV-1 QUANT
The Product
5.2.2 Intended use
Weight 3kg (product code 5555)
The SIMU HIV-1 Quant Test is a quantitative nucleic acid-based testing technology for the quantification of HIV type 1 groups M, N and O RNA in plasma specimens from individuals suspected of HIV-1 infection. The results of this test are intended to be used in conjunction with other markers of disease progress for the clinical management of HIV-1 patients. The assay quantitates from 200 to 10 million copies of HIV-1 RNA per ml. It assesses patient prognosis by measuring the changes in RNA levels during the course of antiretroviral therapy. The SIMU HIV-1 Quant Test is for in vitro diagnostic use only. This assay is not intended to be used for screening of blood donors nor as a part of a diagnostic testing algorithm for HIV. The assay may be used in laboratory environments.
5.2.3 Intended testing population It is intended for us in HIV-1 patients including patients on antiretrotviral therapy.
5.2.4 Intended users The SIMU HIV-1 Quant System is intended to be used by trained healthcare or laboratory professionals or other health care workers who have received appropriate training.
5.2.5 Photographs of kit Insert photographs of all kit configurations with all components and accessories collectively and individual components and accessories, in and out of any packaging. Figure 5-4: Illustration of the SIMU Instrument and backpack
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The Product
5.2.6 A general description of the principle of the test method or instrument principles of operation 5.2.6.1 Specimen handling and processing The specimen volume required is a minimum of 50 µL. When using ethylenediaminetetraacetic acid (EDTA) anti-coagulated plasma, the appropriate volume is transferred into the specimen port by using precision pipetting. Once the specimen is added to the port, the chamber will fill to a line visible on the chamber. Insufficient specimen volume may be clearly seen by the meniscus and additional volume may be added. Once the specimen is added to the cartridge, and the cartridge cap is snapped closed, the cartridge may be stored up to 24 hours from 20–45°C before inserting into the SIMU Instrument and performing the test. After delivering the specimen to the Test Cartridge, the cartridge cap is snapped into place, eliminating the chance of specimen spillage or contamination of the Instrument. The Test Cartridge is inserted into the SIMU Instrument, the patient name and identification number is entered using the keypad on the Instrument touchscreen, and the start button is pressed to initiate the testing. The steps in the following subsections are performed automatically by the SIMU Instrument within the Test Cartridge.
5.2.6.2 RNA target processing Once the start button is pushed, the instrument scans the bar code on the Test Cartridge and a measured aliquot of the specimen is injected into the reaction chamber. A protease and chaotropic lysis buffer is injected into the chamber to solubilize the viral envelope, denature proteins, and release viral RNA. The lysis buffer also contains a specimen processing control. The specimen process control consists of an Armored RNA construct that is co-processed and co-amplified with the HIV targets and controls for the effectiveness of specimen processing, degradation of enzymes, amplification, and specimen inhibition. The reaction chamber contains magnetic microparticles conjugated with capture oligonucleotides complementary to highly conserved regions of the HIV genome (Table 5-5). Selection of the target RNA sequence for HIV-1 was performed using regions within the HIV-1 genome that have maximum sequence conservation among HIV-1 groups M, N, and O. Failures with mono-target HIV-1 NAT assays have been documented for HIV-1 M strains (Chudy, M. et. al., 2012, Transfusion 52(2): 431-439, Fearon M et al, 2016, Transfusion 56(4): 994-995). Dual target primer and probe sequences were therefore selected (two different amplicons are generated with different primer sets, with the amplicons being detected by different probes). The assay was designed with two or more target regions for group M (the most frequent representative group) in addition to amplification of group N and O. The HIV RNA and the specimen process control RNA are specifically bound to the capture oligonucleotides on the magnetic microparticles. The particles are drawn to an electromagnet and washed to remove extraneous components such as salts, proteins and cellular debris. The waste wash solution is moved to the liquid waste chamber within the Test Cartridge. The amplification reagents are described in Table 5.5.
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The Product
Table 5-5: Capture, primer and probe sequences and the region they are derived from for HIV-1 M (dual target)/N/O and specimen process control Oligonucleotide HIV-1 forward primer 1 HIV-1 reverse primer 1 HIV-1 Taqman Probe 1 HIV-1 forward primer 2 HIV-1 reverse primer 2 HIV-1 Taqman Probe 2 HIV-1 capture Specimen process control forward primer Specimen process control reverse primer Specimen process control Taqman probe Specimen process control capture Sequence 5’-xxxxxxxxxxxx-3’ Sequence identifier xx Region sequence derived from xx
The table is provided as an example of how the data may be presented in the product dossier submitted to WHO. The sequence information is expected to be provided by the manufacturer. All proprietary information will be kept confidential by WHO.
5.2.6.3 Real-time HIV target amplification and detection Target amplification and detection of the HIV RNA captured on the microparticles is performed using real-time RT qPCR. Prior to PCR amplification, RNA is reverse transcribed into cDNA. Specific DNA primers hybridize to the RNA target and form a DNA-RNA hybrid. An rTth DNA polymerase then transcribes the RNA into its complementary cDNA by extending the oligonucleotide primer. Reverse transcription is followed by a heat denaturation step to deactivate the reverse transcriptase and separate the RNA-DNA hybrid to make the newly formed cDNA accessible for primer binding and extension by PCR. This real-time multiplex PCR reaction utilizes hydrolysis probes to detect the DNA produced during the PCR reaction. The hydrolysis probes consist of oligonucleotides specific for regions of the HIV cDNA molecules and have a reporter fluorophore covalently attached to one end of the probe and a quencher at the other end. When the probes are intact, the reporter and quencher molecules stay close to each other preventing the emission of fluorescence. Two specific probes with the same fluorophore are used to target two different highly conserved regions of HIV-1 (Group M/N/O). A third specific probe with a unique fluorophore is used to detect the SP control. The HIV target DNA and cDNA created during the reverse transcription step bind specific primers and probes. rTth DNA polymerase extends the primers and during the process cleaves the probe that separates the reporter and quencher molecules allowing the reporter molecules to emit fluorescence. The Instrument automatically repeats the PCR cycle for a designated number of cycles, with each cycle doubling the amount of DNA amplicon and increasing the emission intensity of the individual fluorophores. The amplification of the HIV-1 RNA and specimen process control is measured independently at different wavelengths to quantitatively determine the presence or absence of the targets. Since the specimen process control is added to each specimen at a known copy number, the Instrument calculates the RNA concentration in the test specimens by comparing the HIV-1 signal to the specimen process control signal for each specimen. The test quantitates HIV-1 RNA over the range of 200 to 10 million copies/mL. The Instrument system software interprets the results that are read on the Instrument screen or downloaded to a computer or printer. An example of a test report is shown in Figure 5-6.
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WHO Sample product dossier for SIMU HIV-1 QUANT Figure 5-6: Example of SIMU HIV-1 Quant Test report Specimen Identifier 334-4567 HIV-1 Result 5530 copies/mL Date/Time 2015 FEB 10 10:00hr Test Cartridge Identifier 034289833 Test Cartridge Serial number 0023456 Software version 10.06.8 Specimen Process Control Pass ………
The Product
5.2.7 A description of the components of the test (e.g. reagents, assay controls and calibrators) and the reactive ingredients of relevant components (e.g., antibodies, antigens, nucleic acid primers The SIMU HIV-1 Quant consists of the dedicated components described in Table 5-7. Table 5-7: Description of components of the assay Configuration 25 Test Cartridge test kit Product code M123 Contents 25 x individual waterproof pouches containing a Test Cartridge and desiccant 25 x IFU 100 x individual waterproof pouches containing a Test Cartridge and desiccant 100 x IFU
100 Test Cartridge test kit
M124
The SIMU HIV-1 Quant Test Cartridge comes in two pack sizes (Table 5-7). The reagents for the system are contained in the SIMU HIV-1 Quant System Test Cartridge. The Test Cartridge includes all the materials needed for the test including probes, primers, control oligonucleotides and microparticles. The nucleic acids are in an inorganic buffering solution containing bactericides and fungicides. Positive and negative external controls are available to ordered individually and should be used in accordance with IFU instructions. Further information on the reactive ingredients can be found in table 5-5 and in section 6.1.
5.2.8 A description of the specimen collection and transport materials provided with the product or descriptions of specifications recommended for use. The device has been validated for use with plasma specimens using EDTA as an anticoagulant. Plasma specimens in EDTA tubes can be stored for 48 hours at 2–8°C or stored frozen indefinitely at -20 °C or less. Avoid more than three freeze-thaw cycles.
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The Product
5.2.9 For Instruments of automated assays: a description of the appropriate assay characteristics or dedicated assays See Section 5.2.1, Product Description
5.2.10 For automated assays: a description of the appropriate instrumentation characteristics or dedicated instrumentation. The SIMU Instrument is used for the SIMU HIV-1 Quant Test assay and is also able to run the entire line of SIMU nucleic acid-based testing technology assays. It is a small, free-standing bench-top instrument easily portable by hand or backpack. The Instrument has one slot for Test Cartridge insertion and a simple touch screen control panel interface for inputting patient information and initiation of the assay run. Once the patient information is entered and the start button is pushed, the Instrument will scan the Test Cartridge barcode and match the patient information to the specimen. The Instrument is fully automated after insertion of the Test Cartridge and is powered with an integrated rechargeable battery. The battery operates up to 8 hours if there is an unexpected interruption to the power supply. A supplemental rechargeable battery weighing 3 kg (product code 5555) is also available that powers the Instrument for up to 24 hours. All operations are controlled on the Instrument and results may be read on the Instrument screen or output to a computer or printer.
5.2.10.1 Data export and connectivity The Instrument transmits instrument and test information in real-time to computers, mobile devices, and printers via wireless internet and USB connections The Instrument is water resistant and able to withstand temperature extremes, dust, high altitude, and high humidity. The instrumentation manual is attached in Annex XX.
5.2.11 If applicable, a description of any software to be used with the product Software is incorporated in the SIMU Instrument and no additional software is required. The test software is controlled via the touchscreen interface and is used to: input patient information, initiate the assay run, output data to other devices and other basic functions. The software automatically controls all of the processes necessary for running the assay Test Cartridge once the run is initiated. There is a countdown timer on the Instrument screen to indicate the time remaining prior to result and an alarm function indicating when the test is complete. The software also analyses the results and stores the data for future retrieval. The test data storage module stores more than 30 000 test results. The test data storage module also controls for software or hardware failure by displaying a test failure error code. The assay software is designed and maintained in accordance with International Standard IEC 62304 Medical device software – Software life cycle processes. The design history file (DHF) and instrument software documentation is kept on-site.
5.2.12 If applicable, a description or complete list of the various configurations or variants of product that will be made available The SIMU HIV-1 Quant Test Cartridge comes in two configurations: 25 Test Cartridge Pack (M123) and 100 Test Cartridge Pack (M124).
5.2.13 If applicable, a description of the accessories, and other products that are intended to be used in combination with the diagnostic. See Table 5-1 Test kit configuration and accessories provided with the kit. The following products are not provided but required to operate the assay: desktop centrifuge, bleach or sodium hypochlorite, disposable gloves, precision pipettes measuring to 50 µL, ethanol, printer (optional).
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The Product
5.3 Essential principles check list An Essential Principles checklist has been produced for the test to provide evidence of conformity to the “Essential Principles” as outlined in GHTF document GHTF/SG1/N68:2012 “Essential Principles of Safety and Performance of Medical Devices-November 2012” (http://www.imdrf.org/docs/ghtf/final/sg1/technicaldocs/ghtf-sg1-n68-2012-safety-performancemedical-devices-121102.pdf) and is attached in Annex I: Essential Principles Checklist. The evidence supporting performance requirements is submitted as Section 7 of this dossier and other evidence of manufacturing and quality management is also provided throughout this dossier, in agreement with GHTF document GHTF/SG1/N046 “Principles of Conformity Assessment for In Vitro Diagnostic (IVD) Medical Devices -July 2008”.
5.4 Risk analysis and control summary 5.4.1 Risk analysis policy The risk management policy of THE Manufacturing Company is attached as Annex II: Risk Management Policy. The SOPs lead to the Failure Mode and Effects Analysis (FMEA) output documents attached (Annex IV: Design Inputs FMEA, Annex V: User and Patient FMEA, Test Software FMEA), and to the risk statement (Annex III: Residual Risk Statement), which describes any residual risks and their control by warning statements. The process and supplier management FMEA for this product follow the same format as the submitted FMEA for users and patient and are kept on file on-site but have not been submitted with this dossier. The design input FMEA is prepared before any research and development (R&D) work and is updated as work progresses and the requirements are satisfied, as is the risk FMEA for user and patient. A series of control measures arises from the risk assessment and these are listed in the risk analysis failure mode and effects analysis (FMEA) tables and also identified on the flow diagram of the manufacturing process. The effectiveness of the control measures in eliminating the identified risk is shown in the FMEA. Some of the risks (such as instability, common- (but not specific-) interfering agents) are regarded as routine and evaluated as a matter of course. This data is presented in Section 7 of this dossier. Instability and allowable storage times and temperatures are evaluated for plasma, for the shelf-life of the packaged Test Cartridge itself using several independent manufactured lots, and for the usable life of the Test Cartridge once taken out of the pouch.
5.4.2 Risk categories 5.4.2.1 Erroneous test results Types of erroneous results and their impact: This quantitative assay has been designed to monitor viral load levels in response to antiretroviral treatment. Consequently, the major categories of erroneous results that can result in harm to the patient include: Inaccurate quantitation. This may result in misclassification of the patient as responsive to treatment, leading to a patient remaining on an ineffective antiretroviral regimen and further leading to a serious decline in health and ultimately the death of the patient. An inaccurate result may also lead to a patient being misclassified as non-responsive to treatment resulting in an unnecessary change in treatment regimen. Various types of instability that could lead to erroneous test results have been evaluated including specimen type, shipping conditions, shelf-life of the device, life of the materials once opened, and length of time after adding specimen to Test Cartridge for which the result is valid. Instrument
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The Product
instability that could lead to erroneous results includes optics misalignment, software issues, high dust levels, and electrical supply instability. Evaluations were performed with several independently manufactured lots of Test Cartridges and Instruments, and erroneous results were rarely identified. The test is intended for users with varying levels of laboratory skills, from inexperienced to highly experienced, who are responsible for specimen collection and preparation, performing the test, and interpreting the test result.
5.4.2.2 Labelling Product labelling is an important tool in mitigating these risks. The product packaging and IFU utilizes symbols per ISO 15223-1:2016 Medical Devices—Symbols to be used with medical device labels, labelling and information to be supplied—Part 1: General requirements to instruct users on how to effectively and safely use the device. Internationally recognized symbols are used for certain IVD characteristics which are useful for users who are not familiar with the language in which the IFU is written, to simplify communication. Stability conditions are clearly described in the IFUs for Test Cartridges and instrumentation. In addition, the Test Cartridge does not require any special storage conditions, such as refrigeration. Specimen collection labelling is also important for instructing on proper specimen collection and stability of the specimens. Product labelling is also important for addressing the risks associated with use of the test and includes language or illustrations describing the accuracy of the test and how to interpret the test correctly. Product labelling and language is easily readable (Flesch-Kincaid grade <6). The test is designed to be simple to use so that the intended use population will be able to perform the test properly.
5.4.2.3 Interfering substances Investigation of interfering substances should be relevant to the intended testing population. Risk was initially mitigated through design with careful selection of primers and probes to minimize potential inaccurate results. Residual risk was measured through analytical studies (see Section 7.1.2.3) and confirmed through clinical studies in the population of intended use. Exogenous substances including protease inhibitors, hepatitis C virus, hepatitis B virus medicines, opportunistic infection treatments, such as anti-fungal medicines and anti-mycobacterial medicines, have been tested with this assay. Endogenous substances from patients with medical conditions such as diabetes mellitus and those causing high levels of bilirubin and cholesterol have also been tested. Potential cross-reactions due to related organisms e.g. human T-cell lymphotropic virus (HTLV), were investigated. Results of these studies can be found in section 7.1.2.3. Evaluation of the test in the intended testing population supported findings of analytical testing, indicating the test is robust and the risk of interfering substances is minimal. No impact on test performance was observed and the assay met the pre-established acceptance criteria for the studies. The manufacturer should add/remove discussion of risk categories as appropriate, such as those indicated below.
5.4.2.4 Design A risk of infection to personnel from patient specimens due to leakage of specimen from the Test Cartridge has been excluded by design to the greatest extent possible. This includes permanent sealing of the Test Cartridge door after specimen application, lysis and denaturation of the specimen during specimen processing, and clear instructions on handling and disposal of used Test Cartridges.
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5.4.2.5 Testing process The manufacturer should summarize the risks and mitigations related to the testing process, such as the specimen collection process, minimizing the interventions required by the operator, amplicon contamination etc.
5.4.2.6 Stability The manufacturer should summarize the risks and mitigations related to stability, such as storage temperature of the device, on performance including potential long-term storage by the user after purchase and before testing.
5.4.2.7 Specimen type There are several risks related to specimen type used in the assay. The major risk for specimens is that too low a volume may be added to the specimen port of the Test Cartridge, which could result in a false negative or falsely low quantitative result in the assay. This has been mitigated by design of liquid gradation marks visible through the specimen capillary port window. Insufficient specimen volume may be clearly seen and additional volume may be added prior to closing the Test Cartridge specimen port cap. In addition, inadequate specimen volume added to the port would result in a specimen processing control failure resulting in an invalid assay run report rather than a false negative result. There is a small risk that users may use other types of anticoagulants other than EDTA for plasma. This is mitigated by specific instructions in the IFU to only use EDTA collection tubes. There is a risk hazard of disease transmission during the handling of specimens and the disposal of Test Cartridges. The specimen handling risk was minimized by the design of simple procedures to deliver specimen to the Test Cartridge and detailed instructions in the IFU. Contamination after specimen addition to the Test Cartridge has been minimized by designing the cartridge to completely contain the specimen after the specimen intake door is closed. Used Test Cartridges cannot be opened or reused and will not leak under normal usage. In addition, the specimen processing reagents lyse and denature the virus making it much less likely to be infectious. The used Test Cartridge should be handled and disposed as biohazard waste. The manufacturer should summarize the risks and mitigations related to specimen type if applicable.
5.4.3 Instrument The main risks from the Instrument are for the operator and population in which it is intended for use. These have been outlined in the Instrument FMEA (Annex XX). The main risks identified arise from: • Temperature, humidity, altitude and electromagnetic radiation which have been studied extensively as part of the software development, transport and robustness studies and which are mitigated with clear labelling on the Instrument. Software issues such as confusing user prompts, incorrect mathematical algorithm, undetected errors, timing failure, or incorrect storage of test results in memory. Hardware issues such as electronic failure, physical trauma or vibration, electromagnetic interference, battery reliability, component failure or incorrect manufacturing.
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WHO Sample product dossier for SIMU HIV-1 QUANT •
The Product
Transport stability and robustness studies have been undertaken to assess the impact of these issues and compliance with the recognized standards are listed in the Essential Principles checklist. System issues such as incorrect calibration, calibration failure, or inadequate training. These have been mitigated by appropriate user manual instructions, and integrated QC steps in the assembly of the Instrument.
•
5.4.4 Risk/Benefit
As described above, the main risks are related to erroneous test results, whether they occur through producing or distributing the test, or use of the test. The SIMU HIV-1 Quant Test was compared with the well-established laboratory based HIV viral load assays and found to have a high degree of concordance (see Section 7.4) with the assays tested. In conclusion, the remaining risks posed by potential erroneous results of the test are outweighed by the individual and public health benefits projected from use of the test. The Manufacturer should provide evidence that the risk analysis is part of the manufacturer's risk management plan (inclusion of the relevant manufacturer’s document). The Manufacturer should provide identification of specific standards or guidelines recommended by WHO, when applicable (for example, ISO 14971:2007 “Medical devices - Application of risk management to medical devices”).
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Design and Manufacturing Information
6 Design and Manufacturing Information 6.0 i)
Design control The R&D Department of THE Manufacturing Company (987 Somewhere Street, Somewhere in Europe EU-1234, Europe) is responsible for the control of design of the assay and instrument. The R&D Department is responsible for all design aspects and design validation of the Test Cartridge device at the manufacturing site at company headquarters. Headquarters manufacturing undertakes all aspects of manufacture for Test Cartridges, apart from developing the prototypes in conjunction with the R&D Department. Although manufacturing of the SIMU Instrument is outsourced to an ISO 9001 certified manufacturer of electronic equipment (Imaginative Diagnostic Designers, Top Street Industrial Estate, Some Country, Europe), the design, specification and quality requirements were provided by the R&D Department, and control of final design specifications rests with this group (SOP XXX). Following the development plan there is a risk assessment followed by full staff training, qualification of all the manufacturing processes, re-verification of Test Cartridge performance against the specifications and revalidation of the quality assurance (QA) release-to-market requirements. Packaging materials and desiccant are sourced locally. Every lot is QA inspected and validated for use prior to acceptance by the manufacturer. Any changes to packaging materials are evaluated by risk assessment; any changes to packaging or their labels in immediate contact with product such as the Test Cartridge plastic housing require a revalidation of stability as described in SOP XXX. Any changes to secondary and shipping packaging are re-validated for transport including drop and shock testing as per ASTM D4169-14. Certified copies of certificates for the quality management system (ISO 13485), and the environmental management system (ISO 14001) for the design and manufacturing site are attached as part of Section XXX. The design control system is shown in Figure 6-1. It will be understood that product design is iterative so although the process is shown as a linear flow, each stage might be repeated several times to optimise the whole design. Design change control begins as soon as the customer requirements document is authorized; changes to requirements documents undergo full change control, controlled by SOP XXXX, changes during phase 1 are under R&D change control SOP XXXX, which differ from full design change control only in the extent of revalidation potentially required. All performance factors are obtained with product manufactured following authorized, finalized documentation and QA parameters. Data generated throughout the design input and R&D phases is collected as the DHF, and the finalized specifications as the device master record. Risk analyses are initiated as shown and reviewed regularly with direction from SOP XXXX. Design control review meetings are also held regularly and the output of the meetings stored in the DHF. Training for manufacturing staff commences as soon as possible in the design phase, and during R&D phase 2 at the latest. Process SOPs are qualified in the factory by manufacturing
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staff under R&D supervision. All design work is performed and controlled in our R&D laboratories, manufacturing up to and including devices used for design validation is done in our main factory, where production for all our rest of world version products occurs. xii) Following the development phase there is a risk assessment followed by full staff training, qualification of all the manufacturing processes, re-verification of device performance against the specifications and revalidation of the QA release-to-market requirements, all being completed before validating the device in user’s hands in the intended environment of use. The IFU is written according to ISO 18113 series and printed professionally close to our factory, with translation where necessary from the authorized English version by licensed scientific translators and subsequent approval by our local staff. Packaging materials are sourced locally, every lot is QA inspected and validated for use prior to acceptance by the manufacturer. Any changes to packaging materials are evaluated by risk assessment. Any changes to the design, including to labelling, are controlled within the change control system with risk evaluations and re-qualifications as appropriate at the manufacturing site. Changes to the design are notified in compliance with mandatory WHO reporting requirements and regulatory requirements.
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6.1
Product design
6.1.1 Design overview Please see Section 5.2 for a review of the product features, functioning and general description of the ingredients. Key to type faces and colours in the flow diagram below (Figure 6-1): Reviews and risk evaluations: Phase of work: Activity in the phase: Explanatory text:
Design and development Design inputs User requirements collected Design output validated against this
Figure 6-1: Product design control: flow diagram
Design and development plan begun Design inputs User requirements collected Regulatory requirements collected Manufacturing requirements and capabilities obtained Management expectations defined
Customer requirements document Design inputs converted to requirements (Quality Function Deployment)
Change control begun Design output validated against this documentation Design risk analysis begun Product specifications Numeric design requirements prepared from customer requirements Product verified against this documentation
User, patient, manufacturing risk analyses and regular, planned design reviews begun R&D phase 1 Under R&D change control Format and instrumentation developed Processes developed and qualified Manufacturing documentation started Guard bands for all process parameters defined and validated QA and QC parameters and materials defined, sourced and documented Specimen processing control developed and metrologically traceable Beginning of stability work for in-process intermediates and final device IFU and Instrument manual initiated (continued)
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WHO Sample product dossier for SIMU HIV-1 QUANT R&D phase 2
Design and Manufacturing Information
Transitioning to factory
Under design change control as documents are finalized Instruments and material suppliers finalized and audited Instrumental performance qualification, operational qualification in the factory Pilot batches made, tested against presumed QC Interfering substances evaluated Efficacy of anti-microbials and fungicides proven Process documentation finalized and approved All aspects of device and specimen stability using devices made to approved specifications IFU and Instrument manual finalized and approved Any changes to the IFU other than addition of performance data require in-depth evaluation and revalidation QA and QC specifications finalized and approved
R&D phase 3
Design verification using material made in the factory to approved documentation
Formal completion and documentation of the activities of phase 2 (R&D evaluation of all aspects of the product specification e.g. performance, repeatability, reproducibility, lotto-lot variability, all aspects of stability)
R&D phase 4
Design validation using material made in the factory at scale to approved documentation
(User evaluation of all aspects of product specification and customer requirements: e.g. performance, repeatability, reproducibility, lot-to-lot variability, functionality of IFU, training manuals, software) Normally performed in three user-labs with three independent lots of reagent IFU completed with data from validation work e.g. reproducibility, specificity, sensitivity, cross-reactivity etc.
Final risk analyses and production of risk declaration Manufacture Full scale manufacture under change control On-market surveillance Review of scientific literature for independent clinical evaluations
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Design and Manufacturing Information
6.1.2 Formulation and composition Formulation and composition information such as ingredients of buffers, amino acid sequences for recombinant proteins etc. should be provided. Please note that WHO will ensure that all proprietary information will be treated confidentially. Biochemical information on the critical reagents is shown in Table 6-2. Table 6-2: Biochemical information on the critical reagents Constituent Armored RNA for specimen processing control and external positive control Primer oligonucleotides for HIV-1 Information Armored HIV-1 RNA construct containing HIV-1 primer binding sequences and a unique probe binding region (non-infectious RNA in MS2 bacteriophage). Upstream and downstream primers to the gag and the long terminal repeat (LTR) region of HIV-1. See Table 5-5 for sequence information. Fluorescent and quencher labelled oligonucleotide probes specific for HIV-1 and specimen processing control. See Table 5-5 for sequence and dye information. Sodium citrate dihydrate buffer containing 43% guanidine thiocyanate, 1.4 N-Lauroylsarcosine, 0.9% dithiothreitol, 7.8% proteinase K, 0.05% EDTA. A pH buffered solution with sodium citrate dihydrate and <0.1% N-Methylisothiazolone-HCL.
Probes
Specimen lysis buffer Wash solution contained within the device
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WHO Sample product dossier for SIMU HIV-1 QUANT
Design and Manufacturing Information
6.1.3 Biological safety Information on materials of human, bacterial, viral or animal origin is shown in Table 6-3 below. Table 6-3: Information on materials of human, bacterial, viral or animal origin Material Bovine serum albumin Origin Bovine Steps to decrease risk of transmission or infection All bovine serum albumin used in the reagents contained in the Test Cartridge originate from herds in countries declared free of Transmissible Spongiform Encephalopathies and are obtained from Transmissible Spongiform Encephalopathies-free certified manufacturers. Some of the reagents in the Test Cartridges and the external controls contain defibrinated human plasma. The plasma is negative for hepatitis B surface antigen, antibodies to hepatitis C virus, antibodies to HIV-1 and HIV-2, and HIV antigen when tested with stringently assessed IVD assays authorised for use by a Regulatory Authority of the founding members of GHTF. In addition, the plasma is non-reactive for hepatitis B virus DNA, hepatitis C virus RNA and HIV-1 RNA when tested with licensed nucleic acid-based testing technology. All human blood sourced materials should be considered potentially infectious and should be handled with Universal Precautions (US Food and Drug Administration (FDA) regulations standards– CFR 29 Occupational Safety and Health Standards. Bloodborne pathogens CFR 1910.1030(d)(1).
Pooled defibrinated human plasma
Human
Determination of residual risk All of the reagents and other materials are completely self-contained within the Test Cartridge. The risk of human specimen or reagents leaking from the device during or after use is low and does not pose any significant risk of human infectivity. The Manufacturer should add/remove other components of the test as appropriate. If a residual risk of any component is identified, provide information on how users of the device will be informed of any residual risk.
6.1.4 Documentation of design changes Change control has been described in Section 6.0. It is controlled by SOP234AQ. The change control system notes the following changes: a) Change A1234-2 Reduction of bioburden testing frequency using a process capability/risk based approach. Date of change: 20 December 2012. Phase of work: Research and Development phase 1. The new documentation was incorporated into the Essential Principles checklist. b) Change Y1234-4
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WHO Sample product dossier for SIMU HIV-1 QUANT
Design and Manufacturing Information
Change to the upper limit of detection from 5 million copies/mL to 10 million copies/mL in response to customer input. No significant difference was observed in the other performance parameters of the test compared to the initial validation and verification work. Risk was judged negligible. Date of change: 10 January 2013. Phase of work: Research and Development phase 2. Reference: QMCC Report XXX. The new documentation was incorporated in to the Essential Principles checklist.
6.2
Manufacturing process
6.2.1 Overview of manufacture The flow of product manufacture of the Test Cartridge is shown below in Figure 6-4. In-process quality checks are included and the reasons for each of these checks can be traced back either to a risk management document (see Section 5.4 and annexes) or a routine technical measurement for the process concerned. Critical materials supplied to THE Manufacturing Company are marked in red borders and their sources listed in Table 6-5. Incoming goods are checked against specifications and functional testing is performed as decided from risk analyses and supplier auditing.
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WHO Sample product dossier for SIMU HIV-1 QUANT
Design and Manufacturing Information
Figure 6-4: Manufacturing flow diagram for the SIMU HIV-1 Quant Test Cartridge and SIMU Instrument system
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WHO Sample product dossier for SIMU HIV-1 QUANT
Design and Manufacturing Information
6.3.1.1
Batch release criteria/Final lot release
Final lot release criteria for the Test Cartridge is contained in the verification report AXXXX and for the Instrument system in verification report BXXXX. The final product is inspected to meet the final requirements outlined in the Quality Specifications for the SIMU HIV-1 Quant Test. The final lot release testing is performed using well-qualified panels of specimens to assure the product meets lot release criteria. Inter-lot homogeneity testing is also performed to assure consistent performance between product lots.
6.3.2
Sites of manufacture
The entire Test Cartridge, including all oligonucleotides, is made in the European factory location of THE Manufacturing Company located at 987 Somewhere Street, Somewhere in Europe EU-1234, in accordance with the processes described above. A number of other devices are made at this site under the same design control and quality systems, and in some cases using similar processes. These devices include IVDs for the detection of: • • • • • • Malaria antigens HIV – antibody-antigen Hepatitis C – antibody-antigen Syphilis antibodies Hepatitis B surface antigen HIV-1/2 total nucleic acid-based testing technology (qualitative assay)
A site plan for the factory is included in Annex XXX The company has 96 staff. An organigram is included in Annex XXX. The SIMU Instrument is manufactured at the ISO 9001 certified facility listed in the key suppliers list below in Table 6-5.
6.3.3
Key suppliers
Certified certificates for the manufacturers are attached in Annex XXX. The constituents and their source for critical reagents and the SIMU Instrument are shown in Table 6-5.
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WHO Sample product dossier for SIMU HIV-1 QUANT Table 6-5: Constituents and their source for critical reagents Constituent Certification if available (certified copy provided in Annex XX) ISO 13485 Source
Design and Manufacturing Information
Primers Probes
In-house synthesis Purchased from: Probeandprod Inc. 2 Last Rd, San Francisco, CA USA Purchased from: Universal Oligos Inc. 456 Science Rd, San Diego, CA USA Purchased from: Enzymes R Us, 765 Rotor Rd, San Francisco, CA USA Purchased from: Enzymes R Us, 765 Rotor Rd, San Francisco, CA USA Purchased from: Colossal Health Limited Services 53 Some Street, Some Town, Europe www.CHLS.co.xcvb Purchased from: Impossible Mouldings, Malleable Mansions, ConriceVille Aus8765 www.mouldy.com.au Purchased from: Imaginative Diagnostic Designers, Top Street Industrial Estate, Some Country, Europe Purchased from: IPrint Local street Small Town UK
Specimen processing and External control Armored RNA M-MLV reverse transcriptase rTth DNA polymerase
ISO 13485
ISO 13485
ISO 13485
Magnetic Microparticles
ISO 13485
Plastic components for Test Cartridge assembly SIMU Instrument
ISO 9001 ISO 14001 ISO 9001
Printed materials (IFU, labels) and translations
ISO 9001
The print shop is not quality certified but is regularly inspected according to our supplier management SOP XXXX. The translators they employ are certified by national authorities and all translations are certified by an accredited organization. Information on other suppliers providing essential but non-critical material is shown below in Table 6-6.
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WHO Sample product dossier for SIMU HIV-1 QUANT
Design and Manufacturing Information
Table 6-6: Information on other suppliers providing essential but non-critical material Material Supplier Certification (certified copy provided in Annex XX) ISO 9001 ISO 14001 ISO 9001 Control of incoming goods
Packaging for shipment Instrumentation for automated device assembly
Bags of Boxes Long Way, Forest Ville Europe www.moreWords.com Best Systems Inc. Make and Mend Road, Buzzville USA www.besttest.com Drybyzones Ltd Drought Rd Somewhere CH www.DrybyzonesLtd.co.ch WetrackTemp Ltd Desert Road, USA www.wetracktemp.co.ch SuperPure chemicals Inc., Somewhere, 5600001 www.cleanascanbe.com
SOP XXXX: visual inspection
SOP XXXX – full functional Installation, Operational and Performance Qualification and performance testing SOP XXXX: visual inspection, opening of sachets, visual inspection of water content SOP XXXX : visual inspection
Desiccant sachets used in Test Cartridge pouch Temperature logger
ISO 9001
ISO 9001
General laboratory chemicals
ISO 9001
SOP XXXX: visual inspection and performance testing
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WHO Sample product dossier for SIMU HIV-1 QUANT Product Performance Specifications and Associated Validation and V
7 Product Performance Specifications and Associated Validation and Verification Studies Please note that the production of this sample dossier has preceded the creation of a Technical Specification for WH Prequalification of HIV Quantitative NATs . As such, it is possible that different specifications must be met.
Please read the following important notes about the information provided in this section. NOTE 1. For the purposes of this sample product dossier, validation studies have been presented in varying levels of detail in order to illustrate the reporting requirements. When submitting a dossier for WHO Prequalification assessment, the following should be provided either in the main dossier or as annexes for EACH PERFORMANCE CLAIM: • The complete study protocol • The methods of data analysis • The complete study report (signed and dated), including the study conclusion. For each study presented, the site(s) and principal investigator(s) should be identified. Similarly, the date each study was performed, the lot numbers used, and a description of the study design (including justification of the number of specimens tested) along with the statistical analysis, results and conclusions should be provided NOTE 2. The studies presented in this section should not be taken as representing a complete list of studies that are expected to be performed and submitted; they are provided as an illustrative sample of the type of information that should be submitted. For each claim (including, but not limited to: specimen type to be used, testing population, stability and other performance characteristics), one or more validation studies must be performed to support that claim. NOTE 3. The data provided in this section must be produced using the final version of the assay product submitted for prequalification. Where this has not occurred, the version used should be stated and a justification for the inclusion of the data provided. Depending on the nature of differences between product versions, additional validation evidence may be required. NOTE 4. Where possible, internationally accepted standards should be used to guide not only the design of each study, but also the formulation of criteria for judging the acceptance of the study and to inform the acceptance of the outcomes. These are comprehensively noted in the Essential Principle Checklist (Refer to Section 5.3 and Annex I of this dossier). NOTE 5. The studies and suggested number of specimens for the evaluation of the performance of SIMU HIV-1 Quant Test represent ideal study recruitment.
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WHO Sample product dossier for SIMU HIV-1 QUANT Product Performance Specifications and Associated Validation and V
7.0
Overview of testing procedures
The results of all analytical and clinical performance testing, submitted in this dossier were conducted on the final version of the SIMU HIV-1 Quant Test. Data for earlier Test Cartridge versions and prototype systems and procedures are not included, but the data are retained in the DHF (held on-site at THE Manufacturing Company). For each study presented, the site(s) and principal investigator(s) are identified, the date each study was performed, the lot numbers used, and a description of the study design are given along with the statistical analysis, results and conclusions. All efforts were undertaken to eliminate the potential for bias, including but not limited to randomization of procedures that may unfairly influence the result outcome, and careful selection of reference testing. Additionally, validation studies were designed and executed in a manner to avoid the potential for conflicts of interest. Where possible, internationally accepted standards were used to guide the design of each study and inform on the acceptance of the outcomes. These are comprehensively noted in the Essential Principle Checklist (Refer Section 5.3 and Annex I of this dossier). The results of both verification studies (performed by the manufacturer) and validation studies (performed either by or on behalf of the manufacturer in the setting of intended use) should be submitted in support of the performance of the assay.
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WHO Sample product dossier for SIMU HIV-1 QUANT Product Performance Specifications and Associated Validation and V
7.1 Analytical studies 7.1.1 Specimen types The SIMU HIV-1 Quant Test has been evaluated with plasma using EDTA as anticoagulant. Use of plasma collected in other anticoagulants has not been evaluated. Study Summary Report: Plasma Specimen Stability Protocol: SHST XXX - refer ANNEX XX Full Report: AR XXX - refer ANNEX X Study Dates: xxxxx Conducted by: A Blog, Research and Development Dept, THE Manufacturing Company Testing: Performed on-site, Headquarters Study Objective To evaluate the effect of specimen handling and specimen stability for plasma on the performance of the SIMU HIV-1 Quant Test. Three different storage temperatures were investigated: 5 °C (±3 °C), 30 °C (±3 °C) and 40 oC (±3 oC). Stability conditions for plasma after three freeze-thaw cycles were also investigated. Reagents and Instruments: SIMU HIV-1 Quant Test Cartridge Lot Number: MPOC-1307 expiry 07 2016 SIMU Instrument Lot Number: MPR-11AGG Acceptance Criterion The acceptance criterion was defined as demonstration of acceptable assay performance to support recommended specimen handling and stability. Acceptable assay performance was defined as a mean concentration of 6 x 95% LoD ± 1 standard deviation (SD) of the test (Table 7-7). Methodology/Study Design HIV-1 RNA was spiked into HIV-negative, pooled plasma prepared as described in 7.1.2.2. Analytical Sensitivity Study Summary Report: Limit of Detection (95% LoD) at a concentration of 6 x 95% LoD of the test (Table 7-7). The HIV-1 (IIIB strain) working standard was used as the specimen in this study (and also for the Analytical Sensitivity Studies). Forty replicate specimens were made for each time point. Specimens were stored upright for 24, 48, 72 and 96 hours at three different temperatures; 5 °C (±3 °C), 30 °C (±3 °C) and 40 oC (±3 oC). Before testing, all specimens were allowed to equilibrate to room temperature (18–28°C) for 10 minutes (as per IFU instructions) before being loaded into the Test Cartridge and tested in the SIMU Instrument. As a reference, the specimens were measured within one hour after collection (T= 0 hour). Ten (10) replicates of each specimen were tested at each time point. The remaining 30 replicates from each time point were frozen at -20 °C for three months. The specimens were thawed at 1 month and 10 replicates tested for HIV-1. The remaining replicates were refrozen. At two months, the remaining 20 replicates were thawed, 10 were tested and the remaining 10 were refrozen. These 10 specimens were thawed at 3 months and tested. The mean concentration of the specimens at each temperature and time point were determined (Table 7-1).
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WHO Sample product dossier for SIMU HIV-1 QUANT Product Performance Specifications and Associated Validation and V Table 7-1: Stability of plasma specimens with SIMU Quant HIV-1 Test
Temperature 5 oC 30 oC 40 oC Temperature 5 oC 30 oC 40 oC Temperature 5 oC 30 oC 40 oC Temperature 5 oC 30 oC 40 oC
Virus HIV-1 HIV-1
Mean concentration (10 replicates) at time point month 0 (SD) 0 hour 24 hours 48 hours 72 hours 96 hours The table is for illustrative purposes. WHO expects manufacturers to provide all results for the studies in an easy to read format.
HIV-1 Virus Mean concentration (10 replicates) at time point month 1 (SD) 0 hour 24 hours 48 hours 72 hours 96 hours HIV-1 HIV-1 HIV-1 Virus Mean concentration (10 replicates) at time point month 2 (SD) 0 hour 24 hours 48 hours 72 hours 96 hours HIV-1 HIV-1 HIV-1 Virus Mean concentration (10 replicates) at time point month 3 (SD) 0 hour 24 hours 48 hours 72 hours 96 hours HIV-1 HIV-1 HIV-1
SD: standard deviation Results The mean concentrations each time point and after 3 freeze-thaw cycles were all at 6 x 95% LoD ± 1 SD of the test and met the acceptance criteria. Conclusion: This study provides evidence that plasma specimens can be exposed to 40 oC (± 3 oC) for up to 96 hours after collection and freeze-thawed up to three times without loss in concentration when tested at a concentration of 6 x 95% LoD.
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WHO Sample product dossier for SIMU HIV-1 QUANT Product Performance Specifications and Associated Validation and V
7.1.2 Analytical performance characteristics 7.1.2.1 Accuracy of measurement The manufacturer is expected to provide studies relating to trueness of measurement, precision of measurement (including repeatability and reproducibility in this section).
7.1.2.1.1 Trueness of measurement Study Summary Report: Method Correlation Protocol: SHST XXX - refer ANNEX XX Full Report: AR XXX - refer ANNEX X Study Dates: xxxxx Conducted by: A Blog, Research and Development Dept, THE Manufacturing Company Testing: Performed on-site, Headquarters Study Objective To demonstrate correlation between the SIMU HIV-1 Quant Test and two reference method assays. Reagents and Instruments SIMU HIV-1 Quant Test Cartridge Lot Number: MPOC-1307 expiry 07 2016 SIMU Instrument Lot Number: MPR-11AGG Reference method assay 1 and 2 Acceptance Criteria Bland Altman analysis of the SIMU HIV-1 Quant Test and each reference test. Methodology/Study Design The performance of the SIMU HIV-1 Quant Test was compared to two reference method assays. The reference method assays have been authorized for use by a regulatory authority of the founding members of GHTF and acknowledged in the literature as representing state of the art. They have demonstrated excellent performance in international quality assurance programmes. Ninty (90) prospectively collected HIV-1 group M specimens from individuals with HIV-1/AIDS and not on antiretroviral therapy were tested with the three tests. The specimen viral loads covered the dynamic range of the SIMU HIV-1 Quant Test (200 – 10 million copies/mL). The data were analysed by Bland Altman for valid, paired viral loads within the dynamic ranges of both assays. Results Bland Altman analysis of 90 specimens tested with the SIMU HIV-1 Quant Test and reference method 1 and the SIMU HIV-1 Quant Test and reference method 2 are shown in Figures 7-2 and 7-3.
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WHO Sample product dossier for SIMU HIV-1 QUANT Product Performance Specifications and Associated Validation and V Figure 7-2: Bland Altman analysis of SIMU HIV-1 Quant Test versus Reference method 1 assay
Log10 viral load ref. assay 1- log10 viral load SIMU
2 x SD
Mean
2 x SD
1
2
3
4
5
6
Mean viral load (log10)
Figure 7-3: Bland Altman analysis of SIMU HIV-1 Quant Test versus Reference method 2 assay
Log10 viral load ref. assay 2- log10 viral load SIMU
2 x SD
Mean
2 x SD
1
2
3
4
5
6
Mean viral load (log10)
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WHO Sample product dossier for SIMU HIV-1 QUANT Product Performance Specifications and Associated Validation and V Conclusions The SIMU HIV-1 Quant System showed good correlation with reference method 1 and 2. The differences in levels of the 90 specimens between the SIMU Quant HIV-1 Test and the two reference methods were all within ± 2 SD of the mean difference . 5.4.4.1.1 Precision of measurement Study Summary Report: Precision Protocol: SHST XXX - refer ANNEX XX Full Report: AR XXX - refer ANNEX X Study Dates: xxxxx Conducted by: A Blog, Research and Development Dept, THE Manufacturing Company Testing: Performed on-site, Headquarters Study Objective To demonstrate the precision of the SIMU HIV-1 Quant Test. Reagents and Instruments SIMU HIV-1 Quant Test Cartridge Lot Number: MPOC-1307 expiry 07 2016, MPOC-1409 expiry 09 2016, MOOC-1111 expiry 07 2016 SIMU Instrument Lot Number: MPR-11AGG Acceptance Criteria The log standard deviation (log SD) at each dilution level tested should be ≤log 0.25 for each lot and for all lots combined. Methodology The SIMU working standard based on HIV-1 (lllB Strain) was used for this study. The working standard has been quantified using Reference Method 1 to achieve traceability to the WHO International Standard HIV-1 RNA for Nucleic Acid-Based Techniques. Therefore, one copy of HIV-1 RNA is equivalent to 1.67 International Units (IU) (Holmes HH, Davis C, Heath A, Hewlett I, Lelie N. An international collaborative study to establish the 1st international standard for HIV-1 RNA for use in nucleic acid-based techniques. J Virol Methods 2001;92: 141-150). This material has been described in Annex XXX, Limit of Detection (95% LoD) studies. Serial log dilutions of the working reagent were prepared in HIV-1 negative human EDTA plasma. The preparation of negative human plasma has been described in Annex XXX, Limit of Detection (95% LoD) study. Three reagent lots were analysed and 45 tests per reagent lot were performed for each dilution level. The results for each reagent lot and for the three reagent lots combined are shown in Table 7-4, together with the log SD for each lot and for the combined lots.
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WHO Sample product dossier for SIMU HIV-1 QUANT Product Performance Specifications and Associated Validation and V
Table 7-4:
Precision of the SIMU HIV-1 Quant Test
Concentration (Log copies/mL) 1.0E +3 1.0E +4 1.0E +5 1.0E +6 1.0E +7 a b
Lot 1 Log SD a
Lot 2 Log SD
Lot 3 Log SD
All lots combined Total Log SD Total Lognormal CVb (%)
The table is for illustrative purposes. WHO expects manufacturers to provide all results for the studies in an easy to read format.
Log SD: log standard deviation CV: coefficient of variation
Results Each dilution level was tested in 45 replicates and the log SD for each dilution and each lot varied from log 0.04 to log 0.19. The log SD for all three lots combined varied from log 0.06 to log 0.18 across the five dilutions. Conclusions The log SDs for each dilution and with each lot, as well as for the three lots combined, were less than log 0.25 and met the acceptance criteria for precision.
7.1.2.1.2.2 Reproducibility Study Summary Report: Reproducibility Protocol: SHST XXX - refer ANNEX XX Full Report: AR XXX - refer ANNEX X Study Dates: xxxxx Conducted by: A Blog, Research and Development Dept, THE Manufacturing Company, R Roberts, A Adams, External testing site 1, J Jones, B Bland, External testing site 2, W White, B Brown, External testing site 3 Testing: Performed at three external sites Study Objective To determine the reproducibility of the SIMU HIV-1 Quant Test. The study was designed to evaluate key variables contributing to total precision variance, including lot, site/instrument, operator, day/run, and within-run. Reagents and Instruments SIMU HIV-1 Quant Test Cartridge Lot Number: MPOC-1307 expiry 07 2016, MPOC-1409 expiry 09 2016, MOOC-1111 expiry 07 2016 SIMU Instrument Lot Number: MPR-11AGG, MPR-13BGB, MOR-99GGG Acceptance Criterion The acceptable log-normal percentage variance for each variable tested was 30 to 50%.
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WHO Sample product dossier for SIMU HIV-1 QUANT Product Performance Specifications and Associated Validation and V Methodology/Study Design The reproducibility of the SIMU HIV-1 Quant Test was evaluated in EDTA plasma using a panel made from a well- characterized HIV-1 group M, subtype B cultured virus stock and from EDTA plasma that was negative for HIV-1 RNA and HIV-1/2 antibodies. The panel covered the dynamic range of the SIMU HIV-1 Quant Test (log10(3) – log10(7) copies/mL). The study was designed to evaluate key variables contributing to total precision variance, including lot, site/instrument, operator, day/run and within-run. Additional analyses were conducted to compare the performance characteristics and comparative precision variability between the two workflows. Two operators at each of three sites performed five days of testing with each of three reagent kit lots. A three member panel was tested in triplicate (nine specimens). The concentrations of the specimens were log10 (3.699), log10 (5) and log10 (6.699) copies/mL and were within the dynamic range of the assay (log10 (3) – log10 (7) copies/mL). Reproducibility was evaluated by using a random effects model with terms for (a) lot, (b) site/instrument, (c) operator nested within site/instrument, (d) day/run nested within lot, site/instrument, and operator, and (e) aliquots within-run components by using statistical method statistical method PROC MIXED and log10 transformed results. The percentage of variability due to each component and coefficient of variation of the log10 transformed HIV-1 RNA concentration were calculated. Results The contribution of the various components to the total variance is shown in Table 7-5. Table 7-5: SIMU Quant HIV-1 Test – Percentage of Total Variance, Total Precision SD, and Lognormal CV of HIV-1 RNA Concentration (log10 copies/mL) HIV-1 RNA Concentration Contribution to Total Variance (%) Total (log10 copies/mL) Precision Expected Observed Number Lot Site/ Operator Day/Run Within- SD of valid Instrument Run (Logtests* normal %CV) 3.699 3.724 270 39% 0% 2% 13% 46% 0.08 (19%) 5.000 5.100 270 35% 0% 6% 16% 43% 0.11 (25%) 6.699 6.433 270 45% 0% 4% 13% 38% 011 (26%) * Number of tests within assay range. Within assay range results are from log10 (3) – log10 (7) copies/mL The within-run component contributed more variability than other components except for the highest concentration panel member where the lot-to-lot variation represented the major contribution to the variability. Conclusions The acceptance criterion of a log-normal percentage variance 30–50% was met at all three dilutions, which covered the dynamic range of the assay (Table 7-5).
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WHO Sample product dossier for SIMU HIV-1 QUANT Product Performance Specifications and Associated Validation and V
7.1.2.2 Analytical sensitivity 7.1.2.2.1 Limit of detection (95% LoD) Study Summary Report: Limit of Detection (95% LoD) Protocol: SHST XXX - refer ANNEX XX Full Report: AR XXX - refer ANNEX X Study Dates: 02 August 2012 Conducted by: A Blog, Research and Development Dept, THE Manufacturing Company Testing: Performed on-site, Headquarters Study Objective The LoD is the lowest viral load where the true detection rate is 95%. The LoD was calculated with a PROBIT regression analysis. The objective of this study was to determine the LoD of the SIMU HIV-1 Quant Test for HIV-1 group M subtype and HIV-1 group O. Reagents and Instruments SIMU HIV-1 Quant Test Cartridge Lot Number: MPOC-1307 expiry 07 2016, MPOC-1409 expiry 09 2016, MOOC-1111 expiry 07 2016 SIMU Instrument Lot Number: MPR-11AGG Acceptance Criteria The acceptance criterion for the HIV-1 group M and group O 95% LoD In plasma should be at least 150 copies/mL. Methodology/Study Design The LoD of the SIMU HIV-1 Quant Test was determined by testing the 2nd International HIV-1 RNA WHO Standard, National Institute for Biological Standards and Control (NIBSC) Code 97/65041, HIV-1 subtype B, diluted in HIV-1-negative, human, EDTA plasma. The LoD was determined for three reagent lots. Three dilution series were analysed for each reagent lot. Seven dilutions covering the predetermined 95% hit rate of the test were prepared (Table 7-6). A total of approximately 120 replicates per concentration level were tested. The evaluation was performed according to CLSI Guideline EP17-A Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline—Second Edition. For the LoD studies, a pool of negative, human plasma was prepared and stored in 100 mL aliquots at ≤ -20 °C. Since large volumes of plasma were required for the LoD studies, pooled plasma was purchased from a commercial vendor. The plasma was negative for hepatitis B surface antigen, hepatitis B core antibodies, hepatitis C antibodies, HIV antibodies and non-reactive for hepatitis B virus DNA, hepatitis C virus RNA and HIV RNA using a NAT test authorized for use by a regulatory authority of the founding members of GHTF. Before use, the aliquots of negative plasma were thawed rapidly in a 37 °C water bath with agitation until the plasma was completely thawed. The thawed plasma was then cooled to 4–8 °C before being used for the dilution panels. One copy of HIV-1 RNA is equivalent to 1.67 International Units (IU) (Holmes HH, Davis C, Heath A, Hewlett I, Lelie N. An international collaborative study to establish the 1st International standard for HIV-1 RNA for use in nucleic acid-based techniques. J Virol Methods 2001;92: 141-150). Analysis For each virus, PROBIT analysis on the data combined across dilution series and reagent lots was used to estimate the LoD, along with the lower and upper limit of the 95% confidence interval.
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WHO Sample product dossier for SIMU HIV-1 QUANT Product Performance Specifications and Associated Validation and V Results The concentration of HIV-1 RNA that can be detected with a positivity rate of greater than 95% as determined by PROBIT analysis, was 122 copies/mL or 203.7 IU/mL. The results for the individual lots were 114 copies/mL (95% confidence interval: x–y copies/mL) for lot 1, 130 copies/mL (95% confidence interval: a–b copies/mL) for lot 2 and 122 copies/mL (95% confidence interval: m–n copies/mL) for lot 3. The combined results for all three reagent lots are shown in Table 7-6. A conversion factor 1 copy of HIV-1 RNA equivalent to 1.67 IU was used for converting the results IU/mL (Holmes HH, Davis C, Heath A, Hewlett I, Lelie N. An international collaborative study to establish the 1st international standard for HIV-1 RNA for use in nucleic acid-based techniques. J Virol Methods 2001;92: 141-150). Table 7-6: SIMU Quant HIV-1 Test – Reactivity rate of HIV-1 Group M RNA HIV-1 group M RNA Number reactive Number tested (valid) concentration (copies/mL) 200 120 150 120 expects The table is for illustrative purposes. WHO 130 120 manufacturers to provide all results for the studies 120 in an easy to read format.120 110 120 100 120 50 120
% Reactive
HIV-1 group M subtypes In addition, dilutions of cell culture supernatants representing the sensitivity of the assay for HIV-1 group M subtypes A-H was also determined. Dilutions of cell culture supernatant representing HIV-1 group M, subtypes A-H (purchased from a commercial vendor) were prepared in HIV-1-negative human EDTA plasma and were analysed with two reagent lots. For each HIV-1 subtype isolate, three concentration levels, 100 copies/mL, 150 copies/mL and 200 copies/mL, were tested in 24 replicates per reagent lot. The assignment of nominal concentrations to the cell culture stock materials was performed by averaging the concentrations of two, commercial, HIV-1 quantitative tests, reference 2 method 1 and reference method 2 . Hit rate analysis gave a positivity rate of greater than 95% for all subtypes at 150 copies/mL or lower. The combined results for the two reagent lots are shown in Table 7-7.
Reference method 1 and 2 are stringently regulated product types that have been approved by one of the Regulatory Authorities of the founding members of GHTF.
2
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WHO Sample product dossier for SIMU HIV-1 QUANT Product Performance Specifications and Associated Validation and V Table 7-7: LoD of the SIMU HIV-1 Quant Test for HIV-1 group M subtypes A–H: ≥95% Hit Rate Analysis: Lot 1 Subtype Isolate Number Lowest concentration with ≥ 95% hit rate (copies/mL) A B B B C C C D F G H CRF01_AE CRF01_AE 150 150 150 The table is for illustrative purposes. WHO expects manufacturers to provide all results for the studies 100 in an easy to read format. 150 100 150 100 100 100 150 100 100
HIV-1 group O Dilutions of a HIV-1 group O cell culture supernatant (isolate xxx) in human EDTA plasma were analysed with two reagent lots. The nominal concentration of this material was assigned on the results of reference method 1. Six concentration levels of 50, 100, 110, 120, 130 and 150 copies/mL were tested in 24 replicates per reagent lot. The results of the two reagent lots were pooled. Hit rate analysis showed that the SIMU HIV-1 Quant Test gave a greater than 95% positive rate at a concentration of 120 copies/mL for HIV-1 group O. Conclusions: The LoD of the SIMU HIV-1 Quant Test was 122 copies/mL and met the acceptance criterion of a 95% LoD of 150 copies/mL. The LoD for the SIMU HIV-1 Quant Test for HIV-1 group M (150 copies/ml) was higher than those for other commercial quantitative tests where the LoD for HIV-1 group M is 3 about 20 copies/mL (reference test assays ). This is not surprising since the SIMU HIV-1 Quant Test only uses 50 µL of specimen which is five-fold to ten-fold lower than that used for most commercial tests. No significant lot-to-lot variation was detected with the three lots of the SIMU HIV-1 Quant Test. Hit rate analysis showed that all the common subtypes of HIV-1 were detected at a greater than 95% positive hit rate at 150 copies/mL or lower. The SIMU HIV-1 Quant Test detected HIV-1 group O at 120 copies/mL with a positive rate of greater than 95%.
Reference methods should be stringently regulated product types that have been approved by one of the regulatory authorities of the founding members of GHTF.
3
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WHO Sample product dossier for SIMU HIV-1 QUANT Product Performance Specifications and Associated Validation and V
7.1.2.2.2 Genotype detection Study Summary Report: Genotype Detection Protocol: SHST XXX - refer ANNEX XX Full Report: AR XXX - refer ANNEX X Study Dates: xxxxx Conducted by: A Blog, Research and Development Dept, THE Manufacturing Company. Testing: Performed on-site, Headquarters. Study Objective To determine the sensitivity of the SIMU HIV-1 Quant Test for HIV-1 group M subtypes and HIV-1 group O. Note that studies have already been conducted during R&D using the 2nd WHO International Reference Panel Preparation for HIV-1 Subtypes for NAT (NIBS code: 12/224) to verify the assay detects HIV-1 subtype - A, B, C, D, AE, F, G, AA-GH, group N and group O (see Annex XXX for the study protocol and full report). Reagents and Instruments SIMU HIV-1 Quant Test Cartridge Lot Number: MPOC-1307 expiry 07 2016 SIMU Instrument Lot Number: MPR-11AGG Acceptable Criterion Detection of all subtypes. Methodology/Study Design The performance of the SIMU HIV-1 Quant Test with the eight HIV-1 group M subtypes (A – H) was evaluated by analysis of cell culture stock material of representatives for each HIV-1 group M subtype. The assignment of nominal concentrations to the cell culture stock materials was performed by averaging the concentrations of the reference method 1 and reference method 2. Each cell culture stock material was diluted to nominal concentrations of approximately 5.00E+02, 5.00E+04 and 5.00E+06 copies/mL in EDTA plasma. The concentrations were then tested in 10 replicates with the SIMU HIV-1 Quant Test using one reagent lot. The mean log10 concentrations of all concentrations and subtypes were compared to the respective log10 nominal concentrations. The results are shown in Table 7-8. Table 7-8: Results of HIV-1 group M subtype detection testing with SIMU Quant HIV-1 Test Isolate Test A B C D CRF01_AE F 2.450 2.600 2.577 2.712 2.668 2.788 Nominal 2.699 2.699 2.699 2.699 2.699 2.699 Concentration (log10 copies/mL) Test 4.450 4.600 4.577 4.712 4.668 4.788 Nominal 4.699 4.699 4.699 4.699 4.699 4.699 Test 6.450 6.600 6.577 6.712 6.668 6.788 Nominal 6.699 6.699 6.699 6.699 6.699 6.699
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WHO Sample product dossier for SIMU HIV-1 QUANT Product Performance Specifications and Associated Validation and V
G H
2.489 2.559
2.699 2.699
4.489 4.559
4.699 4.699
6.489 6.559
6.699 6.699
The evaluation of the eight (8) HIV-1 subtype isolates by the SIMU HIV-1 Quant Test demonstrates equivalent results for all tested representatives of the HIV-1 group M subtypes (Table 7-6). Mean log10 concentration results for all subtypes were within ± 0.3 log10 of the assigned input concentration.
HIV-1 group O Ten HIV-1 group O cell culture specimens and one patient specimen (high concentration, >1E +06 4 copies/mL) were quantitated with a commercial, quantitative HIV-1 test (reference method assay ). The specimens were diluted concentrations of approximately 2.00E+02, 2.00E+03 and 2.00E+05 copies/mL in EDTA plasma. The concentrations were then tested in 10 replicates with the SIMU HIV-1 Quant Test using one reagent lot. Results The results are shown in Table 7-9. Table 7-9: Results of HIV-1 group O isolate detection testing with SIMU Quant HIV-1 Test Specimen Test Cell culture 1 Cell culture 2 Cell culture 3 Cell culture 4 Cell culture 5 Cell culture 6 Cell culture 7 Cell culture 8 Cell culture 9 Cell culture 10 Patient yyy 2.450 2.333 2.577 2.412 2.268 2.188 2.489 2.222 2.401 2.189 2.56 Nominal 2.301 2.301 2.301 2.301 2.301 2.301 2.301 2.301 2.301 2.301 2.301 Concentration (log10 copies/mL) Test 4.450 4.333 4.577 4.412 4.268 4.188 4.489 4,222 4.401 4.189 4.56 Nominal 4.301 4.301 4.301 4.301 4.301 4.301 4.301 4.301 4.301 4.301 4.301 Test 6.450 6.333 6.577 6.412 6.268 6.188 6.489 6,222 6.401 6.189 6.56 Nominal 6.301 6.301 6.301 6.301 6.301 6.301 6.301 6.301 6.301 6.301 6.301
The mean log10 concentrations of all concentrations were within ± 0.3 log10 of the respective log10 nominal concentration (Table 7-9).
Reference methods should be stringently regulated product types that have been approved by one of the regulatory authorities of the founding members of GHTF.
4
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HIV-1 group N There are no quantitative assays for HIV-1 group N. Therefore, for HIV-1 group N, log-fold dilutions of a cell culture isolate (from 1:102 to 1:106) were prepared in negative plasma and tested. Four replicates at each dilution were tested. Results The results are shown in Table 7-10. Table 7-10: Detection of dilutions of HIV-1 group N by SIMU Quant HIV-1 Test
HIV-1 Group N dilutions 1:102 1: 103 1: 104 1: 105 1:106
Mean concentration (copies/mL) 1E + 04 1.9E + 02 1.5E + 02 Below level of quantitation Below level of quantitation
Conclusion The SIMU HIV-1 Quant Test was able to detect all the common subtypes of HIV-1 groups M and O circulating in the region. A limited study was done with HIV-1 group N due to the lack of these specific genotype isolates. Thus while this genotype was detected, these data should be viewed with caution since some isolates of HIV-1 group N may not be detected with the SIMU HIV-1 Quant Test. Since no HIV-1 group P isolates were available for testing, no claim for detection of this group can be made for the SIMU HIV-1 Quant Test.
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7.1.2.3 Analytical specificity 7.1.2.3.1 Cross-reactivity with other medical conditions Study Summary Report: Cross-reaction with specimens from individuals with medical conditions unrelated to HIV infection Protocol: SHST XXX - refer ANNEX XX Full Report: AR XXX - refer ANNEX X. Study Dates: xxxxx Conducted by: A Blog, Research and Development Dept, THE Manufacturing Company. Testing: Performed on-site, Headquarters. Study Objective To determine whether specimens representing different categories of medical conditions unrelated to HIV infection cross-react or interfere with the SIMU HIV-1 Quant Test. Reagents and Instruments SIMU HIV-1 Quant Test Cartridge Lot Number: MPOC-1307 expiry 07 2016 SIMU Instrument Lot Number: MPR-11AGG Acceptance Criteria There should be no cross-reactivity with the common infectious agents found in the intended enduser region (Table 7-11). There should be no inhibition of the test by any of the agents. Methodology/Study Design Plasma specimens from individuals with infections that are common in regions where the SIMU Quant HIV-1 test would be used were tested for interference. These infections, unrelated to HIV, are listed in Table 7-11. Such specimens can be obtained from commercial vendors and national biological institutes. The specimens were tested with and without HIV-1 group M added to a concentration of 250 copies/mL. Results The results are summarized in Table 7-11. Table 7-11: Results of analytical specificity study, SIMU Quant HIV-1 Test Plasma without HIV-1 Plasma with added HIV-1 Medical condition Number tested Number reactive Number tested Number (%) reactive (%) Malaria 20 0 (0%) 20 20 (100%) Leishmaniasis 10 0 (0%) 10 10 (100%) Sleeping sickness 10 0 (0%) 10 10 (100%) Chagas’ disease 10 0 (0%) 10 10 (100%) Hepatitis B virus 10 0 (0%) 10 10 (100%) Hepatitis C virus 10 0 (0%) 10 10 (100%) HTLV-I 10 2 (20%) 10 10 (100%) HTLV-II 10 1 (10%) 10 10 (100%) Chikungunya virus 10 0 (0%) 10 10 (100%) Tuberculosis 10 0 (0%) 10 10 (100%) Parvovirus B19 10 0 (0%) 10 10 (100%) Adenovirus type 5 10 0 (0%) 10 10 (100%) Page 52
WHO Sample product dossier for SIMU HIV-1 QUANT Product Performance Specifications and Associated Validation and V Plasma without HIV-1 Number tested Number reactive (%) 10 0 (0%) 10 0 (0%) 10 10 10 10 0 (0%) 0 (0%) 0 (0%) 0 (0%) Plasma with added HIV-1 Number tested Number reactive (%) 10 10 (100%) 10 10 (100%) 10 10 10 10 10 (100%) 7 (70%) 10 (100%) 10 (100%)
Medical condition Hepatitis A virus Yeast (Candida) reactive Cytomegalovirus Dengue virus Epstein-Barr virus Zika virus
There was no cross-reactivity with any of the organisms tested except for HTLV-I and HTLV-II (highlighted), where a low level of cross-reactivity was observed, possibly due to overlap of one of the HIV primer pairs or the probes with the HTLV-I and HTLV-II genome. The acceptance criterion regarding cross-reactivity was met except for HTLV-I and HTLV-II. No inhibition was observed with any of the organisms except with Dengue virus (highlighted) where inhibition caused a drop to a 70% reactive rate. A second study was done in which the Dengue specimen was spiked with HIV-1 group M added to a concentration of 3x LoD, 7x LoD, 10x LoD and 15x LoD. Ten replicates of each spiked specimen were tested with the SIMU HIV-1 Quant Test System and the results are summarized in Table 7-10. The acceptance criteria regarding inhibition were met for all agents with the exception of Dengue virus. Table 7-12: Reactivity of Dengue specimen spiked with HIV-1 Group M at different concentrations Concentration of spiked HIV-1 group M 3x LoD 7x LoD 10x LoD 15x LoD Number tested 10 10 10 10 Number reactive (%) 6 (60%) 7 (70%) 10 (100%) 10 (100%)
Conclusions: The common infectious agents found in regions where the SIMU HIV-1 Quant Test could potentially be used did not cross-react or interfere with the test with two exceptions. There was some crossreactivity with HTLV-I and HTLV-II which may cause a misdiagnosis of HIV in regions where HTLV-I and HTLV-II are prevalent. Dengue virus reduced the sensitivity of the SIMU HIV-1 Quant Test for HIV-1 group M. Therefore, individuals with a Dengue/HIV-1 co-infection may not have an accurate viral load determination below about 10x LoD (1 220 copies/mL), possibly resulting in incorrect information for a treatment decision. This information will be highlighted as a limitation in the IFU.
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WHO Sample product dossier for SIMU HIV-1 QUANT Product Performance Specifications and Associated Validation and V 7.1.2.3.2 Exogenous interfering substances Study Summary Report: Exogenous interfering substances Protocol: SHST XXX - refer ANNEX XX Full Report: AR XXX - refer ANNEX X Study Dates: xxxxx Conducted by: A Blog, Research and Development Dept, THE Manufacturing Company Testing: Performed on-site, Headquarters. Study Objective To determine whether potentially interfering substances, such as endogenous compounds found in blood, as well as drugs and other exogenous compounds commonly used in the region of potential end-users, interfere with the SIMU HIV-1 Quant Test. Reagents and Instruments SIMU HIV-1 Quant Test Cartridge Lot Number: MPOC-1307 expiry 07 2016 SIMU Instrument Lot Number: MPR-11AGG Methodology/Study Design HIV-1 negative human EDTA plasma specimens were spiked with elevated levels of blood analytes listed in Table 7-13. In addition, therapeutic drugs commonly used in the region of potential endusers spiked at 3 x Peak Plasma Level (Cmax). The specimens were tested with the SIMU HIV-1 Quant Test. The testing was performed according to CLSI Guideline EP7-A2 Interference Testing in Clinical Chemistry; Approved Guideline—Second Edition using one lot of reagent.
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WHO Sample product dossier for SIMU HIV-1 QUANT Product Performance Specifications and Associated Validation and V Table 7-13: Results of testing with exogenous interfering substances Interfering substances found in blood and drugs tested Blood Analytes Triglycerides Bilirubin Albumin Human DNA Common medicines Paracetamol Acetylsalicylic Acid Ascorbic Acid Atorvastatin Ibuprofen Loratadine Nadolol Naproxen Paroxetine Cotrimoxazole Ethanol Fluconazole Ivermectin Albendazole Anti-malarial medicines Quinine Artemether + lumefantrine Tuberculosis medicines Rifampicin/isoniazid/ethambutol Antiretroviral medicines Atazanavir Darunavir Lopinavir/Ritonavir Ritonavir Raltegravir Abacavir sulfate Emtricitabine Lamivudine Tenofovir + + + + + + + + + + + + 1324 µmol/L 3620 µmol /L 342 µmol/L 600 µg Eq/L 2425 µmol/L 0.78 µmol/L 3.88 µmol/L 2170 µmol/L 3.04 µmol/L The table is for illustrative purposes. WHO expects manufacturers to provide all results for the studies in an easy to read format. + + + + + + + + + + + + + + up to 33.2 g/L up to 0.236 g/L up to 60 g/L up to 0.002 g/L + + + + Concentration (Illustrative purposes only) NAT reactive Drug Drug + HIV-1
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WHO Sample product dossier for SIMU HIV-1 QUANT Product Performance Specifications and Associated Validation and V Zidovudine Efavirenz Nevirapine Anti-hepatitis medicines- HBV, HCV Adefovir dipivoxil Peginterferon alfa-2a and 2b Entecavir Telbivudine Ribavirin Sofosbuvir Anti-herpes medicines Aciclovir Results All the blood analytes and therapeutic drugs tested were shown not to interfere with the quantitation of the SIMU HIV-1 Quant Test over the linear range of the assay (200 to 10 million copies/mL). Conclusions The exogenous substances tested do not affect the specificity or the accuracy of quantitation of the SIMU HIV-1 Quant Test. As new antimicrobial drugs come onto the market, they will be tested in a similar manner as part of an ongoing study. + +
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7.1.2.4 Traceability of calibrators and control material values See Annex XXX
7.1.2.5 Measuring range of the assay Study Summary Report: Linearity Protocol: SHST XXX - refer ANNEX XX Full Report: AR XXX - refer ANNEX X Study Dates: xxxxx Conducted by: A Blog, Research and Development Dept, THE Manufacturing Company Testing: Performed on-site, Headquarters Study Objective To demonstrate the linearity of the SIMU HIV-1 Quant Test. Reagents and Instruments SIMU HIV-1 Quant Test Cartridge Lot Number: MPOC-1307 expiry 07 2016, MOOC-1300 expiry 07 2016 SIMU Instrument Lot Number: MPR-11AGG Acceptance Criteria The SIMU HIV-1 Quant Test should demonstrate linearity over a range from 200 to 10 million copies/mL. Good correlation with the target HIV-1 viral loads should be demonstrated by Deming Regression analysis. Methodology/Study Design The SIMU working standard based on HIV-1 (lllB Strain) was used for this study. The working standard has been quantified using reference method 1 to achieve traceability to the WHO International Standard HIV-1 RNA for Nucleic Acid-Based Techniques. Therefore, one copy of HIV-1 RNA is equivalent to 1.67 International Units (IU) (Holmes HH, Davis C, Heath A, Hewlett I, Lelie N. An international collaborative study to establish the 1st international standard for HIV-1 RNA for use in nucleic acid-based techniques. J Virol Methods 2001;92: 141-150). (1). This material has been described in Annex XXX, Limit of Detection (95% LoD) studies. Serial log dilutions of the working reagent were prepared in HIV-1-negative human EDTA plasma. The preparation of negative human plasma has been described in Annex XXX, Limit of Detection (95% LoD) study. Serial half-log dilutions were tested. Forty-five replicates of each dilution were tested. Two reagent lots were used to give a total of 90 tests per dilution. The results for one reagent lot are shown in the following Figure 7-14.
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WHO Sample product dossier for SIMU HIV-1 QUANT Product Performance Specifications and Associated Validation and V Figure 7-14: Linear range of SIMU Quant HIV-1 Test
Target concentration as log copies/mL Conclusion: This study provides evidence that the SIMU HIV-1 Quant Test has a linear range of 200 to 10 million copies/mL for HIV-1, group M, subtype B. Deming Regression analysis showed good correlation between the results of the SIMU HIV-1 Quant Test and the target viral loads (The slope and R2 value for the curve were 1.003 and 0.989 respectively).
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7.2
Stability (excluding specimen stability)
Stability studies were performed with the SIMU HIV-1 Quant Test Cartridge in order to determine shelf-life (including storage and transport conditions) and in-use stability of kit components. Stability panels contain HIV-1-negative, human, EDTA plasma spiked with HIV-1 group M (IIIB) virus to a concentration of 3 x LoD. The HIV-1 spiked specimens are traceable to the WHO International Standards for HIV-1 RNA for Nucleic Acid-Based Techniques. It is expected that the results will be comparable for HIV-1 group N and O because the oligonucleotides for these analytes have the same degradation profile (See “Validation of oligonucleotide stability” SLST XXX.xx)
7.2.1 Claimed shelf-life (including transport challenge) Study Summary Report: SIMU HIV-1 Quant Test Cartridge Transport and real-time stability study Protocol: SHST XXX - refer ANNEX XX Full Report: SHST XXX – refer ANNEX XXX Study report SIMU HIV-1 Quant Test Cartridge transport and real-time stability Study Dates: October 2014 – October 2015 Lot number: MOOC-137 expiry 10 2015, MPOG -144 expiry 10 2015, MPOG-143 expiry 10 2015 IFU version: v1.0 Conducted by: A Techie, Research and Development Dept., THE Manufacturing Company Testing: Performed on-site, Headquarters Study Objective The objective was to follow the stability of the cartridge and external positive controls over at least 13 months at multiple temperatures to determine shelf-life of the device. The impact of temperature and humidity extremes on cartridge performance was also considered by preceding real-time testing with simulated transport challenges designed to mimic expected storage and transport conditions. Testing beyond 13 months would allow an understanding of when, in real-time, the device is likely to ‘fail’ and may allow an extension of the proposed shelf-life from the six months that was established in previous testing (Annex XXZ). Acceptance Criterion The acceptance criterion was defined as demonstration of acceptable assay performance to support recommended storage and transport conditions. Acceptable assay performance was defined as a detection rate of 100% at a concentration of approximately 3x LoD HIV-1 M and specificity of 100%. In addition, the cycle threshold value was expected to deviate by no more than 20% over the testing period. The stability was taken as the time point prior to last time point to have met the acceptance criteria, e.g. if the device was stable to 13 months, the stability will be deemed to be 12 months. Methodology/Study Design Stability studies for the SIMU HIV-1 Quant Test evaluated shelf-life when stored at 6 °C, 20 °C, and 45 °C. Stability panels contained HIV-1-negative, human, EDTA plasma spiked with HIV-1 group M (IIIB) virus to a concentration of 3 x LoD. The HIV-1 spiked specimens are traceable to the WHO International Standards for HIV-1 RNA for Nucleic Acid-Based Techniques. Sufficient volume of each stability panel member for the duration of the testing schedule was prepared. Testing was performed in triplicate for each panel member for each condition. Multiple instruments were used to allow simultaneous testing of cartridges at each time point. Three kit lots, from three independent production lots, using a predetermined sampling protocol SOP XXX were tested. At least 10% overage was allowed for unexpected requirements and re-testing.
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WHO Sample product dossier for SIMU HIV-1 QUANT Product Performance Specifications and Associated Validation and V The effect of shipping conditions on SIMU HIV-1 Quant Test Cartridge and external positive controls was evaluated including a freeze-thaw cycle (-20 °C to 2 to 8 °C), and temperature cycling from 20 °C to 55 °C under variable humidity conditions. Prior to temperature cycling conditions, cartridges and external positive controls were stored at 20 ± 5 °C to mimic normal manufacturer storage conditions prior to shipping. Cartridges were removed from storage within one month of manufacture and subjected to a freeze-thaw cycle (-20 °C to 2 to 8 °C). After the freeze-thaw cycle, cartridges and external positive controls were subjected to the following temperature and humidity sequence: • Ambient humidity (60% relative humidity) Put at 20 ± 5 °C storage temperature for 24 ± 4 hours followed by 55 ± 2 °C for 24 ± 4 hours, followed by 20 ± 5 °C storage temperature for 24 ± 4 hours Desert humidity (30% relative humidity) Put at 20 ± 5 °C storage temperature for 24 ± 4 hours followed by 55 ± 2 °C for 24 ± 4 hours, followed by 20 ± 5 °C storage temperature for 24 ± 4 hours Tropical humidity (85% relative humidity) Put at 20 ± 5 °C storage temperature for 24 ± 4 hours followed by 55 ± 2 °C for 72 ± 4 hours, followed by 20 ± 5 °C storage temperature for 24 ± 4 hours Ambient humidity (60% relative humidity) 20 ± 5 °C storage temperature for 24 ± 4 hours
Followed by: •
Followed by: •
Followed by: •
The above complete sequence was used as opposed to separate cartridges or controls held at individual temperatures. Following simulation of transport conditions, cartridges were stored at 6 ± 2 °C, 20 ± 2 °C or 45 ± 5 °C. Testing was conducted at 0, 3, 6, 9, 12 and 13 months. At each time point, cartridges and external controls were brought to room temperature (20 ± 5 °C) and cartridges were used to test both the stability panel and external positive controls. Results Results for Lot 1 are shown in Table 7-15.
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WHO Sample product dossier for SIMU HIV-1 QUANT Product Performance Specifications and Associated Validation and V Table 7-15: Stressed and real-time stability study of SIMU Quant HIV-1 Test Cartridge - results for Lot 1 Manufacturers are expected to submit results for all lots tested at all temperature points. Panel member HIV Negative HIV-1 HIV-2 Time 0 Ambient humidity Desert Humidity Tropical Humidity Ambient humidity
Mean Cycle threshold Ct value [% deviation from Time 0] value value value value [value] value [value] purposes. value [value] The table is for illustrative WHO value [value] value [value] value [value]
expects manufacturers to provide all results value [value] value [value] value [value] for the studiesvalue in an[value] easy to read format . value [value] value [value]
Temperature Lot 1 °C 6 °C
Panel Month member 0 Mean Ct value HIV Negative HIV-1 value value
Stress Month 3
Month 9
Month 12 value value
Month 13 value value
value value
value value
6 °C
Mean Ct value [% deviation from Month 0] HIV Negative HIV-1 value [value] value [value] value [value] value [value] value [value] value [value] value [value] value [value] value [value] value [value] value [value] value [value] value [value] value [value] value [value] value [value] value [value] value [value] value [value] value [value] value [value] value [value]
20 °C
Ct value
HIV Negative HIV-1
20 °C
value value value value [value] [value] [value] [value] The table is for illustrative purposes. WHO expects manufacturers to provide all results for the studies % HIV Neg value value value value to read format . Deviation [value] in an easy [value] [value] [value] from Ct HIV-1 value value value value value [value] [value] [value] [value] Ct value HIV Negative HIV-1 value [value] value [value] value [value] value [value] value [value] value [value] value [value] value [value] value [value] value [value] value [value] value [value] value [value] value [value] value [value] value [value]
45 °C
45 °C
% HIV Deviation Negative from Ct HIV-1 value
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WHO Sample product dossier for SIMU HIV-1 QUANT Product Performance Specifications and Associated Validation and V Ct: cycle threshold Acceptable assay performance was demonstrated through the 13 month time point under all temperature and humidity conditions for cartridges and external positive controls stored at 6 ± 2 °C, 20 ± 2 °C and 45 ± 2 °C. The results indicate that the Test Cartridges are stable under the freeze-thaw and sequential temperature and humidity changes expected during transport. These results suggest that cartridges and controls are stable for 12 months at 6-45 °C taking into consideration storage conditions likely to be encountered during transport. Full study results are available in the Annex XXX Study report SIMU HIV-1 Quant Test Cartridges real-time stability. Conclusions The SIMU HIV-1 QUANT Test Cartridges are stable under the expected transport conditions to target customers. The cartridge and external positive controls are stable up to 12 months at 6 to 45 °C and under likely transport conditions. The shelf-life stability study is ongoing to lengthen the shelf-life beyond 12 months for both the cartridges and external positive controls. Real-time stability studies were conducted for the external positive and negative controls and can be found at Annex XXX.
7.2.2 In-use stability Study Summary Report: SIMU HIV-1 Quant System Test Cartridge In-Use Stability Protocol: AP XXX Full Report: AR XXX – refer ANNEX XXX Study report SIMU HIV-1 Quant Test Cartridge In-Use Stability Study Dates: October 2014 Lot number: MOOC-137 expiry 10 2015 IFU version: v1.0 Conducted by: J. Patrick, Research and Development Dept., THE Manufacturing Company Testing: Performed on-site, Headquarters Study Objective The objective was to determine the stability of the Test Cartridge after removing the Test Cartridge from the pouch package and loading a plasma panel specimen into the device. The intended use population are trained users. Test Cartridges may be subjected to uncontrolled environmental conditions after opening, and a time delay between addition of the specimen to the Test Cartridge and testing. Acceptance Criterion The acceptance criterion was defined as demonstration of acceptable assay performance to support recommended in-use conditions. Acceptable assay performance was defined as a detection rate of 100% at a concentration of approximately 3x LoD HIV-1 M and specificity of 100%. The stability was taken as the time point prior to last time point to have met the acceptance criteria. Methodology/Study Design Stability panels contained HIV-1-negative, human, EDTA plasma spiked with HIV-1 group M (IIIB) virus to a concentration of 3 x LoD. The HIV-1 spiked specimens are traceable to the WHO International Standards for HIV-1 RNA for Nucleic Acid-Based Techniques. In-use stability studies for the SIMU HIV-1 Quant Test Cartridge were performed on one lot of the Test Cartridge. Only one lot was used as lot-to-lot variability had already been demonstrated with minimal variation (CV % < X%). The Test Cartridges was loaded with the panel members described above and the cartridge port closed. Cartridges were tested immediately after opening the cartridge
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WHO Sample product dossier for SIMU HIV-1 QUANT Product Performance Specifications and Associated Validation and V pouch and loading plasma specimen, and after storage at 20 ± 2 °C and 45 ± 5 °C for 1, 2, 6, and 25 hours at 60% humidity. Sufficient volume of each stability testing panel member for the duration of the testing schedule was prepared. Testing was performed in triplicate for each panel member for each condition. Multiple instruments were used to allow simultaneous testing of cartridges at each time point. At least 10% overage was allowed for unexpected requirements and re-testing. The Test Cartridges were divided into two groups and placed at either 20 ± 2 °C or 45 ± 5 °C. Cartridges from both groups were sampled at 0, 1, 2, 6, and 25 hours. Results In-Use Stability acceptable assay performance was demonstrated through the 24 hour time point for Test Cartridges stored at 20 ± 5 °C and 45 ± 5 °C at 60% humidity. These results demonstrate in-use stability at 20 to 45 °C for up to 24 hours after injection of the specimen into the Test Cartridge. Full study results are available in the Annex XXX Study report SIMU HIV-1 Quant System Test Cartridge in-use stability. Conclusion The device can be used for testing up to 24 hours at temperatures ranging from 20 to 45 °C after opening the package and loading an EDTA plasma specimen. The Manufacturer should refer to the WHO TGS-2 document “Establishing stability of an in vitro diagnostic for WHO Prequalification” for further information. http://www.who.int/diagnostics_laboratory/guidance/en/
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7.3 Robustness studies 7.3.1 Cross-contamination Study Summary Report: Cross-contamination Study Protocol: Full Report: Study Dates: Conducted by: Testing: SPXXX – refer Annex XXX AR XXX - refer Annex XXX. xxxxx A Blog, Research and Development Dept, THE Manufacturing Company. Performed on-site, Headquarters.
Study Objective To check for cross-contamination on the SIMU HIV-1 Quant Test Reagents and Instruments SIMU HIV-1 Quant Test Cartridge Lot Number: MPOC-1307 expiry 07 2016 SIMU Instrument Lot Number: MPR-11AGG Acceptance Criteria All negative specimens should be non-reactive and all positive specimens should be reactive. Methodology/Study Design The cross-contamination study used HIV-negative, pooled plasma, prepared as described in 7.1.2.2. Analytical Sensitivity Study Summary Report: Limit of Detection (95% LoD)Full (AR XXX - refer ANNEX X). Twenty high viral load, HIV-1 plasma specimens (1.00E+05 copies/mL) were purchased from a commercial vendor. The viral loads of these specimens were determined by the vendor and confirmed with a reference method assay. The 20 positive specimens and 20 aliquots of the pooled, negative plasma were tested with the SIMU HIV-1 Quant Test. The positive and negative specimens were loaded alternatively on the Instrument. The testing was performed on a second day using a further 20 HIV-1-positive and 20 negative plasma specimens. Results All 40 negative specimens showed no detectable target and all 40 HIV-1-positive specimens showed detection of target at appropriate levels in the HIV-1 channel only, giving a 0% cross-contamination rate. Conclusion No cross-contamination was observed with the SIMU HIV-1 Quant Test.
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7.3.2
Whole system failure SPXXX – refer Annex XXX AR XXX - refer ANNEX X. xxxxx A Blog, Research and Development Dept, THE Manufacturing Company. Performed on-site, Headquarters.
Study Summary Report: Whole system failure Study Protocol: Full Report: Study Dates: Conducted by: Testing:
Study Objective To determine the whole system failure of the SIMU HIV-1 Quant Test. Reagents and Instruments SIMU HIV-1 Quant Test Cartridge Lot Number: MPOC-1307 expiry 07 2016 SIMU Instrument Lot Number: MPR-11AGG Acceptance Criterion The whole system failure rate should be equal to or less than 1%. Methodology/Study Design The whole system failure rate was determined by testing 100 replicates of HIV-negative, pooled plasma, prepared as described in 7.1.2.2. Analytical Sensitivity Study Summary Report: Limit of Detection (95% LoD) (AR XXX - refer ANNEX X), spiked with HIV-1 group M at a concentration of approximately 3x LoD. The HIV-1 specimen used the HIV-1 (IIIB strain) working standard that was used for the Analytical Sensitivity Study (AR XXX - refer ANNEX X). Twenty specimens were tested on five consecutive days with the SIMU HIV-1 Quant Test. Results All 100 specimens were quantitated to acceptable concentrations of HIV-1 copies/mL. Conclusion The SIMU HIV-1 Quant test is robust and met the acceptance criteria.
The following additional robustness studies were undertaken and can be found in Annex XXX
7.3.3 7.3.4 7.3.5 7.3.6 7.3.7
Physical trauma and vibrations (drop and shock study) Power failure, fluctuation and incorrect voltage Use of improperly stored reagents Incorrect volume of specimen ……
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7.4 Clinical evidence (clinical sensitivity and specificity) 7.4.1 Clinical Evaluation by manufacturer Study Summary Report: Clinical Specificity and Sensitivity Protocol: SHST XXX - refer ANNEX XX Full Report: AR XXX - refer ANNEX X Study Dates: xxxxx Conducted by: Three external sites Testing: Performed at three external sites Study Objective To demonstrate the clinical specificity and sensitivity of the SIMU HIV-1 Quant Test using clinical specimens from HIV-negative and HIV-1-positive subjects. Both fresh and frozen EDTA plasma specimens were tested at three test sites in two geographically and demographically diverse regions where the test would be used. This included two high prevalence areas (>5% prevalence), and one low prevalence area (<5% prevalence). Reagents and Instruments SIMU HIV-1 Quant Test Cartridge Lot Number: MPOC-1307 expiry 07 2016 SIMU Instrument Lot Number: MPR-11AGG Acceptance Criteria The acceptance criterion below is for illustrative purposes only. The manufacturer is expected to define acceptance criteria for each specimen during the planning stage of study and prior to commencement of testing. If the results do not fall within the expected range, the manufacturer is expected to investigate why. The specificity was expected to be ≥ 99.5 % and 95% lower CI > 98.4%. The positive and negative percent agreement between the SIMU HIV-1 Quant Test and the expected results should be >99% (lower 95% CI >97%). The overall bias between the results for the SIMU HIV-1 Quant Test and the test viral loads over the dynamic range of the two assays should be ≤log10 0.3 copies/mL. Methodology/Study Design Clinical sensitivity was determined by testing 200 frozen plasma specimens with HIV-1 RNA concentrations >200 copies/mL and 100 fresh specimen in EDTA plasma collected from HIV-1 positive individuals. The specimens were tested for anti-HIV-1 and NAT reactivity using tests that have been authorized for use by a regulatory authority of the founding members of GHTF. The RNA concentrations of the specimens were determined with a reference method assay. Clinical specificity was determined by testing 100 frozen plasma specimens and 200 fresh plasma specimens from commercial vendors shown to be negative for HIV-1/2 and non-reactive for HIV-1 RNA using tests that have been authorized for use by a regulatory authority of the founding members of GHTF . Results A total of 300 evaluable HIV-negative and 300 HIV-1-positive patient specimens were included in clinical specificity and sensitivity analyses. Approximately 50% of the patient specimens were frozen. The demographic characteristics of the 300 evaluable HIV-1-positive specimens are summarized in Table 7-15. The CD4 cell counts of the subjects distributed approximately evenly across CD4 cell count categories (<200, 200-500, >500 cells/µL). Most of the subjects were female (60%) and
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WHO Sample product dossier for SIMU HIV-1 QUANT Product Performance Specifications and Associated Validation and V between 18 to 29 years of age (66.7%). The ethnic distribution in the panel is comparable to that observed in the HIV-1 population of the three regions.
Table 7-15: Demographics of HIV-1 evaluable specimens at the three testing sites Specimen Category characteristics Site 1 Site 2 Site 3 Total number of HIV-1 positive individuals (%) 96 (32%)
CD4 cell counts (cells/µL) Sex Age
<200 200 to 500 >500 Male Female 18 to 29 30 to 49 50 to 65 >65
30
20
46
10 table is for illustrative 50 60WHO expects 120 (40%) The purposes. manufacturers to provide 50 10 all results for 24the studies in an 84 (28%) easy to read format. 30 30 30 120 (40%) 60 70 15 16 1 [value] [value] [value] 60 50 20 12 0 [value] [value] [value] 60 80 15 20 1 [value] [value] [value] 180 (60%) 200 (66.7%) 50 (16.7%) 48 (16.0%) 2 (0.6%) [value] [value] [value]
Ethnicity
African Asian Caucasian
The clinical sensitivity and specificity were calculated from all three sites and are summarized in Table 7-16. Table 7-16: SIMU HIV-1 Quant Test Clinical Sensitivity and Specificity Site 1
Specimen HIV-1 positive
Positive 300
Negative
Total
Clinical sensitivity (95% CI)
Specimen HIV-1 negative
0 300 100% (98.4, 100) The table is for illustrative purposes. WHO expects manufacturers to provide all results for the studies in an Positive Negative Total Clinical specificity easy to read format .
(95% CI)
3
297
300
99% (96.6, 99.7)
The clinical sensitivity was 100% (98.4, 100) and the clinical specificity of the test was 99% (96.6, 99.7). Three of the 300 qualified HIV-1 negative specimens gave false-positive results (all these falsepositive results were obtained at site 2).
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WHO Sample product dossier for SIMU HIV-1 QUANT Product Performance Specifications and Associated Validation and V Method comparison between SIMU HIV-1 Quant Test and the reference test was undertaken using Bland-Altman analysis. Of the 300 specimens in the HIV-1 positive testing panel a total of 250 paired specimen results (for which both test and reference results were within the linear range of both assays) were chosen for analysis. The SIMU HIV-1 Quant Test and reference test were considered to be equivalent if the differences in viral loads of the 250 paired specimens between the SIMU Quant HIV-1 Test and the reference test were all within ± 2 SD of the mean. Bland-Altman analysis, described in XXX Study Report: Bland-Altman Analysis (Appendix XXX), suggests that the SIMU HIV-1 Quant Test and the reference test are equivalent (the differences in viral loads of the paired specimens between the SIMU Quant HIV-1 Test and the reference testwere all within ± 2 SD of the mean. Conclusions The clinical sensitivity and specificity of the SIMU HIV-1 Quant Test as determined by three field evaluations were 99% and 100% respectively. The clinical sensitivity and specificity of the SIMU HIV-1 Quant Test as determined by three field evaluations were 100% and 99% respectively. The mean difference in the viral load of the SIMU HIV-1 Quant Test and the reference method over the dynamic ranges of the assays met the acceptance criterion.
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Labelling
8 Labelling 8.1 Labelling 8.1.1 Instrument labelling The Instrument label is attached to the front of the instrument. It includes the product name, serial number, manufacturing information, Lithium ion battery symbol, power type and consumption, and version number. It is resistant to water, alcohol based cleaning agents and friction. Only internationally recognized symbols are used (ISO 15223-1:2016). The Instrument box label is a well-fixed water resistant label (applied with high quality waterresistant glue) and permanent printing is utilized. As per the International Air Transport Association lithium battery guidance the packaging is labelled with battery handling instructions. Temperature logger tags are included on the box. This allows THE Manufacturing Company to monitor shipments and storage as well as to trace and remediate errors.
8.1.2 8.1.2.1
Test Cartridge pouch packaging and labelling (Figure XXY) Pouch packaging
Each Test cartridge is packed in a single unit pouch. Table 8-1: Characteristics of single unit pouches Materials
Waterproof metallised wrapping • • Heat sealable Indentation to allow easy opening of the device packaging without the need for scissors
Design dimensions Weight Pouch labelling
Length = 5 cm, Width = 2.5 cm, Height = 1 cm 100 gram • Internationally recognised symbols are used (ISO 15223-1) • A well-fixed water resistant label (applied with high-quality water resistant glue) and permanent printing are utilized.
8.2
Instructions for Use
A comprehensive IFU was developed and qualified by THE Manufacturing Company in compliance with the following regulatory requirements, standards and guidance documents: Table 8-2: Requirement, standard and guidance documents for IFU and job aid development Source ISO Document number ISO 181131:2009 ISO 181132:2009 Document name In Vitro Diagnostic Medical Devices - Information Supplied by the Manufacturer (Labelling) - Part 1: Terms, Definitions and General Requirements In Vitro Diagnostic Medical Devices. Information Supplied by the Manufacturer (Labelling) - Part 2: In Year publishe d 2009
ISO
2009
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WHO Sample product dossier for SIMU HIV-1 QUANT Vitro Diagnostic Reagents for Professional Use In Vitro Diagnostic Medical Devices - Information Supplied by the Manufacturer (Labelling) – Part 3: In Vitro Diagnostic Instruments for Professional Use Medical Devices – Symbols to be Used with Medical Device Labels, Labelling and Information to be supplied - Part 1: General requirements Medical devices - Application of risk management to medical devices. Geneva: International Organization for Standardization Label and Instruction for Use for Medical Devices UDI Guidance: Unique Device Identification (UDI) of Medical Devices Guidance on Medical Device Patient Labeling; Final Guidance for Industry and FDA Reviewers Write it Right: Recommendations for Developing User Instruction Manuals for Medical Devices Used in Home Health Care Guidance for Industry and Food and Drug Administration Staff. Design Considerations for Devices Intended for Home Use Guidelines on medical devices. IVD guidances: Supply of Instructions For Use (IFU) and other information for In-vitro Diagnostic (IVD) Medical Devices. A guide for manufacturers and notified bodies Guidance Document - Labelling of In Vitro Diagnostic Devices Guidance for notified bodies on the regulation of IVDs for self-testing
Labelling
ISO
ISO 181133:2009 ISO 152231:2016 ISO 14971:2007
2009
ISO
2016
ISO
2007
GHTF IMDRF US FDA US FDA
GHTF/SG1/N70: 2011 IMDRF/UDIWG/ N7FINAL:2013 1128
2011 2013 2001 1993
US FDA
1750
2014
European Commission
MEDDEV. 2.14/3 rev.1
2007
Health Canada MHRA
2016 2012
The IFU is attached in Annex XX.
8.3
Instrument manual
See Annex XXX
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Commercial History
9 Commercial History 9.1 Countries of supply 9.1.1 List of countries where product is currently supplied The SIMU HIV-1 Quant System has been supplied in South Africa, Kenya, India, Republic of Korea, Brazil, Mexico, and Peru since late 2015. A total of 1 110 000 tests have been supplied.
9.1.2
Minimum and maximum price in 2015
The price per test varies between US$ 5.00 and US$ 9.50. The majority of tests sold have been at US$ 7.50 per test. A number of tests (approximately 10 000) were donated to Nigeria for performance evaluation.
9.1.3 9.1.3.1
Training and support network IFU
The utility of the IFU has been subjected to intense testing by THE Manufacturing Company, as part of our risk analysis for instructions to users. The goal was that these instructions would prove sufficient to a range of users with varying skills levels, acknowledging the fact that the product will be used in a variety of settings. A report of this testing is held at Headquarters (refer DOC XXX).
9.1.3.2
Online training
A video training program for the SIMU HIV-1 Quant Test in English is available on the website of THE Manufacturing Company or on a CD by request, which gives training on the basic functions of the Instrument, and basic trouble shooting instructions.
9.1.3.3
Extensive technical training for users familiar with running of the Instrument
Extensive technical training is provided by THE Manufacturing Company for users who are already familiar with the running of the Instrument and focused on people with responsibility for a number of instruments. super
9.1.3.4
Training the trainer
Technical support is provided by the local distributor as required, and mobile agents are available in country for trouble shooting for the Instrument. Technical support training for local distributors is provided by staff of THE Manufacturing Company staff in all distribution countries.
9.1.3.5
Software updates
Software updates and fixes can be downloaded by internet connection.
9.2
Adverse events and field safety corrective actions
No field safety corrective action has been required since any version of the product has been marketed.
9.2.1
Table of adverse event reports
No adverse events have been reported as yet. Table 9-1: Table of adverse event reports QA reference Type of event (None reported) Country of event Determined cause Action taken
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Regulatory History
10 Regulatory History Certified copies of the Korea Licence Holder Certificate are also provided in ANNEX XXX.
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Quality Management System
11 Quality Management System 11.1 11.1.1 Quality manual Quality management system documents Manufacturer to insert a complete list of all valid quality management system documents with document title and number relevant to the product under prequalification assessment Refer to Annex VIII.
11.1.2
Quality management system procedures 1. Control of design and development changes (SOP XXXX) 2. Risk management planning and implementation (SOP XXXX) 3. Control of non-conforming goods (SOP XXXX) 4. Corrective and preventive actions (SOP XXXX) 5. Recalls procedure (SOP XXXX) 6. Control of key suppliers (SOP XXXX)
Refer to Annex XXX for documented procedures for the following areas:
11.2
Quality management system certification
THE Manufacturing Company holds ISO 13485 Medical devices – Quality management systems – Requirements for regulatory purposes certification for the manufacture of the product under assessment, which is valid until 23 March 2018. A certified copy of the certificate is attached in Annex XX in addition to the two previous inspection reports issued by the certification.
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Annex I: Essential Principles Checklist
Annex I: Essential Principles Checklist Notes This document applies to the following configuration of the SIMU HIV-1 Quant System. The Risk Management File is made up of the Risk Management Plan, Risk Management Report, and associated risk analyses. These documents are located in the DHF. Copies of test results to applicable standards referenced below are located in the DHF. The test system is comprised of the SIMU Instrument with integrated software, SIMU HIV-1 Quant Test Cartridge (consisting of 25 or 100 Test Cartridges) Check list of Essential Principles of GHTF/SG1/N068 for: SIMU HIV-1 Quant Test SIMU HIV-1 Quant Test Document version # 03 Written by: Signature Date Document date: Approved by: QA Signature Regulatory affairs Signature Changes from earlier versions: Version 01 02 03 Date 2011-01-01 Date 2011-06-15 Date 2011-10-15 Item modified N/A B6 C9.3 Modification Document created according to SOP XXX B6 added for instrument readout C9.3 added for instrumentation Date Date Agreed by: R&D Signature Manufacturing Signature Date Date Product Codes: M123, M124
Please Note: The checklist submitted to WHO must include dates and signatures
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Annex I: Essential Principles Checklist
THE Manufacturing Company Essential principles A GENERAL PRINCIPLES A.1 Medical devices should be designed and manufactured in such a way that, when used under the conditions and for the purposes intended and, where applicable, by virtue of the technical knowledge, experience, education or training, and the medical and physical conditions of intended users, they will perform as intended by the manufacturer and not compromise the clinical condition or the safety of patients, or the safety and health of users or, where applicable, other persons, provided that any risks which may be associated with their use constitute acceptable risks when weighed against the benefits to the patient and are compatible with a high level of protection of health and safety Applicable/ Not Applicable (A/NA) A
SIMU HIV-1 Quant Test Product Codes M123 and M124 Method(s) and references used to demonstrate Reference to supporting controlled documents conformity of Manufacturer Application of recognized Standards: • ISO 13485:2016 Medical Devices – Quality management systems-Requirements for Regulatory Purposes. • ISO 14971:2007 Medical devices – Application of risk management to medical devices. • EN 13641:2002 Elimination or reduction of risk of infection related to in vitro diagnostic reagents. • ISO 13485:2016 certificate held by QA department, certified copy submitted for Annex XXX of this dossier. • “SIMU HIV-1 Quant Risk Management and Control Report” held by QA. • Risk analysis output documents “SIMU HIV1 Quant - design risk”, “SIMU HIV-1 Quant processes”, “SIMU HIV-1 Quant risk-users”. • SIMU HIV-1 Quant Residual risk statement. • DHF, design input specification and design validation documentation (held by QA and in summary as Section 7 of this dossier). • Incoming goods analysis and control documentation held by QA “SOP XXX”. • Safety data sheets: Manufacturing department. • Regulation of Hazard control. • Risk management policy document “Policy XXX” and risk analysis SOPs “SOP XXX”, “SOP XXXX” held by Quality management Department • Risk analysis output documents “SIMU HIV1 Quant -design”, “SIMU HIV-1 Quant processes”, “SIMU HIV-1 Quant -users” • “SIMU HIV-1 Quant Risk Management and Control Report” held by QA • SIMU HIV-1 Quant IFU.
A.2
The solutions adopted by the manufacturer for the design and manufacture of the devices should conform to safety principles, taking account of the generally acknowledged state of the art. -When risk reduction is required, the manufacturer should control the risks so that the residual risk associated with each hazard is judged acceptable. The manufacturer should apply the following principles in the priority order listed: • identify known or foreseeable hazards and estimate the associated risks arising from the intended use and foreseeable misuse;
A
Application of recognized Standards: • ISO 13485:2016 Medical Devices- Quality management systems-Requirements for Regulatory Purposes. • ISO 14971:2007 Medical devices – Application of risk management to medical devices. • ISO 18113:2009 In vitro diagnostic medical devices – Information supplied by the manufacturer (labelling) – Parts 1 and 4.
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Annex I: Essential Principles Checklist
THE Manufacturing Company Applicable/ Essential principles Not Applicable (A/NA) • eliminate risks as far as reasonably practicable through inherently safe design and manufacture; • reduce as far as reasonably practicable the remaining risks by taking adequate protection measures, including alarms; and inform users of any residual risks. A.3 Medical devices should achieve the performance A intended by the manufacturer and be designed and manufactured in such a way that, during normal conditions of use, they are suitable for their intended purpose.
SIMU HIV-1 Quant Test Product Codes M123 and M124 Method(s) and references used to demonstrate Reference to supporting controlled documents conformity of Manufacturer
Application of recognized standards: • ISO 13485:2016 Medical Devices - Quality management systems-Requirements for Regulatory Purposes. • ISO 14971:2007 Medical devices – Application of risk management to medical devices. • EN 13612:2002 Performance evaluation of in vitro diagnostic medical devices. • GHTF/SG5/N6:2012 Clinical Evidence for IVD medical devices – Key Definitions and Concepts. • GHTF/SG5/N8:2012 Clinical Evidence for IVD Medical Devices - Clinical Performance Studies for In Vitro Diagnostic Medical Devices. • ISO 23640:2011 In vitro diagnostic medical devices -- Evaluation of stability of in vitro diagnostic reagents. • CLSI. Evaluation of Stability of In Vitro Diagnostic Reagents; Approved Guideline. CLSI document EP25-A. Wayne, PA: Clinical and Laboratory Standards Institute; 2009. • Technical Guidance Series for WHO Prequalification – Diagnostic Assessment: Establishing stability of an in vitro
• Risk management policy document “Policy XXX” and risk analysis SOPs “SOP XXX”, “SOP XXXX” held by Quality management department. • Risk analysis output documents “SIMU HIV-1 Quant -risk-design”, “SIMU HIV-1 Quant - processes”, “SIMU HIV-1 Quant risk-users”. • “SIMU HIV-1 Quant Risk Management and Control Report” held by QA. • All verification and validation studies (refer Section 7 of this dossier). • Traceability of SIMU HIV-1 Quant Control Cells.
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Annex I: Essential Principles Checklist
THE Manufacturing Company Essential principles Applicable/ Not Applicable (A/NA)
SIMU HIV-1 Quant Test Product Codes M123 and M124 Method(s) and references used to demonstrate Reference to supporting controlled documents conformity of Manufacturer diagnostic for WHO Prequalification, TGS–2. Geneva: World Health Organization; 2016 Verification and Validation - Section 7 Studies Application of recognized standards: • ISO 18113:2009 In vitro diagnostic medical devices – Information supplied by the manufacturer (labelling) – Parts 1 and 4. • ISO 14971:2007 Medical devices – Application of risk management to medical devices. • ISO 23640:2011 In vitro diagnostic medical devices -- Evaluation of stability of in vitro diagnostic reagents. • CLSI EP25A:2009 Evaluation of Stability of In Vitro Diagnostic Reagents; Approved Guideline. Stability and (user) Validation -Studies Application of recognized standards: • ISO 18113:2009 In vitro diagnostic medical devices – Information supplied by the manufacturer (labelling) – Parts 1 and 4. • ISO 14971:2007 Medical devices – Application of risk management to medical devices. • ISO 23640:2011 In vitro diagnostic medical devices -- Evaluation of stability of in vitro diagnostic reagents. • CLSI EP25A:2009 Evaluation of Stability of In Vitro Diagnostic Reagents; Approved Guideline. Stability Studies • All verification and validation studies (refer Section 7 of this dossier) including Stability studies (Section 7.2). • Risk management policy document “Policy XXX” and risk analysis SOPs “SOP XXX”, “SOP XXXX” held by Quality management department. • Risk analysis output documents “SIMU HIV1 Quant risk-design”, “SIMU HIV-1 Quant processes”, “SIMU HIV-1 Quant -users”. • “SIMU HIV-1 Quant Risk Management and Control Report” held by QA. • SIMU HIV-1 Quant IFU. • Stability studies (Section 7.2 of this dossier). • Risk management policy document “Policy XXX” and risk analysis SOPs “SOP XXX”, “SOP XXXX” held by Quality management department. • Risk analysis output documents “SIMU HIV1 Quant -risk-design”, “SIMU HIV-1 Quant risk - processes”, “SIMU HIV-1 Quant riskusers”. • “SIMU HIV-1 Quant Risk Management and Control Report” held by QA. • SIMU HIV-1 Quant IFU.
A4
The characteristics and performances referred to in Clauses A1, A2 and A3 should not be adversely affected to such a degree that the health or safety of the patient or the user and, where applicable, of other persons are compromised during the lifetime of the device, as indicated by the manufacturer, when the device is subjected to the stresses which can occur during normal conditions of use and has been properly maintained in accordance with the manufacturer’s instructions
A
A5
Medical devices should be designed, manufactured and packaged in such a way that their characteristics and performances during their intended use will not be adversely affected by transport and storage conditions (for example, fluctuations of temperature and humidity) taking account of the instructions and information provided by the manufacturer
A
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Annex I: Essential Principles Checklist
THE Manufacturing Company Applicable/ Essential principles Not Applicable (A/NA) A6 All known and foreseeable risks, and any undesirable A effects, should be minimized and be acceptable when weighed against the benefits of the intended performance of medical devices during normal conditions of use
SIMU HIV-1 Quant Test Product Codes M123 and M124 Method(s) and references used to demonstrate Reference to supporting controlled documents conformity of Manufacturer Application of recognized standards: • Risk analysis output documents “SIMU HIV• GHTF/SG5/N6:2012 Clinical Evidence for IVD 1 Quant -risk-design”, “SIMU HIV-1 Quant medical devices – Key Definitions and risk - processes”. Concepts. • “SIMU HIV-1 Quant risk-users”. • GHTF/SG5/N8:2012 Clinical Evidence for IVD • “SIMU HIV-1 Quant Risk Management and Medical Devices - Clinical Performance Control Report” held by QA. Studies for In Vitro Diagnostic Medical Devices. • ISO 14971:2007 Medical devices – Application of risk management to medical devices. Application of recognized standards: • ISO 14971:2007 Medical devices – Application of risk management to medical devices. • EN 13612:2002 (Clause 4.5) Performance evaluation of in vitro diagnostic medical devices. • ISO 8601:2004 (Section 4.1). Data elements and interchange formats -- Information interchange -- Representation of dates and times • All verification studies (refer Section 7 of the dossier). • Process validation and software validation report (BXXXXX).
B6 B6.1
Devices with a diagnostic or measuring function Diagnostic devices and devices with a measuring function, should be designed and manufactured in such a way as to provide sufficient accuracy, precision and stability for their intended purpose of the device, based on appropriate scientific and technical methods. The limits of accuracy should be indicated by the manufacturer.
B6.2
The measuring, monitoring or display scale (including colour change and other visual indicators) must be designed and manufactured in line with ergonomic principles, taking account of the intended purpose of the device.
A
Application of recognized standards: • ISO 14971:2007 Medical devices – Application of risk management to medical devices. • IEC 62366-1:2015. Medical devices. Part 1: Application of usability engineering to medical devices
SOPXXXX, SOPXXXX.
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Annex I: Essential Principles Checklist
THE Manufacturing Company Applicable/ Essential principles Not Applicable (A/NA) B6.3 Wherever possible values expressed numerically A should be in commonly accepted, standardized units, and understood by the users of the device. C C1 C1.1 Essential Principles Applicable to IVD Medical Devices Chemical, physical and biological properties The IVD medical devices should be designed and manufactured in such a way as to ensure the characteristics and performance referred to in Section A. -Particular attention should be paid to the possibility of impairment of analytical performance due to incompatibility between the materials used and the specimens and/or analyte (measurand) to be detected (such as biological tissues, cells, body fluids and micro-organisms), taking account of its intended purpose The IVD medical devices should be designed, manufactured and packaged in such a way as to minimize the risk posed by contaminants and residues to the persons involved in the transport, storage and use of the devices and to patients, taking account of the intended purpose of the device. -
SIMU HIV-1 Quant Test Product Codes M123 and M124 Method(s) and references used to demonstrate Reference to supporting controlled documents conformity of Manufacturer Application of recognized standards: SIMU HIV-1 Quant IFU • ISO 18113:2009 In vitro diagnostic medical devices – Information supplied by the manufacturer (labelling) – Parts 1, 2 and 3. Application of recognized standards: • ISO 13485:2016 Medical Devices - Quality management systems-Requirements for Regulatory Purposes. • ISO 14971:2007 Medical devices – Application of risk management to medical devices. • ISO 18113:2009 In vitro diagnostic medical devices – Information supplied by the manufacturer (labelling) – Parts 1 and 4. Verification and Validation Studies- Section 7 Application of recognized standards: • ISO 14971:2007 Medical devices – Application of risk management to medical devices. • ASTM D4169 – 14 Standard Practice for Performance Testing of Shipping Containers and Systems • All verification -studies (refer Section 7 of this dossier). • Risk analysis output documents “SIMU HIV-1 Quant -risk-design”, “SIMU HIV-1 Quant risk - processes”. • “SIMU HIV-1 Quant risk-users”. • “SIMU HIV-1 Quant Risk Management and Control Report” held by QA. • SIMU HIV-1 Quant IFU (“Warnings for Users”, ”Specimen Collection, Preparation and Storage”). • Risk analysis output documents “SIMU HIV-1 Quant -risk-design”, “SIMU HIV-1 Quant - processes”, “SIMU HIV-1 Quant risk-users”. • “SIMU HIV-1 Quant Risk Management and Control Report” held by QA. • Packing and Shipping SOP XXX. • SIMU HIV-1 Quant -Robustness Studies (held on-site and Section 7.3). • Package Robustness Studies (held on-site). • Risk analysis output documents “SIMU HIV-1 Quant -risk-design”, “SIMU HIV-1 Quant - processes”, “SIMU HIV-1 Quant risk-users”.
A
C1.2
A
C1.3
The IVD medical devices should be designed and manufactured in such a way as to reduce as far as reasonably practicable and appropriate the risks posed by substances that may leach or leak from the
A
Application of recognized standards: • ISO 14971:2007 Medical devices – Application of risk management to medical devices.
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Annex I: Essential Principles Checklist
THE Manufacturing Company Applicable/ Essential principles Not Applicable (A/NA) IVD medical device. -Special attention should be given to substances which are carcinogenic, mutagenic or toxic to reproduction. C1.4 IVD medical devices should be designed and manufactured in such a way as to reduce as far as reasonably practicable and appropriate risks posed by the unintentional ingress or egress of substances into or from the IVD medical device taking into account the device and the nature of the environment in which it is intended to be used Infection and microbial contamination The IVD medical devices and manufacturing processes should be designed in such a way as to eliminate or to reduce as far as reasonably practicable and appropriate the risk of infection to user, professional or lay, or, where applicable, -other person . -The design should: allow easy and safe handling ; and, where necessary: reduce as far as reasonably practicable and appropriate any microbial leakage from the IVD medical device and/or microbial exposure during use; and prevent microbial contamination of the IVD medical device or specimen where applicable, by the user, professional or lay, or other person IVD medical devices labelled either as sterile or as having a special microbiological state should be designed, manufactured and packaged to ensure they remain so when placed on the market and remain so A
SIMU HIV-1 Quant Test Product Codes M123 and M124 Method(s) and references used to demonstrate Reference to supporting controlled documents conformity of Manufacturer • “SIMU HIV-1 Quant Risk Management and Control Report” held by QA. • SIMU HIV-1 Quant Robustness Studies (held on-site). Application of recognized standards: • Risk analysis output documents “SIMU • ISO 14971:2007 Medical devices – HIV-1 Quant -risk-design”, “SIMU HIV-1 Application of risk management to medical Quant risk - processes”, “SIMU HIV-1 devices. Quant risk-users”. Verification and Validation studies – Section 7 • “SIMU HIV-1 Quant Risk Management and Control Report” held by QA. • SIMU HIV-1 Quant Cartridge Robustness Studies (held on-site). Application of recognized standards: • ISO 13485:2016 Medical Devices - Quality management systems-Requirements for Regulatory Purposes • ISO 14971:2007 Medical devices – Application of risk management to medical devices • EN 13641:2002 Elimination or reduction of risk of infection related to in vitro diagnostic reagents Verification and Validation Studies – Section 7 • All verification studies (refer Section 7 of the dossier). • Risk analysis output documents “SIMU HIV-1 Quant -risk-design”, “SIMU HIV-1 Quant risk - processes”, “SIMU HIV-1 Quant risk-users”. • “SIMU HIV-1 Quant Risk Management and Control Report” held by QA. • Materials management requirements and policy kept in R&D (control materials contain potentially infectious components. Policy reflects requirements to source materials that pose the least possible risk of transmission of infection).
C2 C2.1
A
C2.2
NA
Not provided in a sterile state.
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Annex I: Essential Principles Checklist
THE Manufacturing Company Applicable/ Essential principles Not Applicable (A/NA) under the transport and storage conditions specified by the manufacturer, until the protective packaging is damaged or opened C2.3 IVD medical devices labelled either as sterile or as NA having a special microbiological state should have been processed, manufactured and, if applicable, sterilized by appropriate, validated methods. C2.4 IVD medical devices intended to be sterilized should NA be manufactured in appropriately controlled (e.g. environmental) conditions. C2.5 Packaging tests for non-sterile IVD medical devices A should maintain the integrity and cleanliness of the device
SIMU HIV-1 Quant Test Product Codes M123 and M124 Method(s) and references used to demonstrate Reference to supporting controlled documents conformity of Manufacturer
Not provided in a sterile state.
Not provided in a sterile state. Application of recognized standards: • Robustness studies (results available in R&D Department). • ISO 13485:2016 Medical Devices - Quality management systems -Requirements for • Control Specimen Antimicrobial Regulatory Purposes. effectiveness study (results available in R&D • ISO 14001:2015 Environmental management Department). tests -- Requirements with guidance for use. • Environmental Control SOP XXX. Dossier Sections 6&7. • No Transmissible spongiform
C3 C3.1
IVD medical devices incorporating materials of biological origin Where IVD medical devices include tissues, cells and substances originating from animals, the processing, preservation, testing and handling of tissues, cells and substances of animal origin should be carried out so as to provide optimal safety for user, professional or lay, or other person In particular, safety with regard to viruses and other transmissible agents should be addressed by implementation of validated methods of elimination or inactivation in the course of the manufacturing process. -This may not apply to certain IVD medical devices if the activity of the virus and other transmissible agent are integral to the intended
A
Application of recognized standards: • ISO 14971:2007 Medical devices – Application of risk management to medical devices. • EN 13641:2002 Elimination or reduction of risk of infection related to in vitro diagnostic reagents • ISO 13485:2016 Medical Devices - Quality management systems -Requirements for Regulatory Purposes. • WHO Tables on Tissue Infectivity Distribution in Transmissible Spongiform Encephalopathies Updated 2010
the device but Management and Control Report” held by QA. • Materials management requirements and policy kept in R&D. • Policy reflects requirements to source materials that pose the least possible risk of transmission of infection. • Document control policy requires ongoing review of risk posed by scientific methods used to reduce or eliminate potential infectious agents in components for Tests Page 81
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WHO Sample product dossier for SIMU HIV-1 QUANT
Annex I: Essential Principles Checklist
THE Manufacturing Company Applicable/ Essential principles Not Applicable (A/NA) purpose of the IVD medical device or when such elimination or inactivation process would compromise the performance of the IVD medical device. National regulations may require that the manufacturer and/or the Regulatory Authority retain information on the geographical origin of the animals C3.2 Where IVD medical devices include human tissues, A cells and substances, the selection of sources, donors and/or substances of human origin, the processing, preservation, testing and handling of tissues, cells and substances of such origin should be carried out so as to provide optimal safety for user, professional or lay, or other person In particular, safety with regard to viruses and other transmissible agents should be addressed by implementation of validated methods of elimination or inactivation in the course of the manufacturing process. –This may not apply to certain IVD medical devices if the activity of the virus and other transmissible agent are integral to the intended purpose of the IVD medical device or when such elimination or inactivation process would compromise the performance of the IVD medical device
SIMU HIV-1 Quant Test Product Codes M123 and M124 Method(s) and references used to demonstrate Reference to supporting controlled documents conformity of Manufacturer WHO/EMP/QSM/2010.1 already on the market. • List of Bovine Spongiform Encephalopathy • Material specification sheets. Risk Status of Member Countries published on the World Organisation for Animal Health website Verification and Validation Studies. Application of recognized standards: • The human plasma used for external • ISO 14971:2007 Medical devices – controls is the only human material used in Application of risk management to medical the kit. -see C3.1 for THE Manufacturing devices. Company’s policy on such materials. • EN 13641:2002 Elimination or reduction of risk of infection related to in vitro diagnostic reagents • ISO 13485:2016 Medical Devices - Quality management systems -Requirements for Regulatory Purposes. • WHO Tables on Tissue Infectivity Distribution in Transmissible Spongiform Encephalopathies Updated 2010 WHO/EMP/QSM/2010.1 • List of Bovine Spongiform Encephalopathy Risk Status of Member Countries published on the World Organisation for Animal Health website Verification and Validation Studies. Application of recognized standards: • ISO 14971:2007 Medical devices – Application of risk management to medical devices • EN 13641:2002 Elimination or reduction of No such materials in the device but -see C3.1 for THE Manufacturing Company’s policy on such materials.
C3.3
Where IVD medical devices include cells and substances of microbial origin, the processing, preservation, testing and handling of cells and substances should be carried out so as to provide optimal safety for user, professional or lay, or other
A
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Annex I: Essential Principles Checklist
THE Manufacturing Company Essential principles person. In particular, safety with regard to viruses and other transmissible agents should be addressed by implementation of validated methods of elimination or inactivation in the course of the manufacturing process. -This may not apply to certain IVD medical devices if the activity of the virus and other transmissible agent are integral to the intended purpose of the IVD medical device or when such elimination or inactivation process would compromise the performance of the IVD medical device. Applicable/ Not Applicable (A/NA)
SIMU HIV-1 Quant Test Product Codes M123 and M124 Method(s) and references used to demonstrate Reference to supporting controlled documents conformity of Manufacturer risk of infection related to in vitro diagnostic reagents • ISO 13485:2016 Medical Devices - Quality management systems -Requirements for Regulatory Purposes. • WHO Tables on Tissue Infectivity Distribution in Transmissible Spongiform Encephalopathies Updated 2010 WHO/EMP/QSM/2010.1 • List of Bovine Spongiform Encephalopathy Risk Status of Member Countries published on the World Organisation for Animal Health website. Verification and Validation Studies. Application of recognized standards: • ISO 13485:2016 Medical Devices - Quality management systems-Requirements for Regulatory Purposes. • ISO 14971:2007 Medical devices – Application of risk management to medical devices. Validation Studies Section 7 • Risk analysis output documents “SIMU HIV-1 Quant risk-design”,“SIMU HIV-1 Quant risk - processes”,“SIMU HIV-1 Quant risk-users”. • “SIMU HIV-1 Quant Test Risk Management and Control Report” held by QA. • Design specifications (held on-site). • SIMU HIV-1 Quant Test – IFU, SIMU Instrument Users’ Manual.
C4 C4.1
Environmental properties If the IVD medical device is intended for use in combination with other devices or equipment, the whole combination, including the connection test should not impair the specified performance of the devices. -Any restrictions on use applying to such combinations should be indicated on the label and/or in the IFU
A
C4.2 C4.2.1
IVD medical devices should be designed and manufactured in such a way as to remove or reduce as far as reasonably practicable and appropriate: the risk of injury to user, professional or lay, or other person in connection with their physical and ergonomic features;
A
Application of recognized standards: • ISO 13485:2016 Medical Devices - Quality management systems-Requirements for
• Risk analysis output documents, mostly related to lancets -“ SIMU HIV-1 Quant risk-design”, “SIMU HIV-1 Quant risk Page 83
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Annex I: Essential Principles Checklist
THE Manufacturing Company Essential principles Applicable/ Not Applicable (A/NA)
C4.2.2
the risk of use error due to the ergonomic features, human factors and the environment in which the IVD medical device is intended to be used;
A
C4.2.3
The risks connected with reasonably foreseeable external influences or environmental conditions, such as magnetic fields, external electrical and electromagnetic effects, electrostatic discharge, pressure, humidity, temperature or variations thereof;
A
SIMU HIV-1 Quant Test Product Codes M123 and M124 Method(s) and references used to demonstrate Reference to supporting controlled documents conformity of Manufacturer Regulatory Purposes. processes”, “SIMU HIV-1 Quant risk• ISO 14971:2007 Medical devices – users”. Application of risk management to medical • “SIMU HIV-1 Quant Risk Management devices. and Control Report” held by QA. Validation - Section 7 Studies. • Design specifications (held on-site). • All validation data (refer Section 7.4 of this dossier). Application of recognized standards: • Risk analysis output documents “SIMU • ISO 13485:2016 Medical Devices - Quality HIV-1 Quant -risk-design”, “SIMU HIV-1 management systems-Requirements for Quant risk - processes”, “SIMU HIV-1 Regulatory Purposes Quant risk-users”. • ISO 14971:2007 Medical devices – • “SIMU HIV-1 Quant Risk Management Application of risk management to medical and Control Report” held by QA. devices • Design specifications (held on-site). • ISO 18113:2009 In vitro diagnostic medical • SIMU HIV-1 Quant IFU. devices – Information supplied by the • All validation data (refer to Section 7.4 of manufacturer (labelling) – Part 4 this dossier). Validation - Section 7 Studies Application of recognized standards: • Copy of subcontractor’s Declaration of • ISO 13485:2016 Medical Devices - Quality Conformity (Annex IV) to DIRECTIVE management systems-Requirements for 2004/108/EC (held on-site). Regulatory Purposes • Routine audits of subcontractor’s compliance to required specifications, • ISO 14971:2007 Medical devices – Application of risk management to medical including safety testing. devices • Risk analysis output documents “SIMU • ISO 23640:2011 In vitro diagnostic medical HIV-1 Quant risk-design”, “SIMU HIV-1 devices -- Evaluation of stability of in vitro Quant - processes”, “SIMU HIV-1 Quant diagnostic reagents risk-users”. • CLSI EP25A:2009 Evaluation of Stability of In • “SIMU HIV-1 Quant Test Risk Vitro Diagnostic Reagents; Approved Management and Control Report” held by Guideline QA. • IEC 60601-1-11:2015 Preview • Design specifications (held on-site). Page 84
WHO Sample product dossier for SIMU HIV-1 QUANT
Annex I: Essential Principles Checklist
THE Manufacturing Company Essential principles Applicable/ Not Applicable (A/NA)
C4.2.4
The risks associated with the use of the IVD medical device when it comes into contact with materials, liquids, and gases to which it is exposed during normal conditions of use;
A
C4.2.5
the risk associated with the possible negative interaction between software and the environment within which it operates and interacts;
A
C4.2.6
the risks of accidental penetration of substances into the IVD medical device;
A
SIMU HIV-1 Quant Test Product Codes M123 and M124 Method(s) and references used to demonstrate Reference to supporting controlled documents conformity of Manufacturer • Medical electrical equipment -- Part 1-11: General requirements for basic safety and essential performance -- Collateral standard: Requirements for medical electrical equipment and medical electrical systems used in the home healthcare environment Validation and Stability -Studies Section 7.4 Application of recognized standards: • Risk analysis output documents “SIMU • ISO 13485:2016 Medical Devices - Quality HIV-1 Quant -risk-design”, “SIMU HIV-1 management systems-Requirements for Quant risk - processes”, “SIMU HIV-1 Regulatory Purposes. Quant risk-users”. • ISO 14971:2007 Medical devices – • “SIMU HIV-1 Quant Risk Management Application of risk management to medical and Control Report” held by QA. devices. • Design specifications (held on-site). Validation Studies - Section 7. • All validation data (refer Section 7.4 of this dossier). Application of recognized standards: • Refer to subcontractor’s “Software performance testing - Robustness study” • IEC 62304:2006 Medical device software (dossier Section 7.3 and held on-site). Software life cycle processes. The software is built into the HIV-1 Quant • Refer to joint study THE Manufacturer and Instrument. subcontractor’s “Usability Testing Report”. The SIMU Instrument software can detect hardware failure. Application of recognized standards: • Risk analysis output documents “SIMU • ISO 13485:2016 Medical Devices - Quality HIV-1 Quant -risk-design”, “SIMU HIV-1 management systems-Requirements for Quant risk - processes”, “SIMU HIV-1 Regulatory Purposes. Quant risk-users”. • ISO 14971:2007 Medical devices – • “SIMU HIV-1 Quant Risk Management Application of risk management to medical and Control Report” held by QA. devices. • Design specifications (held on-site). Validation Studies Section 7. • All validation data (refer to Section 7.4 of Page 85
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Annex I: Essential Principles Checklist
THE Manufacturing Company Essential principles C4.2.7 Applicable/ Not Applicable (A/NA) A
the risk of incorrect identification of specimens;
C4.2.8
the risks of reasonably foreseeable interference with other devices such as carry-over between IVD medical devices.
A
C4.3
IVD medical devices should be designed and manufactured in such a way as to minimize the risks of fire or explosion during normal use and in single fault condition. -Particular attention should be paid to IVD medical devices whose intended use includes exposure to or use in association with flammable substances or substances which could cause combustion.
A
SIMU HIV-1 Quant Test Product Codes M123 and M124 Method(s) and references used to demonstrate Reference to supporting controlled documents conformity of Manufacturer this dossier). Application of recognized standards: • For clinical use, ISO 22870 applies. • ISO 13485:2016 Medical Devices - Quality • Risk analysis output documents “SIMU management systems-Requirements for HIV-1 Quant -risk-design”, “SIMU HIV-1 Regulatory Purposes. Quant risk - processes”, “SIMU HIV-1 • ISO 14971:2007 Medical devices – Quant risk-users”. Application of risk management to medical • “SIMU HIV-1 Quant Risk Management devices. and Control Report” held by QA. • ISO 22870:2016 Point-of-care testing (POCT) • Design specifications (held on-site). — Requirements for quality and • All validation data (refer Section 7.4 of this competence. dossier). Validation Studies Section 7. • SIMU HIV-1 Quant IFU. Application of recognized standards: • For clinical use, ISO 22870 applies. • ISO 13485:2016 Medical Devices - Quality • Risk analysis output documents “SIMU management systems-Requirements for HIV-1 Quant -risk-design”, “SIMU HIV-1 Regulatory Purposes. Quant risk - processes”, “SIMU HIV-1 • ISO 14971:2007 Medical devices – Quant risk-users”. Application of risk management to medical • “SIMU HIV-1 Quant Risk Management devices. and Control Report” held by QA. • ISO 22870:2016 Point-of-care testing • Design specifications (held on-site). (POCT) — Requirements for quality and • All validation data (refer Section 7.4 of this competence. dossier). Validation Studies Section 7 • SIMU HIV-1 Quant IFU, Application of recognized standards: • Copy of subcontractor’s Declaration of Conformity (Annex IV) to DIRECTIVE • ISO 13485:2016 Medical Devices - Quality 2006/95/EC (held on-site). management systems-Requirements for Regulatory Purposes. • Routine audits of subcontractor’s Section 7.4. compliance to required specifications, including safety testing. • MSDS data sheets
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Annex I: Essential Principles Checklist
THE Manufacturing Company Applicable/ Essential principles Not Applicable (A/NA) C4.4 IVD medical devices should be designed and A manufactured in such a way that adjustment, calibration, and maintenance, where such is necessary to achieve the performances intended, can be done safely C4.5 IVD medical devices should be designed and manufactured in such a way as to facilitate the safe disposal of any waste substances A
SIMU HIV-1 Quant Test Product Codes M123 and M124 Method(s) and references used to demonstrate Reference to supporting controlled documents conformity of Manufacturer Application of recognized standards: • Refer to SIMU HIV-1 Quant IFU. • ISO 13485:2016 Medical Devices - Quality • SIMU Instrument Test User Manual management systems-Requirements for “Section XYZ Calibration . Regulatory Purposes. Section 7.4 Application of recognized standards: • ISO 14001:2015 Environmental management tests. Requirements with guidance for use. • ISO 14971:2007 Medical devices – Application of risk management to medical devices. • Risk analysis output documents “SIMU HIV-1 Quant -risk-design”, “SIMU HIV-1 Quant risk - processes”, “SIMU HIV-1 Quant risk-users”. “SIMU HIV-1 Quant Risk Management and Control Report” held by QA. Design specifications (held on-site). SIMU HIV-1 Quant IFU. Design specifications (held on-site). All validation and verification studies, and stability studies (refer to all of Section 7 of this dossier). Lot release procedures “SOP QC XXX”.
• • •
C5 C5.1
Performance characteristics IVD medical devices should be designed and manufactured in such a way that the performance characteristics support the intended use, based on appropriate scientific and technical methods. -In particular, where appropriate, the design should address sensitivity, specificity, accuracy which is trueness and precision (repeatability and reproducibility), control of known relevant interference and limits of detection These performance characteristics need to be maintained during the lifetime of the IVD medical device as indicated by the manufacturer.
A
Application of recognized standards: • • ISO 13485:2016 Medical Devices - Quality • management systems-Requirements for Regulatory Purposes. • ISO 23640:2011 In vitro diagnostic medical • devices - Evaluation of stability of in vitro diagnostic reagents. • CLSI EP25A:2009 Evaluation of Stability of In Vitro Diagnostic Reagents; Approved Guideline. • EN 13612:2002 Performance evaluation of in vitro diagnostic medical devices. • CLSI EP07-A2 Interference Testing in Clinical Chemistry; Approved Guideline—Second Edition. • CLSI EP14-A2 Evaluation of Matrix Effects; Approved Guideline—Second Edition.
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Annex I: Essential Principles Checklist
THE Manufacturing Company Essential principles Applicable/ Not Applicable (A/NA)
C5.2
Where the performance of devices depends on the use of calibrators and/or control materials, the traceability of values assigned to such calibrators and/or control materials should be assured through available reference measurement procedures and/or available reference materials of a higher order.
A
C5.3
Wherever possible values expressed numerically should be in commonly accepted, standardized units, and understood by the users of the device. Protection against radiation IVD medical devices should be designed, manufactured and packaged in such a way that exposure of user, professional or lay, or other person to the emitted radiation (intended, unintended, stray or scattered) is reduced as far as reasonably practicable and appropriate. When IVD medical devices are intended to emit potentially hazardous, visible and/or invisible radiation, they should as far as reasonably practicable and appropriate be designed and manufactured in
A
SIMU HIV-1 Quant Test Product Codes M123 and M124 Method(s) and references used to demonstrate Reference to supporting controlled documents conformity of Manufacturer • FDA Guidance for Industry - Bioanalytical Method Validation. • EN 13975:2003 Sampling procedures used for acceptance testing of in vitro diagnostic medical devices - Statistical aspects. Section 7 Performance and Stability Studies. Application of recognized standards: • Refer Records SIMU HIV-1 Quant • ISO 15193:2009 In vitro diagnostic medical Specimen processing Control and devices - Measurement of quantities in Traceability Policy (held on-site). samples of biological origin - Requirements for content and presentation of reference measurement procedures. • ISO 17511:2003 In vitro diagnostic medical devices - Measurement of quantities in biological samples - Metrological traceability of values assigned to calibrators and control materials. Application of recognized standards: • ISO 18113:2009 In vitro diagnostic medical devices – Information supplied by the manufacturer (labelling) – Parts 1, 2 and 3.
C6 C6.1
NA
C6.2
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Annex I: Essential Principles Checklist
THE Manufacturing Company Applicable/ Essential principles Not Applicable (A/NA) such a way as to ensure that the characteristics and the quantity of radiation emitted can be controlled and/or adjusted; and fitted with visual displays and/or audible warnings of such emissions. C7 IVD medical devices that incorporate software and standalone IVD medical device software C7.1 For IVD medical devices which incorporate software A or for standalone software that are IVD medical devices in themselves, the software must be validated according to the state of the art taking into account the principles of development life cycle, risk management, verification and validation.
SIMU HIV-1 Quant Test Product Codes M123 and M124 Method(s) and references used to demonstrate Reference to supporting controlled documents conformity of Manufacturer
Application of recognized standards: • IEC 62304:2006 Medical device software Software life cycle processes. • IEC 62366-1:2015. Medical devices. Part 1: Application of usability engineering to medical devices. • ISO 14971:2007 Medical devices – Application of risk management to medical devices. The software is built into the SIMU HIV-1 Quant Instrument.
• •
Refer to subcontractor’s “Software Validation and Verification Studies” (held on-site). Refer to subcontractor’s “Software Risk Management Report” (held on-site).
C8 C8.1
C8.2
C8.3
IVD medical devices connected to, or equipped with, an energy source IVD medical devices where the safety of the patient depends on an internal power supply in the IVD medical device should be equipped with a means of determining the state of the power supply. IVD medical devices should be designed and manufactured in such a way as to reduce as far as reasonably practicable and appropriate the risks of creating electromagnetic interference which could impair the operation of this or other devices or equipment in the usual environment. IVD medical devices should be designed and manufactured in such a way as to provide an
A A • Design of the SIMU Instrument includes a screen that provides instructions, allowing confirmation it is turned on. A LED turns on when the SIMU Instrument is “ON”. Copy of subcontractor’s Declaration of Conformity (Annex IV) to DIRECTIVE 2004/108/EC (held on-site).
A
A
Application of recognized standards: • • IEC 61010-2-101: Safety requirements for electrical equipment for measurement, control and laboratory use - Part 2-101: Particular requirements for in vitro diagnostic (IVD) medical equipment. Application of recognized standards: • • EMC Testing for Medical Devices IEC 60601-
Copy of subcontractor’s Declaration of Conformity (Annex IV) to DIRECTIVE Page 89
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Annex I: Essential Principles Checklist
THE Manufacturing Company Applicable/ Essential principles Not Applicable (A/NA) adequate level of intrinsic immunity to electromagnetic disturbance to enable them to operate as intended. C8.4 IVD medical devices should be designed and A manufactured in such a way as to avoid, as far as reasonably practicable, the risk of accidental electric shocks to the user, professional or lay, or other person both during normal use of the device and in the event of a single fault condition in the device, provided the IVD medical device is installed and maintained as indicated by the manufacturer. C9 Protection against mechanical and thermal risks C9.1 IVD medical devices should be designed and A manufactured in such a way as to protect the user, professional or lay, or other person against mechanical risks connected with, for example, resistance to movement, instability and moving parts C9.2 Where there are risks due to the presence of moving parts, risks due to break-up or detachment, or leakage of substances, then appropriate protection means must be incorporated A
SIMU HIV-1 Quant Test Product Codes M123 and M124 Method(s) and references used to demonstrate Reference to supporting controlled documents conformity of Manufacturer 1-2:2007 Electromagnetic Compatibility 2004/108/EC (held on-site). (EMC) Testing. • The SIMU Instrument is battery operated (Li-ion rechargeable battery). Application of recognized standards: • IEC 61010-2-101: Safety requirements for electrical equipment for measurement, control and laboratory use - Part 2-101: Particular requirements for in vitro diagnostic (IVD) medical equipment. The SIMU HIV-1 Quant Instrument does not incorporate moving parts. The SIMU HIV-1 Quant Instrument and rechargeable batteries are manufactured in accordance with the EC EMC standards. Application of recognized standards: • Copy of subcontractor’s Declaration of Conformity (Annex IV) to DIRECTIVE 2004/108/EC (held on-site).
•
Copy of subcontractor’s Declaration of Conformity (Annex IV) to DIRECTIVE 2004/108/EC (held on-site).
• •
•
•
•
EN 61010-1:2010 Safety requirements for electrical equipment for measurement, control, and laboratory use. General requirements IEC 61010-2-081:2015 Safety requirements for electrical equipment for measurement, control and laboratory use - Part 2-081: Particular requirements for automatic and semiautomatic laboratory equipment for analysis and other purposes IEC 61010-2-101: Safety requirements for
Electrical safety report 14-445, rev 2 (ABS Laboratories, Inc.) SOP XXXX (Held on-site).
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Annex I: Essential Principles Checklist
THE Manufacturing Company Essential principles Applicable/ Not Applicable (A/NA)
SIMU HIV-1 Quant Test Product Codes M123 and M124 Method(s) and references used to demonstrate Reference to supporting controlled documents conformity of Manufacturer electrical equipment for measurement, control and laboratory use - Part 2-101: Particular requirements for in vitro diagnostic (IVD) medical equipment. • EN ISO 12100:2010 Safety of machinery - General principles for design - Risk assessment and risk reduction
C9.3
C9.4
IVD medical devices should be designed and manufactured in such a way as to reduce to the lowest practicable level the risks arising from vibration generated by the devices, taking account of technical progress and of the means available for limiting vibrations, particularly at source, unless the vibrations are part of the specified performance. IVD medical devices should be designed and manufactured in such a way as to reduce to the lowest practicable level the risks arising from the noise emitted, taking account of technical progress and of the means available to reduce noise, particularly at source Terminals and connectors to the electricity, gas or hydraulic and pneumatic energy supplies which the user, professional or lay, or other person has to handle should be designed and constructed in such a way as to minimize all possible risks.
A
Application of recognized standards: • EN 61010-1:2010 • IEC 61010-2-081:2009 • EN 61010-2-101:2002 • EN ISO 12100:2010. Application of recognized standards: • EN 61010-1:2010 • IEC 61010-2-081:2009 • EN 61010-2-101:2002 • EN ISO 12100:2010. Application of recognized standards: • IEC 62133 Electromagnetic compatibility (EMC) – Part 6-3: Generic standards – Emission standard for residential, commercial and light-industrial environments. • IEC 61010-2-101: Safety requirements for electrical equipment for measurement, control and laboratory use - Part 2-101: Particular requirements for in vitro diagnostic (IVD) medical equipment.
• •
Electrical safety report 14-445, rev 2 (ABS Laboratories, Inc.) SOP XXXX (Held on-site).
A
• •
Electrical safety report 14-445, rev 2 (ABS Laboratories, Inc.) SOP XXXX (Held on-site).
C9.5
A
•
Copy of subcontractor’s Declaration of Conformity (Annex IV) to DIRECTIVE 2004/108/EC (held on-site).
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Annex I: Essential Principles Checklist
THE Manufacturing Company Essential principles Applicable/ Not Applicable (A/NA)
C9.6
IVD medical devices should be designed and manufactured in such a way as to reduce to the lowest practicable level, the risk of error when certain parts within the device are intended to be connected or reconnected before or during use.
A
C9.7
C10 C11 C11.1
Accessible parts of the IVD medical devices (excluding the parts or areas intended to supply heat or reach given temperatures) and their surroundings should not attain potentially dangerous temperatures under normal use Protection against the risks posed by IVD medical devices for self-testing Labels and Instructions for Use Users should be provided with the information needed to identify the manufacturer, to use the device safely and to ensure the intended performance, taking account of their training and knowledge. -This information should be easily understood
A
SIMU HIV-1 Quant Test Product Codes M123 and M124 Method(s) and references used to demonstrate Reference to supporting controlled documents conformity of Manufacturer The SIMU HIV-1 Quant Instrument is battery operated (Li-ion rechargeable battery). Application of recognized standards: • Copy of subcontractor’s Declaration of Conformity (Annex IV) to DIRECTIVE • IEC 62133 Electromagnetic compatibility 2004/108/EC (held on-site). (EMC) – Part 6-3: Generic standards – Emission standard for residential, commercial and light-industrial environments. • IEC 61010-2-101: Safety requirements for electrical equipment for measurement, control and laboratory use - Part 2-101: Particular requirements for in vitro diagnostic (IVD) medical equipment. The SIMU HIV-1 Quant Instrument is battery operated (Li-ion rechargeable battery). See Section C9.3.
NA
This device is for professional use only. However a broad range of user skills have been considered in the design. Application of recognized standards: • • ISO 14971:2007 Medical devices – Application of risk management to medical devices. • ISO 18113-1:2009 In vitro diagnostic • medical devices - Information supplied by the manufacturer (labelling) - Part 1: Terms, definitions and general requirements. • Risk analysis output documents “SIMU HIV-1 Quant -risk-design”, “SIMU HIV-1 Quant risk - processes”, “SIMU HIV-1 Quant risk-users”. “SIMU HIV-1 Quant Test Risk Management and Control Report” held by QA. SIMU HIV-1 Quant Test IFU, SIMU Page 92
A
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Annex I: Essential Principles Checklist
THE Manufacturing Company Essential principles Applicable/ Not Applicable (A/NA)
SIMU HIV-1 Quant Test Product Codes M123 and M124 Method(s) and references used to demonstrate Reference to supporting controlled documents conformity of Manufacturer Instrument User Manual. • ISO 18113-2:2009 In vitro diagnostic medical devices - Information supplied by the manufacturer (labelling) - Part 2: In vitro diagnostic reagents for professional use. • ISO 18113-3:2009 In vitro diagnostic medical devices - Information supplied by the manufacturer (labelling) - Part 3: In vitro diagnostic reagents for professional use. • MEDDEV. 2.14/3 rev.1 Guidelines on Medical Devices: IVD guidances: Supply of Instructions For Use (IFU) and other information for In-vitro Diagnostic (IVD) medical devices. A guide for manufacturers and notified bodies. Brussels, Belgium. European Commission Enterprise and Industry Directorate-General; 2007 • GHTF/SG1/N70:2011: Label and Instructions for Use for Medical Devices. Global Harmonization Task Force (GHTF) Steering Committee; 2011. • EN 13612:2002 Performance evaluation of in vitro diagnostic medical devices.
C12 C12.1
Performance evaluation including analytical performance and, where appropriate, clinical performance For an IVD medical device a performance evaluation should be conducted in accordance with GHTF guidance. -The performance evaluation should review analytical performance data and, where appropriate, clinical performance data in the form of any:
A
Application of GHTF Guidance: • GHTF/SG5/N6:2012 Clinical Evidence for IVD medical devices – Key Definitions and Concepts. • GHTF/SG5/N7:2012 Clinical Evidence for
•
Performance Evaluation Summary (refer Section 7 of this dossier).
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Annex I: Essential Principles Checklist
THE Manufacturing Company Essential principles literature, performance study reports; and experience gained by routine diagnostic testing to establish that the IVD medical device achieves its intended performance during normal conditions of use and that the known, and foreseeable risks, and any undesirable effects, are minimized and acceptable when weighed against the benefits of the intended performance. C12.2 Clinical performance studies using specimens from human subjects should be carried out in accordance with the spirit of the Declaration of Helsinki. -This includes every step in the clinical performance study from first consideration of the need and justification of the study to publication of the results. In addition, some countries may have specific regulatory requirements for informed consent. Applicable/ Not Applicable (A/NA)
SIMU HIV-1 Quant Test Product Codes M123 and M124 Method(s) and references used to demonstrate Reference to supporting controlled documents conformity of Manufacturer IVD medical devices – Scientific Validity Determination and Performance Evaluation. • GHTF/SG5/N8:2012 Clinical Evidence for IVD Medical Devices - Clinical Performance Studies for In Vitro Diagnostic Medical Devices. Ethics committee approval of all prospective clinical performance studies. Documentation of all ethics committee approval (held on-site).
A
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Annex II: Risk Management Policy
Annex II: Risk Management Policy THE Manufacturing Company DOC XXX Please Note: The following DOC XXX Risk Management Policy has been prepared for the purposes of this sample dossier, and is not a complete document. It is to provide an example of some aspects to be considered in such a document and must reflect the internal policies of the company. NOTE: all documents submitted to WHO must be signed and dated. Risk Management Policy Document version # 02 Written by: Signature Date Document date: 2012 09 15 Approved by: Head of QA Signature Head of manufacturing Signature Changes from earlier versions: Version 01 02 03 2012 01 01 2012 09 15 … Item modified N/A Para. 6 c) … Modification Document created according to SOP x3w Reference to the proposed European in vitro diagnostic regulation added Date Date
Introduction 1. The company is committed to the effective management of risk at every level: 1.1. Reducing as far as possible any risks associated with any product developed or manufactured by the company, at every stage of the product life cycle from design to in-use surveillance. 1.2. Ensuring a safe environment for its employees and customers. 1.3. Training to enable its employees to undertake their work effectively, efficiently and safely. 1.4. Enhancing and protecting the local environment. 2. The company will achieve these objectives 2.1. By ensuring company management fully accepts the need for risk control, which cannot be balanced against financial profit. a) The Head of QA will be responsible for risk management and control throughout the company. b) The Head of Research & Development will be responsible for risk management and control in the design of product and process. c) The Head of Manufacturing will be responsible for risk management and control related to supply of product, safety in the facility, and respect for the environment. d) These responsibilities cannot be passed to subordinates.
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Annex II: Risk Management Policy
2.2. By following the guidelines of the GHTF/SG3/N15R8 and 98/79/EC in a hierarchy of control methods: a) Inherent safety by design of any items we develop or manufacture, and their manufacturing processes, including risks related to security of supply. b) Protective measures for the user and patient in the device, and for our employees in the manufacturing processes. c) Information for safety, such as warnings, as a last resort for risks that cannot be removed by design of the products or the processes. 2.3. By ensuring that risk management is integrated into the quality management system of the company, to include risk management planning and plans for all aspects of our work and product development. 2.4. By training of all employees in the importance of safe practices in all aspects of their work. 2.5. By training specific employees in the regulations and methods of risk analysis and control. a) ISO 13485 Medical devices -- Quality management systems - Requirements for regulatory purposes, ISO 14971:2007, Medical Devices. Application of risk management to medical devices documentation, GHTF and IMDRF guidelines, US FDA and ICH Q9 and Q10 guidance. b) Standard methods for the tools of risk analysis, including Failure Mode and Effects Analysis (FMEA), Fault Tree Analysis, Preliminary Risk Analysis, Risk Ranking and Filtering and Hazard and Operability Studies. 3. The company will ensure consistent application of risk control methods through a set of SOP directed by this policy. The SOPs will include, but are not limited to: a) SOP and template for FMEA – who, how, when b) SOP for training in the use of risk management tools c) SOP for estimation of degrees of hazard and control measures This is not intended to be a complete policy document.
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Annex III: Residual Risk Statement
Annex III: Residual Risk Statement SIMU HIV-1 Quant Test, including SIMU Instrument
THE Manufacturing Company Following optimisation of the design and performance characteristics by comprehensive testing inhouse and in the hands of intended users, as verified when testing populations representative of the intended patient population, THE Manufacturing Company considers the remaining risks to users and patients are minimal and acceptable for the SIMU HIV-1 Quant System. The results of this test are intended to be used in conjunction with other markers of disease progress for the clinical management of HIV-1 patients in resource limited settings. Any unlikely, unexpected test result will be balanced by the major clinical value for patients who would otherwise have limited or no access to viral load testing. The remaining risks to manufacture, continuity of supply, and to manufacturing staff are also minimal and acceptable in view of the training and safety measures in place for our staff and the supplier management and material testing specified for this product. Documented evidence to support these statements is filed on-site in the Risk Management and Control Report of the Risk Management File for this product. This report contains the assessment of all remaining risks after implementation of risk control measures. This report is subject to continuous review, based on experience with the device, to ensure the positive status of the benefit versus risk profile remains unchanged. Signed: Date:
Head of QA, THE Manufacturing Company: responsible for risk management and control. Signed: Date:
Head of R&D, THE Manufacturing Company: responsible for design and process risk control Signed Date:
Head of Manufacturing, THE Manufacturing Company: responsible for risk management and control related to supply of product, safety in the facility, and respect for the environment. NOTE: Submitted documents must be signed and dated
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WHO Sample product dossier for SIMU HIV-1 QUANT 1
Annex IV: Design Inputs FMEA
Annex IV: Design Inputs FMEA Design inputs FMEA: SIMU HIV-1 Quant Test Product codes: M123, M124 FMEA Version: 4 Date: 2013 02 26
THE Manufacturing Company design input FMEA template version 2 Controlling SOP: Design input risk analysis SOP XXXX version 3 Version Control 1.0 2.0 3.0 Revision date 2010 09 03 2012 12 20 2013 01 10 Changes Initial, following finalization of customer requirements documentation Inadequate analytical sensitivity for HIV-1 resulted in a change in formulation for the test to increase the sensitivity for HIV-1 (Change A1234 – 2.) Change to the upper limit of detection from 5 million copies/mL to 10 million copies/mL in response to customer input. (Change Y1234 – 4.)
Approval of this version: Head of department or project leader (SOP XXXX) Department Marketing Manufacturing QA R&D Name Anne Smith Bill Jones Pete Brown Joe White Signature Date
2013 02 29 2013 02 26 2013 02 27 2013 02 26
Present at FMEA meetings at least two representatives from each department (SOP 0 XXXX) Department Marketing Manufacturing QA R&D Marketing Manufacturing QA R&D Name Anne Smith Tom Jackson Jean Roberts Dave White Simon Richard John Jensens Sylvie Martin Sam Dupont Signature Date
2013 02 29 2013 02 26 2013 02 27 2013 02 26 2013 02 29 2013 02 26 2013 02 27 2013 02 26
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WHO Sample product dossier for SIMU HIV-1 QUANT Design inputs FMEA: SIMU HIV-1 Quant Test Product codes: M123 and M124 Prepared by: Simon Richard Blogs, Marketing
Annex IV: Design Inputs FMEA
Occurrence
Known or suspected problem Specimens likely to be HIV positive and contain other infectious agents.
Potential effects Health risk to user
Severity
Hazard N (from inputs) 1a
o
Risk index
Recommended action Design to minimize specimen handling, safety in handling. Test Cartridge designed to contain all specimens after specimen port cap is closed. Used Test Cartridges cannot be opened or reused. Specimen processing lyses and denatures virus. Single specimen throughput and detailed specimen loading instructions. The IFU must be pictorial and absolutely clear. Test Cartridges sealed after start of reaction, all reagents contained.
Comments
4
4
16
1b
Specimens likely to be HIV positive and contain other infectious agents.
Disposal risk
4
4
16
3
Specimen cross-contamination. Users might be illiterate and will likely not speak European languages. Carry-over contamination.
Invalid results/incorrect quantification
3
1
6
Clinical evaluations did not identify Invalid results/incorrect quantification due to contamination.
4
Invalid use
3
4
12
5
Invalid results/incorrect quantification
3
1
6
Clinical evaluations did not identify Invalid results/incorrect quantification due to contamination.
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Annex IV: Design Inputs FMEA
Occurrence
Known or suspected problem Specimen amplification inhibitors.
Potential effects Inaccurate quantitation or invalid test results
Severity
Hazard N (from inputs) 6
o
Risk index
Recommended action Specific target capture specimen processing eliminates inhibitors. Door for Test Cartridge bay seals before and after insertion of Test Cartridge. Error code added to software that will appear on operator screen. Test Cartridge air intake channels modified.
Comments Clinical evaluations did not identify invalid test results due to specimen amplification inhibition.
4
1
4
7
High dust levels may affect Instrument operation. Instrument optics misalignment. Low air pressure at high altitude may affect system performance.
Instrument unreliability
2
3
6
8
Unreliable or no results
4
1
4
…99999 …
Unreliable results
4
1
4
Analytical testing in low pressure environment demonstrated reliable results.
The manufacturer should work through each section (user, regulatory, management, manufacturing) of the customer input documents (Annex XXX) giving due consideration to all possible hazards. This ensures that the R&D department have a solid basis for work and results in innovation to meet customers’ needs. Outputs from this FMEA lead to product requirement document Annex XXX. This FMEA should be updated if there are any design changes.
The results of FMEA are expressed in semi-quantitative terms (see risk grids and occurrence tables in Extracts from SOP XXX Preparation of design input FMEA below). The reason for this, rather than the attempted quantitation frequently seen, is provided by Shebl NA, Franklin BD, Barber N, “Is failure mode and effect analysis reliable?” J. Patient Saf. 5 (2009) 86-94, and Shebl NA et al., “Failure mode and effects analysis outputs: are they valid?” BMC Health Services Research 12 (2012) 150-160. Regardless of how it is performed, the actions involved in generating FMEA early in the life of an IVD are invaluable and give evidence that the manufacturer has considered the user, patient and design risks.
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WHO Sample product dossier for SIMU HIV-1 QUANT
Annex IV: Design Inputs FMEA
Please Note: The following SOP XXX “Preparation of design input FMEA” has been prepared for the purpose of this sample dossier, and is not a complete document. It is to provide an example of some aspects to be considered in such a document and must reflect the internal policies of the manufacturer. NOTE: all documents submitted to WHO must be signed and dated. Extracts from SOP XXX Preparation of design input FMEA 1. Health, safety and the environment There are no health and safety implications as this is a documentation SOP. 2. Training Requirements Complete the sheet in Appendix 1 to indicate the trainee has read and understood this procedure • Signatures by trainee and trainer required.
3. Responsibilities The R&D project leader must: • • • • • establish who will participate in the FMEA. This must include at least representation from the R&D project team, marketing, QA and manufacturing groups ensure that an FMEA is started at the time the first draft of the input documentation is being written ensure the FMEA is updated as required until product launch ensure that each version is approved as below after launch of the product, the FMEA for design changes are addressed in SOP x/yy. The project is no longer a R&D department responsibility.
The heads of department or departmental project leaders must all • review the content and approve each version of the FMEA.
4. Procedure For A Design Input FMEA Ensure that the customer input responses are available • • • • • Customers include: users, patients, distributors, funders, regulators, manufacturing, management, finance. Complete the general information relating to the FMEA requested at the top of the form. Complete each major section and subsection in the FMEA form. Work through the input requirements point by point and document any potential hazard, using previous experience, literature research, general knowledge. For each hazard record the effect(s) that could be caused. o o o there may be more than one effect for each hazard assess the severity of each effect score the severity using the definitions in the Severity Table in Appendix 3 and record it the severity column.
Complete the effect severity supporting information in Appendix 4. and so on
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WHO Sample product dossier for SIMU HIV-1 QUANT Table Annex IV–1: Hazard categorisation: Appendix 3 to SOP XXX Vernacular term Catastrophic Critical Serious Minor Negligible Description Results in patient death
Annex IV: Design Inputs FMEA
Category 4 4 3 2 1
Results in life threatening injury or permanent disability Results in injury or disability requiring qualified medical intervention Results in temporary injury or disability not requiring qualified medical intervention Inconvenience or temporary discomfort
Table Annex IV–2: Severity supporting information: Appendix 4 to SOP XXX Hazard # 1.1.1 1.1.2 Rationale / Support for assigned category of hazard
ISO 14971 and ISO/TR 24971 for general risk severity groupings Approval of severity to be by a qualified medical professional as specified by ISO 14971:2007 Annex H 2.5.2 Table Annex IV–3: Occurrence categorisation: Appendix 5 to SOP XXX Vernacular term Probable Probable Occasional Rare Improbable Description Very high: non-conformance is almost certain: High: similar functions or activities have frequent non-conformance Moderate: non-conformances with similar functions or activities occur occasionally Low: non-conformances with similar functions or activities occur rarely Very low: non-conformances with nearly identical functions or activities occur rarely Rate of nonconformance >1:3 >1:20 >1:2 000 >1:15 000 >1:150 000 Category 4 4 3 2 1
Improbable Remote: Non-conformance unlikely >1:1 500 000 1 ISO 14971:2007 and ISO/TR 24971:2013 for general risk occurrence probability groupings. This table is modified from one published by the Automotive Industry Action Group: actual values were specified and agreed at Head of QA level and are company specific.
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WHO Sample product dossier for SIMU HIV-1 QUANT
Annex IV: Design Inputs FMEA
Table Annex IV–4: Occurrence supporting information: Appendix 6 to SOP XXX Hazard # 1.1.1 1.1.2 Rationale / Support for assigned category of occurrence
Figure Annex IV–5: Risk Grid: Appendix 7 to SOP XXX Severity of Effect 4 Critical Probability of Occurrence 4 3 2 1 Probable Occasional Rare Improbable High High Med Low 3 Serious High Med Low Low 2 Minor Med Low Low Low 1 Negligible Low Low Low Low
All items must be addressed: High Med Low Redesign or improve Redesign and/or improve, or add a control method to reduce the categorisation to Low Review with QA and marketing and/or improve if possible
This risk grid applies to both design input FMEA and user and patient FMEA. It is modified to require that if a medium risk is found during manufacturing process FMEA that process must be redesigned.
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WHO Sample product dossier for SIMU HIV-1 QUANT
Annex V: User and Patient FMEA User and patient FMEA: SIMU HIV-1 Quant System Product codes: M123 and M124 FMEA Version: 4 Date: 2013 02 26
THE Manufacturing Company design input FMEA template version 2 Controlling SOP: Design input risk analysis SOP XXXX version 3 Version Control 1.0 2.0 3.0 Revision date Changes Initial, following finalization of customer requirements documentation including FMEA Reduction in bioburden testing frequency using a process capability/risk based approach (Change A1234 – 2.) Change to the upper limit of detection from 5 million copies/mL to 10 million copies/mL in response to customer input. (Change Y1234 – 4.)
2010 09 05 2012 12 20 2013 01 10
Approval of this version: Departmental Project leader (SOP 00967) Department Marketing Manufacturing QA R&D Name Anne Smith Bill Jones Pete Brown Joe White Signature Date 2013 02 27 2013 02 27 2013 02 27 2013 02 27
Present at FMEA meetings at least two representatives from each department (SOP XXXX) Department Marketing Manufacturing QA R&D Marketing Manufacturing QA R&D Name Anne Smith Steve White Jean Roberts Dave White Simon Richard Tom Weber Adrian Becker Sharon Dupont Signature Date 2013 02 24 2013 02 24 2013 02 24 2013 02 24 2013 02 24 2013 02 24 2013 02 24 2013 02 24
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WHO Sample product dossier for SIMU HIV-1 QUANT
Annex V: User and Patient FMEA
User and patient FMEA: SIMU HIV-1 Quant Test System This is an extract of a larger spreadsheet, attached as document 3 (Annex III user & patient risk FMEA_01.xlsx) The appendices of Annex IV: Design Inputs FMEA are applicable to User and patient FMEA. The User and patient FMEA is controlled by SOP YYY. This FMEA is re-evaluated at each project group meeting and at each major development point. It ceases to be an R&D department responsibility once the product is launched. Maintenance is taken over by the marketing department using SOP x/yy as noted in SOP XXX. Status at Initial FMEA Hazard Activity # Potential Function Failure Modes Potential Effects Of Failure Mode Severity Potential Causes of Failure Current Controls Occur Risk Recommenrence Index ded Action Status After Risk Minimization Method Action Taken Action (Ref to Change SeveOccurrRisk Notes and rity (As ence After Owne DocumentaIndex Comments tion or Before) Control r Notebook) Software modified to produce screen readout Redesign of capillary specimen port Specimen processing control failure indication with inadequate specimen volume Patient ID must be inputted before a result is issued
Test Cartridge User Initiate Run does No assay not correctly 1 assay run not initiate result inserted into Instrument User Pipetting 2 Deliver plasma into device Deliver plasma into device Inaccurate Plasma quantitatio volume n, failure insufficient to treat Inaccurate Inadequat quantitatio e plasma n, failure volume to treat Wrong patient result given out, treatment failures
2
Untrained Training, operator, statements in poor lancets, IFU poor pipettes Capillary specimen port inadequate
2
3
None
4
User Pipetting 3
3
Training, Training, instrumenta- statements in tion IFU
3
Readout on screen notifies Low operator to R&D reinsert Test Cartridge Design device to enable easy High and complete R&D plasma insertion Design device to control failure result Med when R&D specimen volume too low Develop a better method R&D Med of identification
2
1
Low
3
1
Low Acceptable
3
1
Low
User Labelling 4
Erroneous Link identificati result to on of patient device and specimen
3
No positive link of the specimen to the patient
Writing patient ID on the Test Cartridge
3
3
1
Low
Draft for public comment 26 October 2016
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WHO Sample product dossier for SIMU HIV-1 QUANT Annex VI: Input Requirements for the HIV-1 Quant Test
Annex VI: Input Requirements for the HIV-1 Quant Test Customer Requirements This document follows from the input requirements produced according to SOP-DDD of THE Manufacturing Company following market research with users, regulators, purchasers, funders. The notes in black are from the template in SOP-DDD and those added in green are compiled from customer responses and will form the basis of the numeric, measurable product requirements. 1. Functional Requirements
This section is unchanged by user inputs – it is the highest managerial level description of the device 1.1 What is the kit supposed to do? 1.1.1 For the quantitative detection of viral RNA of HIV-1 in the general population from early to advanced infection. The test is to be used to identify virological failure in patients on antiretrovirals, and enable early switching of failing patients to new antiretroviral regimens before accumulation of drug resistance mutations. The test should have a lower limit of detection of at least 800 copies/mL and an upper limit of detection of at least 1 million copies/mL. 1.1.2 The test can be performed on EDTA plasma. 1.1.3 Reference test: Comparable to established HIV-1 viral load (VL) technology available 1.2 What inputs and what outputs? 1.2.1 Inputs: EDTA plasma 1.2.2 Outputs: printed, and results can be automatically transmitted to central databases using internet or they can be submitted by SMS. 2. Management Requirements
This section is unchanged – management has already made inputs according to SOP XXX prior to release of the design to other “customers”. 2.1 Financial including staff allocation 2.1.1 Staffing in R&D to be kept within budget constraints, no new staff to be taken on except as replacements. 2.1.2 Total costs to be less than $100 000 per staff member per year. 2.2 Administration and control structure 2.2.1 The usual R&D, QA and manufacturing control tests, overseen by the HIV team. 2.3 Reporting methods and intervals 2.3.1 By the normal project management group, with reporting to senior management through the design control committee at a minimum of two monthly intervals. 3. 3.1 Format Interfaces to other systems (measurement system; result recording) Page 106 of 140
WHO Sample product dossier for SIMU HIV-1 QUANT Annex VI: Input Requirements for the HIV-1 Quant Test 3.1.1 The Instrument will have a readout screen for results and can interface to other computers via the internet or SMS. 3.2 3.2.1 NAT a) b) c) NAT to detect HIV-1 RNA. Specimen processing and inhibition controls. External controls. Methodology – rapid diagnostic test, enzyme immunoassay, or NAT
3.3 Presentation of the product 3.3.1 Instrument a) b) c) d) e) f) g) h) low throughput, one in one out battery powered with spare battery small footprint fully automated standard WIFI connection, USB port all operations controlled on the Instrument easily portable (backpack or handle) easy to clean/disinfect and fix (minimal moving parts)
3.3.2 IVD a) b) c) Package must be easily opened in the obvious and correct manner and easily, safely disposable Package must completely protect the product against the environment expected in the operational sites No parts of value for anything other than these contents
3.3.3 Labelling in accordance with ISO 18113-5 and aligned with Jacobs et al., Malaria Journal 13 (2014) 505-514 a) 4. 4.1 Ensure place for Unique Device Identifier
Operating Requirements Expected physical environment including temperature, power availability, equipment, materials available (distilled water, pipette tips), transport capability, physical stability) 4.1.1 From tertiary hospital settings at district level though to antenatal care clinics in community settings in resource limited Member States. No power, no equipment, no water and no external requirements allowable. Limited capabilities for transport is anticipated. a) b) c) d) The expected environment can be particularly harsh, dusty and with microbial contamination. High altitudes and extremes of temperature, humidity and pressure can be expected. Transport to end-users and storage by users can be chaotic and it is likely that the conditions or transport are not controlled. Recommended storage conditions in the distributors cannot be guaranteed.
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WHO Sample product dossier for SIMU HIV-1 QUANT Annex VI: Input Requirements for the HIV-1 Quant Test e) Available resources to measure time might not be possible. There may be limited access to timers, watches, phones, therefore the instrument must be fully automated with minimal operator interventions.
4.2
Expected technological environment (nature of the working area) 4.2.1 To be used by health care workers in laboratories, antenatal care clinics and tertiary hospital settings. These workers may have had minimal training and are often not lab technicians. a) b) This will have major consequences for documenting instructions, their interpretation and subsequent actions by users. A fail-safe design is required so that there is no confusion over role of each interactive design feature e.g. where to insert Test Cartridge, on/off switches etc. Obtaining plasma from patient blood may be the determining factor for where the test is used. A plasma separator or centrifuge must be accessible at the testing site or plasma specimens must be obtained from other facilities.
c)
5. 5.1
Performance Requirements Safety critical 5.1.1 Specimen collection, use and disposal to be safe in completely untrained hands a) c) d) Plasma may be contaminated with infectious agents other than HIV hence a negative test result does not mean a used Test cartridge is safe. Disposal facilities may be subject to scavenging, the used Test cartridge must be tamperproof. Test cartridges must be single-use; it must be impossible to attempt to reuse device Test cartridge.
5.2
Specimen types 5.2.1 EDTA plasma a) Clear instructions regarding use with anticoagulants.
5.3
Operating temperatures for the device 5.3.1 From 12–40 °C a) Tolerance to high and low humidity and pressure are preferable
5.4
Sensitivity, specificity, precision at the cut-off, degree of confidence in these values, definition of populations 5.4.1 To meet performance characteristics a) Must be suitable for all major subtypes present in HIV-1 endemic countries especially M, N, O and circulating recombinant form.
5.5
Precision, trueness and accuracy: if quantitative a) LOD <800 copies/ml Page 108 of 140
WHO Sample product dossier for SIMU HIV-1 QUANT Annex VI: Input Requirements for the HIV-1 Quant Test b) 5.6 Interfering factors 5.6.1 To meet CLSI expectations and risk evaluated potential infections in HIV prevalent populations a) Cross-reactions due to malaria, Human African trypanosomiasis, Leishmaniasis and Chagas disease are all important. b) Interference from antituberculosis, antimalarial medicines and medicines for hepatitis C. 5.7 Internal QA requirement (“run controls”) 5.7.1 Internal controls: a) b) c) d) 5.8 Stability of device 5.8.1 Transport stability: to meet American National Standards Institute packaging expectations and to survive shipment and storage in resource limited settings a) b) c) d) Temperatures during transport can reach 55°C in some articulated trucks and in airports Storage temperatures can reach freezing (0 °C) during transportation at high altitude and high latitude Vibrations and movement during transport in trucks Humidity during transport and storage. Amplification control (low and high) such as Armored RNA Volume adequacy control to ensure sufficient volume Specimen processing control acting as a housekeeping gene Control for software and hardware failure to display an ‘invalid result’ error code. Precision <0.3 log
5.8.2 Shelf-life after manufacture under stated conditions for Test Cartridges and controls: at least 1 year following transport to the end-user with subsequent storage at up to 40 °C a) b) Transport temperatures can be vary from very high to lowfor long periods and Humidity and pressure should be considered also.
5.8.3 Stability after first use: Not applicable, single-use, self-contained. 5.8.4 Stability on-board: at least 6 hours between specimen addition to Test Cartridge and Test Cartridge being run in the Instrument. 5.8.5 Life of the Instrument: 3-5 years. Ensure policy for replacement. 5.8.6 Stability of result after test (time allowed prior to reading): resource restricted, timing might be an issue, long period of stability a) Printed results/USB export as txt. file/wireless connection to mobile device, datacentre. Results visible on the instrument screen. If printing fails, memory on instrument will also retain the results, but it is not intended as a long-term results storage device.
5.9
Stability of specimens 5.9.1 Plasma specimens Page 109 of 140
WHO Sample product dossier for SIMU HIV-1 QUANT Annex VI: Input Requirements for the HIV-1 Quant Test a) Plasma: Usable for 48 hours when stored at 2-8 °C and can be used indefinitely when stored at <20 °C.
5.10 Robustness or fault tolerance, “ruggedness”, “guard band studies” a) Insensitive to temperature, volume, bubbles (resulting in insufficient volume), humidity, variable pressure, light within wide limits, dust b) Resistant to mould, and tampering by the user, c) Readable by healthcare workers without laboratory expertise d) Back-up battery power supply 5.11 Speed to result and batching of tests 5.11.1 Rapid (less than 60 minutes), no batching. a) Need to have a countdown on the Instrument screen to indicate the time remaining prior to result, and an alarm to indicate when the result is ready
5.11.2 Capacity – tests per technician or Instrument per hour or per day a) b) 6. Can run one test per hour. Machine recognizes the Test cartridge from the barcode laser printed on the Test cartridge Instrument available in a modular fashion to allow running of multiple specimens simultaneously. The instrument not dedicated to one analyte.
Manufacturing Requirements
This section will be company specific; the information below is asuggestion of things to be considered but specific guidance is not given. Examples for Sections 6.7 - 6.10 will be provided in other sections of the dossier. 6.1 Location of manufacture 6.1.1 Test to be made in-house, by THE Manufacturing Company, except for moulded parts 6.1.2 Instrument: to be outsourced and control of key suppliers as per SOP XXX and audits every 12 months. 6.2 Equipment, staff, space available or to be obtained 6.2.1 Qualification of workspace, instruments, services. 6.3 Cost of production 6.3.1 No more than XXX. 6.4 Cost of materials 6.4.1 No more than YYY % of total cost of production. 6.5 Constraints on materials to be used: consideration to be given to safety, storage, environmental impact 6.5.1 As per standard practice within THE Manufacturing Company, and with additional attention to safe disposal and minimal waste in-use. 6.6 Sourcing of raw materials
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WHO Sample product dossier for SIMU HIV-1 QUANT Annex VI: Input Requirements for the HIV-1 Quant Test 6.6.1 Supplier qualification and monitoring processes as per SOP XXXX. Thebiological agents are to be developed and qualified in-house with the exception of outsourcing for oligonucleotides, primers, probes. Aback-up supplier for the outsourced materials to be identified and audited. 6.7 Storage, in-process stability of intermediates, product 6.7.1 To meet SOP-XXX of THE Manufacturing Company. 6.8 Packaging 6.8.1 Labelling to meet international guidance, IFU to be clearly written and validated for use. 6.9 QA factors: statistical analysis of the“manufacturing capability” 6.9.1 Based on known manufacturing site capability analysis for other instrument based devices made by THE Manufacturing Company. 6.10 In-process and release QA values 6.10.1 To meet SOP-XXX. 7. 7.1 Maintainability and Support Requirements Maintenance requirements 7.1.1 Internal controls to calibrate the machine, warning alert/error alerts on screen when controls out of specification 7.1.2 Remote connectivity allows for software updates via cloud/GSM network or CD distribution through local distributor where internet not available 7.1.3 Local mobile representatives and free phone number for product support 7.1.4 No on-site service and maintenance required; broken instruments can be swapped with replacement instrument a) 7.2 Availability of controls: External positive and negative controls included with the kits. Additional controls can be ordered from the manufacturer.
Supportability requirements 7.2.1 Will require considerable user feedback in the days after commercial launch to ensure that validation of the product was accurate and that it can be used and interpreted in the expected environments a) b) Connectivity to allow automatic feedback of system errors, including user errors User feedback mechanisms provided as part of the user interface.
7.3 8. 8.1
Installation requirements: Regional technician to provide training and installation if required. Cultural and Political Requirements Cultural requirements: consideration to use of bovine or porcine materials.
8.2 Political requirements: to ensure that the product has the ability to transmit results from multiple users into a central database for programmatic monitoring by e.g. ministry of health. 9. Regulatory Requirements Page 111 of 140
WHO Sample product dossier for SIMU HIV-1 QUANT Annex VI: Input Requirements for the HIV-1 Quant Test 9.1 Compliance requirements (compliance to guidance and regulations published by the International Organization for Standardisation, the European Commission, World Health Organization, and US Food and Drug Administration) 9.1.1 Environmental standard ISO 14001 a) In addition, to cover any national use and export regulations not covered by international regulation.
9.1.2 Risk management standard ISO 14971:2007 9.1.3 Material safety data sheets 9.1.4 Electrical standards 9.1.5 Connectivity standards 9.1.6 Waste management standards 9.2 Clinical trials requirements standard ISO 14155:2009 9.2.1 Helsinki Declaration 10. Usability and “Human Factors” Requirements
10.1 Ease of use 10.1.1 Critical for trained users 10.2 Ease of learning including training material and consideration to the staff’s technical ability 10.2.1 Training material must be self-explanatory. 10.2.2 The user must not be able to tamper with the Test cartridge or the Instrument. The instrument should be designed to ensure that no result is given without controls. 10.3 Accessibility requirements: consideration to colour blindness, readability including using a large font or graphics 10.3.1 Require minimal manipulation so that accessible to untrained users 10.3.2 Simplified operating dashboard on the instrument
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WHO Sample product dossier for SIMU HIV-1 QUANT
Annex VII: THE Manufacturing Company Quality Manual
Annex VII: THE Manufacturing Company Quality Manual
THE Manufacturing Company Quality Manual THE Manufacturing Company, 987 Somewhere Street, Somewhere in Europe, EU-1234, Europe (20 pages) Version 5: (08/2015)
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WHO Sample product dossier for SIMU HIV-1 QUANT Document Number Document Title QM 001
Annex VII: THE Manufacturing Company Quality Manual
THE Manufacturing Company Quality Manual
NAME Author Reviewer Authorizer
TITLE
SIGNATURE
DATE
Effective Date: Document Version Updates Prepared by Version Version 1 Version 2 Version 3 Version 4 Version 5 Summary of changes First release …. Change of organization Addition of manufacture of SIMU HIV 12 Qual Update to reflect inclusion of WHO post-market surveillance requirements Date 01.01.2011 ….. 01.01.2013 01.01.2014 06.08.2015
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Annex VII: THE Manufacturing Company Quality Manual
Letter of commitment Manufacturers are encouraged to include a letter of commitment signed by higher management as part of the Quality Manual
Scope THE Manufacturing Company Quality System covers the Design, Manufacturing and Supply of in vitro diagnostic medical devices including reagents and related systems in all areas and locations. Company Background THE Manufacturing Company is a venture capitalist supported ISO 9001-, ISO 13485- certified manufacturing company founded in 2001 and based in Europe. Manufacturers should add a description of the field of activities related to IVD and other fields. Manufacturers should add a description of the range of products and customers.
Quality System normative references THE Manufacturing Company Quality System meets the requirements of ISO 9001:2015, ISO 13485:2016. The scope of the current valid ISO 13485:2016 Certificate obtained by THE Manufacturing Company is as follows: “The development, production, distribution of in-vitro diagnostics and supporting products for infection diseases”. In addition, THE Manufacturing Company Quality System meets the quality system requirements of the In-vitro Diagnostics Medical Devices Directive 98/79/EC (The IVD Medical Devices Regulations 2002 - UK Statutory Instrument Number 618),the Korea FDA and the China FDA, and the Indonesia National Agency of Food and Drug Control.
Definitions and Abbreviations BPIC DHF DMR OEM PMS QA SOP Inventory Control System Design History File Device Master Record Original Equipment Manufacturer Post-market Surveillance Quality Assurance Standard Operating Procedure
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WHO Sample product dossier for SIMU HIV-1 QUANT
Annex VII: THE Manufacturing Company Quality Manual
1. List of Major Procedures Procedure 1. Document Management 2. Quality Record Management 3. Management Review Management 4. Management Responsibilities and Authorities Regulation Management 5. Training Management 6. Infrastructure, Management 7. Equipment management 8. Working Environment Management 9. Design Management 10. Verification Management 11. Supplier Management 12. Purchasing Management 13. Logistics Management 14. Incoming Inspection Management 15. Production Process Management 16. Equipment Management 17. Product Identification and Traceability Management 18. Monitoring and Measuring Device Management 19. Product Inspection Management 20. Product Release Management 21. Customer Feedback and Complaint Management 22. Process Monitoring and Measurement Management 23. Internal Audit Management 24. Non-conforming Product Management 25. Corrective and Preventive Actions Management 26. Vigilance Management 27. Risk Management Planning and Implementation Document number(s) Document owner Users
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Annex VII: THE Manufacturing Company Quality Manual
2. Quality Management System General Requirements • The Quality Manual and SOPs describe the processes for the quality.
Insert the company quality management system process structure chart here. Documentation Requirements General The Quality Management System Documentation includes the documents shown below: Policy Documents are generated by individual departments to give more detailed guidance of activities carried out by or managed by the particular department. Insert the company quality documents structure chart here. Quality Policies, Procedures and Processes define quality system requirements. A List of Documents held under the QMS should be appended here. Technical Documentation/Technical File/Design Dossiers form the total documentary evidence that a product conforms to the appropriate requirements of the various regulatory bodies as well as the Essential Principles. Technical Files and Design Dossiers provide a summary of the Technical Documentation. Preparation and maintenance of Technical Files and Design Dossiers is described in SOP XXX. Quality Manual The Quality Manual is maintained according to document control procedure.
3. Control of Documents SOPs are written for systems and processes that may affect product quality or the quality of service. SOPs are controlled by the central Documentation Group and circulation is usually across Departments. SOPs are technical or administrative instructions intended to provide standard methods and/or procedures for conducting scientific tests, processes, manipulations or administrative procedures. The writing and departmental control of SOPs is described in SOP XXX & SOP YYY and the authorization, approval and change control of SOPs is described in SOP ZZZ. Production Documents are controlled by the central Documentation Group. Work Instructions/Local Procedures are written for tasks that are only used within a single working group. The control of Work Instructions and Local Procedures is detailed in SOP XXX. Technical Specifications are written for raw materials and packaging items which are manufactured specifically by a supplier for THE Manufacturing Company and/or where specific additional testing is required by either THE Manufacturing Company or the supplier, and also, if the item is manufactured from materials of human or animal origin, to ensure compliance with the Essential Principles. Technical Specifications are agreed with and authorized by the supplier together with representatives of THE Manufacturing Company. Writing, authorization and Control of Technical Specifications is defined in SOP XXX.
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Product Structure & Routing Specifications are a document set for a reagent or finished pack that includes the bill of materials for a manufacturing operation and the associated department instructions. Product Structure & Routing Specifications are used in nitrocellulose striping, coating, drying, labelling and final packing of product. The relevant SOP describing writing, authorization and control of these documents is SOP XXX. Quality Assurance Product Release Specifications detail the testing that is carried out by Product Quality Assurance team to ensure that the claims for the product detailed in the Instruction for Use (IFU) are met. Writing and authorization of these documents is detailed in SOP XXX. Device Master Records (DMRs) reference the location of all documents containing the design specifications, manufacturing procedures, quality assurance requirements and labelling of THE Manufacturing Company manufactured and marketed products. The preparation, authorization and maintenance of DMRs is described in SOP XXX. Manufacturing activities are conducted in accordance with these documents. Controlled documents are authorized and issued following the appropriate and correct SOPs. The distribution and revision of most of the controlled documents is by the central Documentation Group. The Planning department is responsible for the control and maintenance of Product Structure and Routing Specifications. Changes are proposed, processed, authorized and implemented using the procedure known as THE Manufacturing Company Change Management System. This includes changes to a production process, production documentation, technical documentation, QA specification, IFU, other printed material, labels, or other documentation which may affect either the performance claim of the product, the manufacturing process or product presentation. The change procedure is defined in SOP XXX. Changes to quality documents (e.g. correction of content-related errors) may be made according to SOP XXXX-Change. Certain changes to THE Manufacturing Company products and THE Manufacturing Company Quality System must be notified to the various Competent Authorities or their recognized assessment body (for example, the Notified Body under the provisions of the IVD Directive (98/79/EC) for CE marked products). The process for determining and notifying of ‘significant changes’ is outlined in SOP XXXX-Change. In addition, copies of applicable national or international standards/regulations are controlled by Regulatory Affairs. Control of Records Records are maintained to provide evidence of conformity to requirements and of the effective operation of the quality management system and to ensure the traceability of the operations. Records are completed according to SOP XXX, and must be legible and readily identified. The major record types and retention times are defined in SOP XXX. Quality records are maintained in such a way that they are readily retrievable and unlikely to deteriorate.
4. Management Responsibility Management Commitment The senior management demonstrates its commitment to the development and implementation of the quality management system requirements by: • Establishing and maintaining a quality system.
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Defining the quality policy and quality objectives (quality plan) and communicating these throughout the organization. Ensuring the availability of resources. Conducting management reviews (SOP XXX).
Customer Focus The senior managers ensure that customer requirements are defined throughout all stages of product realization. Performance against these is reviewed to improve customer satisfaction via the Complaint Handling process (SOP XXX), Customer Requirements (SOP XXX), Design Reviews, Post-Market Surveillance (SOP XXX) and CAPA Oversight / Management Review (SOP XXX). In addition THE Manufacturing Company Marketing Executive communicates within the company and with customers to provide further definition of customer needs.
5. Quality Policy and Objectives The Quality Policy of THE Manufacturing Company (THE Manufacturing Company) is to improve health care by providing high quality, safe and effective diagnostic products. This is achieved a) b) c) d) e) f) Through the processes of design, development, manufacture and distribution carried out by competent and empowered staff. By striving for continuing quality improvement. By recognizing that the involvement and commitment of all THE Manufacturing Company personnel is essential. By providing appropriate training and an organizational structure that promotes empowerment. By assessment of and effective communication with original equipment manufacturers (OEM) suppliers. By ensuring appropriate investment in technology and systems.
Effectiveness is measured by g) h) i) j) Customer feedback through the enquiry and complaint system. Product availability. Quality metrics. Employee feedback.
The Quality Policy is communicated to all employees via the annual Quality System training; the policy is reviewed at management Review Meetings (SOP XXX). Planning Quality Objectives The requirements for quality are defined within the relevant Quality System Procedures, including Technical Specifications, and QA Product Release Specifications and the Design & Development
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Plan for new products. The activities include identification and acquisition of resources and skills to achieve the required quality. Senior managers establish Quality objectives as part of the Quality Plan for each year. Each employee has a job description that includes the quality accountabilities of the position. In addition, an employee may have specific quality goals. Quality Management System Planning Senior managers review data relating to the quality system requirements and objectives at the sixmonthly Management Review and at the monthly meetings of the CAPA Oversight Review Board and Management Team. This includes identification and acquisition of resources and skills to achieve the Quality Policy. Key metrics of the quality system are reviewed at these meetings. SOP XXX details the aspects of the quality system that are reviewed. Responsibility, Authority and Communication Insert the company organizational flowcharts. Senior managers are responsible for ensuring that responsibilities and authorities are defined and communicated. Senior managers include especially the following responsibilities: Site Director This position has overall responsibility for the site. Functional Managers in R&D, QA and Finance These positions report into their respective directorates within the company but also report to the Site Director on a day-to-day operational basis. The position holder has overall responsibility for THE Manufacturing Company Quality Policy and for the quality of all products produced by THE Manufacturing Company, and is chairman of the CAPA Oversight Review Board and Management Review Board. Operations Manager The prime accountability of the Operations Manager is to ensure that THE Manufacturing Company laboratories meet their cost, quality and service level goals and that the facilities and functions are effectively managed. This is achieved through delegated responsibilities to line reports. Financial Controller The principal responsibilities of this position are to provide the executive and line management of THE Manufacturing Company and other Companies managed from the site with accurate and timely financial information on which informed business decisions can be made. The position holder is also responsible for safeguarding the Companies' assets through the maintenance of a system of internal accounting controls and ensuring that the Companies are at all times compliant with all statutory financial requirements. The Financial Controller is responsible to the Site Director for the operation and development of electronic information systems. This includes the purchase and maintenance of hardware; systems security; data security; software licensing; and software development. Basic user training is provided in the use of systems. The position holder is also responsible for the development of improved business processes, in collaboration with other managers.
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The position holder is responsible for ensuring that THE Manufacturing Company Quality System is in compliance with regulations and is operating to assure quality in all products and services. It is the responsibility of this position holder to ensure that THE Manufacturing Company Quality Systems requirements are communicated to all THE Manufacturing Company managers and employees and that the actions required to maintain compliance with ISO 9001:2000, ISO 13485:2016 and the requirements of the In-vitro Diagnostics Medical Devices Directive 98/79/EC (the “Directive”) and other relevant regulations are highlighted to appropriate personnel. The QA Manager is responsible for ensuring that the performance of THE Manufacturing Company Quality System is reviewed in order to improve its effectiveness. Product release for sale is the responsibility of the respective Product QA Manager, but may be delegated to appropriate authorized personnel from within Quality Assurance. Other responsibilities include the Internal Audit System, training personnel on the Quality Policy and Quality System, defining criteria for release of products, assessment and release of incoming raw materials and packaging items, issuing Quality Holds and Recalls due to internal failure and/or customer complaints and authorization of the Directive Declaration of Conformity. The QA Manager reports to the Director, Immunoassay and Clinical Chemistry Quality Assurance. Regulatory Affairs Manager The Regulatory Affairs Manager is responsible to the QA Manager for ensuring that Site Management is aware of legal and regulatory requirements, which affect the company and its products. The Regulatory Affairs Manager has defined regulatory responsibilities for labelling and product safety, including defining the products already on the market to which the Directive applies, and the classification of these products according to the various regulations in country of export. The position holder has sign off authority for non-conformances and all changes to THE Manufacturing Company products. The position holder facilitates any changes in processes and procedures that are needed in order to meet new regulatory requirements. It is the responsibility of the Regulatory Affairs Manager to ensure the knowledge of national and international regulatory requirements affecting THE Manufacturing Company’s products is maintained up-to-date within the Regulatory Affairs department. This includes ensuring the requirements are met for both existing and new products. Where appropriate, new requirements are incorporated into THE Manufacturing Company Quality System documentation. The Regulatory Affairs Manager is responsible for Product Support and has vigilance responsibilities under the various regulations. Services QA Manager The Services QA Manager reports to the QA Manager. The position holder is responsible for the management of documentation systems and administration of systems such as change management. The position holder is also responsible for the environmental quality through the use of effective sampling and monitoring, and the assessment and release of incoming goods using appropriate sampling and test methods. These responsibilities are met through the management of accountable teams.
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The Product QA Manager reports to the Quality Assurance Manager and is responsible for the management of the trend analysis process to ensure that production departments carry out effective trend reviews and that appropriate action is taken. Other responsibilities include ensuring that Test Method Validation is completed according to plans and approving all product related validation plans and reports. Human Resources Manager Reporting to the Site Director, the Human Resources Manager has responsibility for manpower resourcing, training, development and education, employee relations and reward. Manufacturing Services Manager Reporting to the Site Director, the Manufacturing Services Manager is responsible for all manufacturing operations. Supply Chain Manager Reporting to the Site Director, the Supply Chain Manager is responsible for ensuring that all the Manufacturing areas know what to manufacture, for planning orders to OEM suppliers and for the availability of purchased materials and other items to support the forecasted demands. The Supply Chain Manager is supported by a team of Planners and Purchasing staff. Responsibility for the different aspects of planning and procurement are allocated to these staff. These responsibilities extend to include the control and design of Packaging Materials. Plans include both quantities and due dates, and consist of both short- and mid-term requirements. Short-term requirements include specific lots with priorities and expediting requirements. Mid-term requirements focus on ensuring overall capacity requirements for both labour and plant are communicated in a timely manner to the manufacturing area, Managers and OEM suppliers. Procurement activities aim to optimise quality and costs while maintaining high service level performance. Health, Safety and Environmental Manager Reporting to the Operations Manager, the Health, Safety & Environmental Manager is responsible for providing a comprehensive health and safety service to all functions of the company. The position holder is responsible for ensuring that the demands of relevant national and international legislation are met, taking into consideration what is reasonably practicable in relation to the level of risk. In addition to the above responsibilities the position holder advises on environmental issues that affect the company's operation. The position holder is also the Dangerous Goods Safety Advisor for the company and advises on the shipping of items that are classified as dangerous under the various mandatory codes and regulations. Research & Development department Manager The Research and Development Manager is responsible for all aspects of assay projects within Research and Development including: a) b) c) The development of new products. The introduction and approval of new and improved materials and processes to be used for the manufacture of existing products. Approval of changes to manufacturing processes. Page 122
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The authorization of production documentation relating to these projects. The content of the IFU. Validation of new instruments and generation of validation protocols for running THE Manufacturing Company products. Management of THE Manufacturing Company Marketing Executive who is the company’s principal customer contact for developing Customer Requirements and Marketing Plans. In addition, the position holder has responsibility to the Site Director for the resolution of technical problems related to the performance of products already on the market.
h)
Facilities Manager Reporting to the Operations Manager, the Facilities Manager is responsible for installation, service, maintenance and repair of all manufacturing machinery, building services, utilities, environmental control equipment and qualification of equipment, utilities and facilities. The position holder is also responsible for the calibration policy of quality critical devices and for providing traceable primary reference devices. The Facilities Manager is responsible for ensuring that the Company complies with all legal and statutory requirements in respect of electrical, mechanical and building services. Internal Communication The senior managers are responsible for communicating customer, statutory and regulatory requirements to all members of the company. This is achieved by means of All-Employee Meetings, Team Briefs, Communication Meetings and annual Quality System training. Management Review General Monitoring and review of THE Manufacturing Company Quality System is performed by the Management Review Board (SOP XXX), which includes the Site Director and senior managers from Operations, R&D and Quality. At least twice per calendar year the Management Review Board reviews the adequacy and effectiveness of THE Manufacturing Company Quality System, opportunities for improvement and the need for changes to the quality management system, including the Quality Policy and Quality objectives. Review Input Inputs to Management Review include review of internal audits, Complaint Issues, review of process and product conformance, Post-Market Surveillance Reviews, issues from Corrective and Preventive Action, Supplier issues, review of training and Regulatory issues and other changes that could affect the Quality System. Review Output Outputs of the Management Review Board are documented, including summaries of data evaluation, analyses, and recommendations and actions relating to the effectiveness of the Quality System and its processes.
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6. Resource Management Provision of Resource THE Manufacturing Company identifies resources required through the budgeting process and inputs from the senior managers to maintain the Quality System and to ensure Customer and Regulatory requirements are met. Human Resources General All staff have a job description, describing the primary objective of the position, major accountabilities, supervisory responsibilities, education and background experience required for the job and an outline training plan (SOP XXX). Competence, Awareness and Training It is a policy of THE Manufacturing Company that all personnel take responsibility for the quality of their work. All staff will receive the necessary training to enable them to perform their job effectively and safely (SOP XXX). This training will be both formal and informal and will be provided by the Human Resources Department, external trainers or local area supervisors as appropriate. It is the responsibility of individual managers to assess whether their staff require re-training following changes to procedures. Direct job-related training will be supplemented by educational and developmental opportunities in line with the business needs. Job-related, functional training of all critical operating tasks will be provided by a formal system in accordance with SOP XXX. This system also covers other non-critical operating tasks, which are of a functional nature. Training on the processes and procedures is completed by reading SOPs and signing off on the Electronic Training Management System. If competency assessment is required this is documented by means of a Training Assessment Form as described in SOP XXX. All departments identify individual training needs on an annual basis via the performance appraisal process and these are consolidated by the Human Resources Department into a company training plan. Annual Quality System training is given to all employees and includes consideration of how they can contribute to the achievement of the quality objectives. Infrastructure and Work Environment Systems have been established to provide an infrastructure to ensure conformity to product requirements. Where special arrangements are required e.g. Category III working, these are defined in specific SOPs and training is given. Equipment is qualified and is maintained to ensure continuing process capability. Monitoring the requirement for maintenance is carried out either locally according to the SOP for the equipment concerned or by the Engineering Department. Environmental monitoring is carried out, according to SOP XXX, to ensure that product performance is not impacted by the environment.
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Facility cleaning is defined by the Cleaning Contract specification for Contract Cleaners, and cleaning of work surfaces by SOP XXX. The monitoring of facility cleaning is described in SOP XXX. Clothing procedures for staff working in manufacturing areas are detailed in SOP XXX.
7. Product Realization Planning of Product Realization Stock and work in progress is considered before determining the net requirements. Firm orders for finished goods are raised on the system and become the driver for the manufacture of lower local components, bulks and the purchase of raw materials. Purchase orders are also placed for OEM products. The Design Control Procedures and responsibilities of personnel within the system are described in SOP XXX. Projects are approved and design goals set within the budgeting process. Products are then developed according to a procedure that ensures the product has been designed to meet the design inputs. A Design History File (DHF) is compiled during the development of a product, and is updated throughout the life cycle of the product. The methods of how a product is manufactured and released for sale are detailed in SOPs for the processes used. Customer-related processes Determination of requirements related to the product A Customer Requirements Document (CRD) and Product Requirements Document (PRD) are written for new or redeveloped products (SOP XXX). The CRD defines the physical and performance requirements of a device based on input from internal and external customers. The PRD translates customer requirements into a technical product description that is measurable and verifiable. These include statutory and regulatory requirements. Determination of Requirements Related to the Product The ongoing review of requirements to ensure customer needs are met is through the Product Coordination Group, chaired by THE Manufacturing Company Marketing Executive and through annual Post-Market Surveillance Reviews (SOP XXX). At each Design Review, and for changes made during the product life cycle, the appropriate requirements of the Directive will be considered. Risk Analysis (User, Patient) is carried out according to SOP XXX. Customer Communication Customers are provided with information relating to the products through THE Manufacturing Company Marketing Executive and the organization. Information on products is also communicated to customers through Product Information Letters, Technical Bulletins, letters to customers in response to complaints informing the customer of the outcomes of complaint investigations, and communication to the customer where product requirements have not been met. Design and Development Design and Development Planning The design and development activities fall into the key project stages listed below. These are defined in the Design and Development Plan (SOP X/XXX). At each stage there may be several organizational functions involved. During the course of the project there will be regular reviews of the development activities against Design Input requirements.
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The Design and Development Template is developed into the project plan by the Project Manager and is circulated to Project Group Members. As the project progresses, the plan is updated/revised as necessary and re-issued. Progress with the relevant parts of the Design and Development Plan are noted as the project progresses. During the initial planning stage, appropriate and adequate resource is assigned to each activity and is reviewed during the course of the project. Having received the approval to develop a product, the Project Group is the controlling body for a project. Regular meetings (normally monthly) are held, chaired and minuted by a Project Manager; copies of these minutes are distributed to Project Group members and appropriate members of the Site Management Team. Review of progress against the project plan is made by this group. Detailed issues are addressed outside the Project Group at R&D Technical meetings and Operations meetings. Technical Meetings run by R&D are normally held monthly and include members from operations. Minutes of these meetings form part of the DHF and are circulated appropriately. The functional leader for a specific area will report back to the next project on resulting issues. Design and Development Inputs The Design Inputs are defined according to SOP XXX. The product requirements (SOP XXX) are documented and agreed by Marketing and R&D. The needs of the user and patient are considered during this process. A summary of the regulatory requirements relevant to the product in the countries into which it will be sold is prepared according to SOP XXX. The conformity assessment route to be followed will be determined according to the risk class that the product falls into (Refer GHTF/SG1/N045:2008 Principles of IVD Medical Devices Classification). Where a product may fall into several classes according to the risk classification rules, the conformity assessment route must be determined by the highest risk class that may apply. Products are then designed and developed to meet their documented specifications with regular reviews of the product against the Design Inputs. Current statutory safety requirements are addressed by performing Control of substances hazardous to health assessments, providing Material Safety Data Sheets and in the "Warnings & Precautions" section in the package inserts. Each of these activities is covered by the Design and Development Plan or project minutes. Design and Development Outputs The design output is routinely monitored through Design Review, and Technical and Project Group meetings to ensure that it meets the requirement of the Design Inputs. Design outputs in the form of documentation and data such as Process Operating Instructions, QA Specifications, SOPs and stability reports, is reviewed before release. Design and Development Review An independent review of the design output against the Design Input requirements takes place at various stages during product development, including design input, design verification, and design validation. For products that will be CE marked under the IVD Directive, Product QA cannot release the first batch for sale until the Declaration of Conformity is signed. Design and Development Verification During the development process R&D undertake evaluations using materials of clinical origin and if available appropriate external standards to ensure that the product meets the Product Specification (SOP XXX). A Design Verification review is performed according to SOP XXX.
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Design and Development Validation Design validation is carried out by undertaking Performance Evaluation Trials under the direction of the Project Manager. The new product is evaluated against the CRD using clinical specimens (SOP XXX). Results are analysed and assessed by R&D team. Details of how the evaluation is planned and carried out can be found in SOP XXX. For products classified by the Directive as Annex II List A, the requirements of the Common Technical Specifications are met as part of the design validation. Control of Design and Development Changes During the development phase of a new product, any changes that are proposed are reviewed, agreed by all signatories, and incorporated into the Product Specification. The Design Change Control Procedure is defined in SOP XXX. Once design validation has been undertaken, changes are managed through a controlled procedure for the review, approval and implementation of change, detailed in SOP XXX. The correct transfer of product design into POIs is checked by R&D and Manufacturing personnel during the Pre-Production Phase (SOP XXX). Process validation is a key part of design and development in order to ensure quality critical processes are sufficiently well defined and controlled. The DHF (SOP XXX) is completed throughout the design phase. It is a compilation of records that describe the design history of the finished device and includes the Design and Development Plan, the Product Specification and the dossier from each review meeting. Purchasing Purchasing Process Materials that form part of the manufacturing process for THE Manufacturing Company products are identified by means of an item coding system. Ad hoc purchases for R&D purposes, facilities maintenance and administration are dealt with separately. Where possible THE Manufacturing Company item codes are linked to supplier catalogue codes and both are stated on purchase orders. Where this combination is not possible, Technical Specifications are agreed with suppliers and referenced to THE Manufacturing Company item code. These specifications define the dimensional and quality requirements together with any other parameters critical to the performance and acceptability of the item being purchased. Where a finished product is purchased from an OEM supplier, the process for evaluation and approval of the product is defined in SOP XXX. Suppliers are selected on the basis of ability to supply the required items or services at the right quality in the most timely and economic manner. Suppliers are the subject of a rating/approval scheme (SOP XXX) that assesses either the suitability to supply (for a new supplier) or the effectiveness of supply (for existing suppliers). Ratings are regularly reviewed and updated and the results of the review process determine the priority of the requirement to audit. Suppliers are approved following assessment of their Quality System (SOP XXX). A list of Approved Suppliers is maintained. Purchasing Information Requirements are communicated to suppliers by means of authorized Purchase Orders. Purchasing documents are controlled by Standard Operating Procedures. Purchase Orders will contain references, as appropriate, to THE Manufacturing Company item codes, Supplier Catalogue Codes, agreed Technical or Purchasing Specifications or legal
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agreements between THE Manufacturing Company and the Supplier. If necessary, copies of specifications, drawings etc. will be referenced in the Purchase Order document and that document will be annotated accordingly. Review and authorization of Purchase Orders is carried out as described in SOP XXX. Purchase orders are quality records and are retained for traceability purposes. Verification of Purchased Product Inspection and verification of incoming goods, including raw materials, packaging components and instrumentation is carried out according to documented procedures (SOP XXX). Testing is only performed at THE Manufacturing Company when quality critical material is involved and it is not possible to be sure that adequate controls are exercised at source. If components are required urgently for production, there are systems to allow production to progress before testing has been completed, but the final product cannot be released before the testing has been satisfactorily completed. Production and Service Provision Control of Production and Service Provision Manufacturing processes are controlled in accordance with POIs or Production Specifications. Some processes, such as filling, are monitored and controlled using statistical process control techniques throughout the operation. Product structure and routing information to support the production of products is defined by Product Structure & Routing Specifications that are controlled by the Planning Section. Products are manufactured using software, facilities, utilities, equipment, materials and processes that have undergone appropriate validation (SOP XXX). Transfer of manufacture of critical reagents between sites is detailed in SOP XXX. All materials from incoming goods through intermediate manufacturing stages to final product are handled in accordance with written, approved specifications and Standard Operating Procedures (SOPs XXX). The intention of THE Manufacturing Company is that premises are, as far as possible, suited to their intended use, being secure, of adequate size and design to allow product security by minimizing the risk of mix-up occurring. Safety, ease of cleaning and adequate pest control receives high priority. Procedures are followed to maintain labelling integrity and to prevent labelling errors. The packing process, including the information printed by THE Manufacturing Company on the labels and packaging, is controlled by Product Structure & Routing specifications. Final product can only be released for distribution if it has been approved for issue by Product QA. Product packaging and shipping containers are designed to protect the products from damage during normal conditions of storage, handling and distribution. Records relating to the identification and quantity of product shipped and the identity of the consignee are retained. Product installation and Servicing Activities are not undertaken by THE Manufacturing Company. Validation of Processes for Production and Service Provision The approach to validation is defined in SOP XXX. Equipment qualification is performed to ensure that equipment used in the manufacture of quality critical processes has been designed to meet the needs of that function and will operate consistently to meet the needs of the intended process (SOP XXX).
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Process validation is performed to establish a high level of confidence that quality critical processes are sufficiently well controlled so as to ensure a consistently high level of quality in terms of efficacy and product stability (SOP XXX). Test Method Validation is performed to establish that the performance characteristics of the method meet the requirements of the intended use of the test (SOP XXX). Software validation is completed according to SOP XXX. Identification and Traceability Materials used as part of the manufacturing process for products are identified by a part code and the manufacturer's lot number or THE Manufacturing Company allocated batch number. All intermediate products and bulks are identified by unique THE Manufacturing Company lot numbers assigned by Manufacturing. Final components and kits are labelled with the component or kit product code together with individual batch numbers. The Batch Histories that are maintained by the Quality Assurance department can be used to trace the history of the product or component batch to the Production Records kept by Manufacturing. Material/component/product status is computer driven and under the control of Purchasing Quality Services/Product QA. Inspection and testing activities that verify the specified requirements for that product are met are defined in the relevant Quality and System Procedure, DMR and quality control specifications. In-Process inspection and testing of THE Manufacturing Company products is carried out by manufacturing personnel and quality control personnel following procedures described in Production and QC Specifications. Quality control personnel also perform in-process inspection and testing following QC Specifications. Depending on the results of the inspection and testing, products may be passed, referred or rejected. Final inspection, and testing where appropriate, of THE Manufacturing Company products is carried out by Quality control personnel following QC Specifications. Product release for sale is the responsibility of the respective Product QA Manager, but may be delegated to appropriate authorized personnel from within Quality Assurance. For CE marked products classified as Annex II List A products, the Product QA Manager is responsible for ensuring that the verification of manufactured product by the Notified Body is received before the batch is released for sale (SOP XXX). Production records containing the results of inspection and testing by Manufacturing and quality control personnel are held within the Manufacturing area before archiving. Batch Histories (Secondary Manufacturing records and Quality control testing, batch release by QA of each product batch) are held accessible as original hard copy for up to 3 months beyond the expiry of the product. Beyond that point QA records are archived in the form of microfiche. The personnel responsible for the release of product are defined in appropriate SOPs and indicated on the Batch Histories. Preservation of Product Storage areas preclude adverse environmental effects on stored materials and allow orderly stock control by providing effective separation of different materials and materials of different status. Appropriate facilities are available for the storage and handling of materials that are potentially infectious.
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All quality influencing equipment is subject to regular calibration and is traceable to national standards. The management of routine calibration work will, for the most part, be the responsibility of the Facilities Manager. This responsibility will be shared by responsible personnel in each area who ensure that only properly calibrated equipment is in routine use. The frequency with which equipment is calibrated and the tolerances that are allowed before adjustments are made will be as recommended in manufacturer's user guides and/or service manuals. In deciding on the optimum retest cycle and adjustment limits the Engineering Department will take account of the reliability and criticality of the relevant equipment. Calibration records will be kept adjacent to the relevant equipment in the various operating areas and/or centrally by the Engineering Department as appropriate. Implementation of this policy is controlled in SOP XXX. Where products contain calibrators or quantified controls, traceability to an independent standard where available is ensured through design input and the QA Release Specifications.
8. Measurement, Analysis and Improvement General Procedures have been designed / developed and implemented to monitor • • • If customers’ requirements for products and service delivery have been met. The effectiveness of the Quality Management System. The ongoing improvement of the Quality Management System.
Monitoring and Measurement Customer Satisfaction Procedures have been developed and implemented that define the process for the determination of product and service quality levels. End-user satisfaction is monitored by the distributors in country. The distributors provide feedback through the complaint management system. A review is held annually for each product (SOP XXX) as part of Post-Market Surveillance. Internal Audit Internal audits are coordinated by the Audit Co-ordinator within QA and are performed by trained internal auditors from a range of departments. Audits are performed by personnel independent of the process or area being audited. Audits are performed of specified activities (e.g. Hold/Corrective Action, Control of Change, Calibration) and of specific areas, to cover all relevant aspects of IS0 9001, ISO 13485 and the Directive. The procedure followed is described in SOP XXX. The progress with corrective actions arising from internal audits involves visits to the appropriate area. Failure to meet agreed dates is highlighted to the Corrective and Preventive Action (CAPA) Oversight Review Board.
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Monitoring and Measurement of Processes and Product Processes have been designed and implemented to ensure that the data on records relating to the Quality Management System and product quality are gathered, evaluated and analysed for trends. This trend data is then used to implement corrective and/or preventive actions. In-process materials are sampled, inspected and tested by trained personnel in accordance to documented, standardized and validated test procedures. Requirements are stated in the applicable testing procedures and sampling plans. Material conformance is based on test and/or inspection results and work order review. Disposition is assigned by trained personnel. Materials are held until all tests and inspections have been completed and approved. Any non-conforming in-process materials are controlled, segregated where practicable, and the non-conformity documented. Final sampling, testing, inspection and disposition of product are done by trained quality control personnel in accordance to documented, standardized and validated test procedures. Requirements are stated in the applicable testing procedures and referenced sampling plans. Final product test records that certifying that all required tests have been satisfactorily completed are required prior to disposition by authorized personnel. Appropriate statistical techniques are used for packaging materials inspection, and in-process inspection and testing during manufacture. These are defined in SOPs XXX. Where appropriate, sampling methods are reviewed in the light of non-conformances in product or processes or other appropriate information. Assessment of product performance for Design Verification is performed using techniques that are the accepted norm in the IVD industry. Product trends are reviewed according to SOP XXX. Product is released to distribution upon final approval or, in cases where regulatory requirements have to be met, upon regulatory approval or consent (e.g. in case of notifications). The stability of products is monitored after release for sale (SOP XXX). Post-market surveillance and measurement A post-market surveillance and reporting system (SOP XXX and Recall SOP XX) is followed that is aligned with the responsibilities outlined in the WHO document Post-Market Surveillance of in vitro diagnostics. The aim of the system is to ensure that non-conformities, changes and complaints are identified and examined, including a risk analysis (as per figure 2 pg 14 of the guidance) and that necessary action is taken. Any customer complaints are to be documented by the team member in charge of complaints reporting, as per SOP XXX. It is the responsibility of the Safety Officer to perform a risk analysis. The responsibilities of all staff involved in PMS are outlined in SOP XXX. It is the responsibility of the Quality manager to ensure that an analysis of risks and causes and initiation of a CAPA is undertaken as per SOP XXX. The timeframe for the investigation depends on the severity of the adverse event as defined by Table 4 pg 25 of the guidance. Recalls Recalls are measures to avert the risks to customers due to products that have deviated from the intended product specifications. Product recalls involve the following actions • Notification to the relevant competent authority prior to a recall (if appropriate). Page 131
WHO Sample product dossier for SIMU HIV-1 QUANT
Annex VII: THE Manufacturing Company Quality Manual
• Notification of customers and users. • Returns. • Destruction. • Revision of IFUs. The recalls procedure is described in SOP XXX. THE Manufacturing Company follows: • • • • MEDDEV 2 12-1 rev. 8 Vigilance, European Commission guidelines on a medical devices vigilance system. GHTF/SG2/N54R8:2006 Medical Devices Post-Market Surveillance: Global Guidance for Adverse Event Reporting for Medical Devices. GHTF/SG2/N008R4:1999 Guidance on How to Handle Information Concerning Vigilance Reporting Related to Medical Devices. GHTF/SG2/N57R8:2006 Medical Devices Post-Market Surveillance: Content of Field Safety Notices.
Control of Non-conforming Product The control of non-conforming raw material or components and non-conforming final product is the responsibility of appropriate Quality Assurance personnel. The procedures followed are described in SOP XXX. The procedure for quarantining non-conforming material is detailed in SOP XXX. Appropriate corrective action following a product failure after release is initiated and coordinated by the Quality Assurance Manager. The procedures followed are described in SOP XXX. The review and disposition of non-conforming product is carried out according to SOP XXX. If product is reworked, the specific requirements of SOP XXX are followed. It is the responsibility of the Regulatory Affairs Manager or agreed deputy to ensure regulatory requirements are met before authorizing a non-conformance report. The procedure for the complete rejection of product and subsequent disposal is described in SOP XXX. Analysis of Data Procedures have been implemented to collect and analyse appropriate data. Data is evaluated for the reviews by Site Management. Improvement Post-market surveillance and related activities to meet the requirements of the Directive (Annex III (5), Annex IV (3.1) or Annex VII (3.1)) is carried out according to SOP XXX for ALL products, regardless of the regulatory version. Continual Improvement Data on trends in non-conformances related to the Quality Management System, suppliers, product and processes are input to the Management Review Meeting to determine that appropriate corrective / preventive action is taken. Corrective Action Customer complaints are received, investigated, reported, and replied to by the Product Support Group. SOP XXX describes the procedures followed and includes the requirements for vigilance reporting under the various regulations. The investigation of the cause of non-conforming product following customer complaints is detailed in SOP XXX
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WHO Sample product dossier for SIMU HIV-1 QUANT
Annex VII: THE Manufacturing Company Quality Manual
The procedure for investigations and defining of Corrective Action following a non-conformance or a Customer Complaint is detailed in SOP XXX. Subsequent to implementation of that Corrective Action Plan, the effectiveness of the action is reviewed. The following SOPs outline the activities associated with corrective action and preventive actions: • Control of non-conforming products (SOP XXX) • Control of non-conforming incoming goods (SOP XXX) • Control of key suppliers (SOP XXX) • Customer complaints (SOP XXX) • Internal audits (SOP XXX) • Risk management policy (SOP XXX) Preventive Action A variety of sources of information are reviewed in order to detect, analyse and eliminate potential causes of non-conformities. The information reviewed includes Non-Conformance reports, Investigations and Corrective Actions reports from internal and external audits, change notes, trend analysis, and complaints. Preventive action is progressed or monitored by the Management Review Board (SOP XXX). Control of Key Suppliers Suppliers are subject to an approval evaluation before being included in the approved list of suppliers. The suppliers of quality related products and key components (as identified by the risk analysis) are subject to yearly evaluation (using the rating scale defined in SOP XXX). The evaluation is organized by the purchasing team and overseen by the quality management department. Yearly evaluation is conducted on a risk-based analysis and frequency may be decreased as set out in SOP XXX. Suppliers are evaluated on a number of different indicators: • Quality management • Commercial aspects and pricing • Service • Ability to meet deadlines and quantity requirements. Internal feedback is also used for continual yearly evaluations.
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The Prequalification Team - Diagnostics Assessment sample product dossiers are based on a fictitious in vitro diagnostic medical devices and aim to provide manufacturers with an example of the type of information to be included in a product dossier submitted to WHO Prequalification.
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