WHO Sample product dossier for SIMU™self-test for HIV 12O
WHO Prequalification: Sample Product Dossier for an IVD intended for HIV self-testing SIMU™ self-test for HIV 12O PQDx5432-98-00 THE Manufacturing Company DRAFT DOSSIER FOR PUBLIC COMMENT
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 WHO requirements.
Working document 21 December 2015 WHO Sample product dossier for SIMU™self-test for HIV 12O
© World Health Organization 2015
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Contact: Irena Prat, EMP Prequalification Team Diagnostics
WHO - 20 Avenue Appia - 1211 Geneva 27 Switzerland
Working document 21 December 2015 WHO Sample product dossier for SIMU™ self-test for HIV 12O
Table of contents
Abbreviations ...... 7
1 Introduction ...... 9 1.1 Purpose of the sample product dossier ...... 9 1.2 Content of the sample product dossier...... 9 1.3 Completeness of the sample product dossier ...... 9 1.4 Format of the sample product dossier ...... 9 1.5 Feedback on the sample product dossier ...... 9
2 Intended audience ...... 10
3 The product dossier ...... 11 3.1 WHO product dossier elements ...... 11 3.2 When to submit a product dossier ...... 11
4 WHO Product Dossier checklist ...... 12
5 The product ...... 20 5.1 Regulatory versions of this product ...... 20 5.2 Product description including variants (configurations) and accessories ...... 20 5.2.1 Product description ...... 20 5.2.2 Intended use ...... 22 5.2.3 Intended users ...... 22 5.2.4 Photographs of kit ...... 22 5.2.5 A general description of the principle of the assay method or instrument principles of operation...... 23 5.2.6 A description of the components of the assay ...... 24 5.2.7 A description of the specimen collection and transport materials provided with the product or descriptions of specifications recommended for use...... 24 5.2.8 For instruments of automated assays: a description of the appropriate assay characteristics or dedicated assays ...... 24 5.2.9 For automated assays: a description of the appropriate instrumentation characteristics or dedicated instrumentation...... 24 5.2.10 If applicable, a description of any software to be used with the product...... 24 5.2.11 If applicable, a description or complete list of the various configurations or variants of product that will be made available ...... 25 5.2.12 If applicable, a description of the accessories and other products that are intended to be used in combination with the diagnostic ...... 25 5.3 Essential principles (EP) check list ...... 25 5.4 Risk analysis and control summary...... 25 5.4.1 Risk analysis policy ...... 25 5.4.2 Risk Categories ...... 26 5.4.2.1 Erroneous test results ...... 26 5.4.2.2 Interfering substances ...... 27 5.4.2.3 Testing process ...... 27 5.4.2.4 Stability ...... 27
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5.4.2.5 Specimen type ...... 28 5.4.3 Risk/Benefit ...... 28
6 Design and manufacturing information ...... 29 6.0 Design control ...... 29 6.1 Product design ...... 30 6.1.1 Design overview ...... 30 6.1.2 Formulation and composition ...... 32 6.1.3 Biological safety ...... 33 6.1.4 Documentation of design changes ...... 34 6.2 Manufacturing process ...... 35 6.2.1 Overview of manufacture ...... 35 6.2.1.1 Batch release criteria/Final lot release ...... 36 6.2.2 Sites of manufacture ...... 37 6.2.3 Key suppliers ...... 38
7 Product performance specifications and associated validation and verification studies...... 39 7.0 QC panel for SIMU™ self-test for HIV 12O Product Codes: Y1234-B and Y1234-O ..... 41 7.0.1 Validation of the QC calibrator scale for use in stability studies and at release-to-sale ...... 41 7.0.1.1 Introduction ...... 41 7.0.1.2 Study objective ...... 41 7.0.1.3 Study design and planning ...... 42 7.0.2 QC panel members, criteria, rationale ...... 45 7.0.2.1 QC panel for SIMU™ self-test for HIV 12O Product Codes: Y1234-B and Y1234-O ...... 45 7.1 Analytical studies ...... 48 7.1.1 Specimen types ...... 48 7.1.1.1 Specimen type equivalence ...... 48 7.1.1.2 Specimen stability ...... 49 7.1.2 Analytical performance characteristics ...... 51 7.1.2.1 Accuracy of measurement ...... 51 7.1.2.2 Analytical sensitivity ...... 53 7.1.2.3 Analytical specificity - Effect of interfering substances and unrelated medical conditions...... 59 7.1.2.4 Traceability of calibrators and control material values ...... 63 7.1.2.5 Measuring range of the assay ...... 63 7.1.2.6 Validation of assay cut-off ...... 63 7.1.2.7. Validation of assay procedure – reading time ...... 63 7.2 Stability (excluding specimen stability)...... 66 7.2.1 Claimed shelf life ...... 66 7.2.2 In-use stability and stability of result ...... 67 7.2.3 Shipping stability ...... 68 7.3 Robustness studies ...... 70 7.3.1 Robustness to volume variation ...... 71 7.3.2 Robustness to environment: temperature, humidity, time out of pouch ...... 74 7.4 Establishing clinical performance of SIMU™ self-test for HIV 12O device for professional use and self-testing ...... 76
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7.4.1 Part 1: Clinical performance evaluation - professional use ...... 76 7.4.2 Part 2: Qualification of Usability (Validation of labelling and device interpretation for self-testing; Observed self-testing in trained and untrained users) ...... 84 7.4.2.1 Part 2-a: Validation of label comprehension for finger stick and OMT job aid and IFU ...... 85 7.4.2.2 Part 2-b: Validation of result interpretation of results from pre- made Y1234-B/O cassettes ...... 86 7.4.2.3 Part 2-c Validation of device usability by observed self-testing in trained users ...... 88 7.4.3 Part 3: Clinical performance evaluation – self testing ...... 89
8 Labelling ...... 97 8.0 Packaging ...... 97 8.0.1 Shipping packaging ...... 97 8.0.2 Outer packaging for single test kit ...... 97 8.0.3 Pouch ...... 97 8.1 Labelling ...... 97 8.1.1 Outer packaging for single test kit labelling ...... 97 8.1.2 Pouch ...... 99 8.2 Instructions for Use ...... 100 8.3 Instrument manual ...... 100 8.4 Any other instructional materials provided to the user ...... 101 8.4.1 Job aid ...... 101 8.4.2 Other material – pre- and post-testing information and instructional video .... 101
9 Commercial history ...... 102 9.1 Countries of supply ...... 102 9.1.1 List of countries where product is currently supplied ...... 102 9.1.2 Minimum and maximum price in 2014 ...... 102 9.1.3 Training and support network ...... 102 9.2 Adverse events and field safety corrective actions ...... 102
10 Regulatory history ...... 103
11 Quality Management System ...... 104 11.1 Quality manual ...... 104 11.1.1 Quality manual system documents ...... 104 11.1.2 Quality manual system procedures ...... 104 11.2 Quality manual system certification ...... 104
Annex I: Essential Principles checklist ...... 105
Annex II: Risk management policy ...... 128
Annex III: Residual risk statement ...... 130
Annex IV: Design inputs FMEA ...... 131
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Annex V: User and patient FMEA ...... 136
Annex VI: Input requirements self-testing device ...... 138
Annex VII: THE Manufacturing Company Quality Manual ...... 145
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Abbreviations
ACD-A anticoagulant citrate dextrose solution
CE Conformité Européenne (European Conformity)
CLSI Clinical and Laboratory Standards Institute
CV coefficient of variation
DF degrees of freedom
EDTA ethylenediaminetetraacetic acid
EIA enzyme-linked immunoassay
FMEA failure mode and effects analysis
GHTF Global Harmonization Task Force
HBsAg hepatitis B surface antigen
HBV hepatitis B virus
HCV hepatitis C virus
HIV human immunodeficiency virus
IgA, IgG, IgM Immunoglobulins A, G and M
IFU instructions for use
IMDRF International Medical Devices Regulators Forum
ISO International Organization for Standardization
IVD in vitro diagnostic medical device
NAT nucleic acid test
OMT oral mucosal transudate
OD optical density
OQ operational quality
POCT point of care test
POS positive
QA quality assurance
QC quality control
QMS quality management system
R&D research and development
RDT rapid diagnostic test
ROW rest of world
SOP standard operating procedure
WRT with reference to
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Authors and Acknowledgements The document WHO Prequalification: Sample Product Dossier for an IVD intended for HIV self- testing was prepared by Julian Duncan (consultant, London, UK), Mark Lanigan (consultant, Australia), Mary-Kay Romero (consultant, USA), Deirdre Healy (WHO/HIS/EMP) and Robyn Meurant (WHO/HIS/EMP). This document was developed as part of the Bill & Melinda Gates Foundation Umbrella Grant and the UNITAID grant for “Increased access to appropriate, quality-assured diagnostics, medical devices and medicines for prevention, initiation and treatment of HIV/AIDS, TB and malaria”. This document was produced under the coordination and supervision of Deirdre Healy, Robyn Meurant and Irena Prat (WHO/HIS/EMP), Geneva, Switzerland. This document is now available for public consultation from 18 December 2015.
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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. The product dossier should contain evidence submitted by the manufacturer to demonstrate to WHO that the diagnostic 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, 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 self-test antibody diagnostic.
1.2 Content of the sample product dossier This dossier is based on a fictitious diagnostic, the Simu self-test for HIV 1.2(O) 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.
1.3 Completeness of the sample product dossier Because of its invented nature, the information provided is considered exemplary and not necessarily 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 red coloured boxes to indicate where additional information may be expected. This sample product dossier is still in development and not all prequalification requirements have been addressed. WHO will continue to incorporate relevant sections. However, it is important to repeat that the purpose of this document to provide examples. This sample product dossier can never be considered to represent all the evidence that may be needed to meet WHO Prequalification requirements. Each manufacturer is responsible for identifying the type and volume of evidence that will be sufficient. WHO Prequalification staff are available to assist manufacturers at any point in the prequalification process. Staff may be contacted by email at [email protected].
1.4 Format of the sample product dossier The format of this sample product dossier, including the section numbering system, follows that contained in WHO Publication PQDx_018 “Instructions for Compilation of a Product Dossier”. This document can be found on the WHO website (www.who.int) at the following link: http://www.who.int/diagnostics_laboratory/evaluations/100506_pqdx_018_dossier_instructns_v1. pdf
1.5 Feedback on the sample product dossier Comments on this sample product dossier and its utility are welcomed by WHO at [email protected]. The document has been published for public comment from 21 December 2015.
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2 Intended audience This document has been created to assist manufacturers who wish to submit a product dossier for a self-test antibody diagnostic. This document provides an example of how a WHO Product Dossier should be compiled in accordance with the instructions and format described in the PQDx_018 “Instructions for Compilation of a Product Dossier”. This document is available at: http://www.who.int/diagnostics_laboratory/evaluations/100506_pqdx_018_dossier_instructns_v1. pdf
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3 The product dossier
3.1 WHO product dossier elements For the purposes of WHO Prequalification – Diagnostics, 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 conforms to the Essential Principles of Safety and Performance of Medical Devices1 and meets other WHO requirements. During the WHO review of a product dossier, WHO will take into account the information that was previously submitted in the WHO Publication PQDx_015 “Prequalification of Diagnostics – Pre- submission form”. Therefore, manufacturers should ensure that the content of the product dossier is consistent with the information submitted with the pre-submission form and that any changes in the information submitted with the respective pre-submission form are promptly notified to WHO. Furthermore, inadequacies identified at the pre-submission form stage and communicated by WHO to the manufacturer are expected to be addressed as part of the product dossier submission.
3.2 When to submit a product dossier Manufacturers should only submit a product dossier to WHO Prequalification when formally requested to do so by WHO. Dossiers that are submitted without a request from WHO will be returned to the manufacturer without review. Manufacturers should ensure that the dossier contains all the information as is prescribed in PQDx_018 “Instructions for Compilation of a Product Dossier”. The prequalification procedure may be terminated if the dossier does not contain the prescribed information, or where the information supplied is inadequate to complete the prequalification assessment effectively or where the requested information is not provided by the manufacturer within a specified time period.
1 GHTF/SG1/N41R9:2005 Essential Principles of Safety and Performance of Medical Devices http://www.imdrf.org/documents/documents.asp
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4 WHO Product Dossier checklist The attached Product Dossier contains information in support of the previously submitted Prequalification of Diagnostics – Pre-submission form (Document PQDx_015) for the following product:
PQDx Number: PQDx5432-98-00 Product Name: Simu self-test for HIV 12O Manufacturer Name: THE Manufacturing Company
PRODUCT DOSSIER CHECKLIST
Dossier Content Requirement Provided Location: NOTE: The below matches that of PQDx_018, Instructions for Yes/No Volume/Section compilation of a Product Dossier. Page number – Page number Letter of Agreement The Letter of Agreement is attached to the front page of the dossier Yes Annex XXX and supports attestation of payment Page XX The information concerning the product is the same on the Letter of Yes Annex XXX Agreement and the Prequalification Dossier Page XX 4. Dossier Format Yes 4.1. Product Dossier Submission Format Yes Entire dossier One printed copy and one electronic copy of product dossier submitted Yes Not applicable A signed document attesting that the content of the electronic version Yes Annex XXX is an exact duplicate of the printed copy was submitted Page XX Dossier is clearly presented (bound or in a clearly marked set of ring- Yes Entire dossier binders) 4.2. Layout and Order Yes Proper formatting of 1 of 2, 2 of 2, etc., used Yes Entire dossier The submission is clearly divided into sections as described and all Yes Entire dossier pages are numbered Table of contents included Yes This checklist is attached to the front of the submission and used as a Yes Page 6 cross-reference The physical pages of the dossier and the pages numbers correspond Yes Entire dossier There are appropriately named tab identifiers Yes Entire dossier Standard A4 paper is used for all submissions Yes Entire dossier Font sizes are easily legible Yes Entire dossier 4.2.1. Electronic Copy Requirements Yes The electronic copy is in PDF form with no password required Yes The electronic copy is organized in the same format as the printed copy Yes The name of the file is descriptive and doesn’t contain any of the noted Yes special characters
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Dossier Content Requirement Provided Location: The electronic copy is in PDF form with no password required. Yes 4.3. Language and Units of Measurement Yes Entire dossier English language and units of measure used Yes Entire dossier Any translations must be carried out by a certified translator Yes Entire dossier 5. Product Yes Page 20 5.1. Regulatory versions of this product Yes Page 20 All regulatory versions of the product are identified and the version Yes Page 20 being submitted for assessment is indicated For all submissions, the regulatory version to which it relates is Yes Entire dossier identified 5.2. Product description including variants (configurations) and Yes Page 20-21 accessories The intended use of the diagnostic , testing population, user, and Yes Page 22 setting of use for the diagnostic is included Photographs of all kit components, both packaged and individual, are Yes Page 22 included A description of the principle of the assay method/instrument Yes Page 23-24 principles of operation are provided A description of the components and reactive ingredients are included Yes Page 24 A description of the specimen collection and transport materials are Yes Page 24 provided A description of the appropriate assay and instrumentation Yes Page 24 characteristics are included If applicable, there are descriptions of software to be used with the Yes Page 24 product, a list of variants/configurations of the product, and a description of accessories are included. 5.3. Essential principles (EP) checklist Yes Page 25 Annex I A checklist in the form of a table that lists all relevant material is Yes Annex I included 5.4. Risk analysis and control summary Yes Page 25-28 Annex II, III, IV, V There is a summary report of the risks identified during the risk analysis Yes Page 25-28 process Annex II, III A description of how risks have been controlled to an acceptable level Yes Page 25-28 A signed conclusion with evidence that the remaining risks are Yes Annex III acceptable is presented There is evidence that the risk analysis is part of the manufacturer’s risk Yes Page 25 management plan Annex II When applicable, specific standards/guidelines recommended by the Yes Annex II WHO are identified 6. Design and manufacturing information Yes Page 29-38 6.1. Product design Yes Page 29-35
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Dossier Content Requirement Provided Location: 6.1.1. Design Overview Yes Page 30 Annex VI Information to provide a general understanding on design is provided Yes Page 20-24, 30-32 There is a flowchart of the design process Yes Page 30-32 A general description of the critical assay ingredients for use with the Yes Page 32-33 product is provided If applicable, a controlling site is identified Yes Page 29 6.1.2. Formulation and composition Yes Page 32-33 For each of the ingredients, formulation/composition information is Yes Page 32-33 provided Sources of IVD component materials are identified Yes Page32-33 6.1.3. Biological safety Yes Page 33-34 Annex X There is a table, including all needed information, listing all biological Yes Page 33-34 components included in the product If applicable, a determination of the residual risk of Yes Page 33-34 transmission/infection to the user is provided There is information on how users of the device are informed of any Yes Page 33-34 residual risk 6.1.4. Documentation of design changes Yes Page 34-35 Records of each design change for the product submitted, with all Yes Page 34-35 pertinent information, is included 6.2. Manufacturing process Yes Page 35-38 6.2.1. Overview of manufacture Yes Page 35-36 A flow chart of the entire manufacturing process is included Yes Page 35-36 A site master file, with a diagram of the floor plan, is provided Yes Page 35-36 If applicable, certified copies of Quality Management System Yes Annex XX certificates are annexed to the dossier There are details of each major step in the manufacturing process with Yes Page 35-36 all needed information included in the proper form There is an overview of verification, validation, and quality-control Yes Page 35-36 activities for all stages of design and manufacture Batch release criteria for the product are included Yes Page 36 Annex XX 6.2.2. Sites of manufacture Yes Page 37 All critical manufacturing sites for all necessary stages of manufacture Yes Page 37 are listed with all necessary information 6.2.3. Key suppliers Yes Page 38 All key suppliers are listed with all needed information Yes Page 38 If applicable, certified copies of the key suppliers’ certificates are Yes Annex XX annexed to the dossier 7. Product performance specifications and associated validation and Yes Page 39-96 verification studies
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Dossier Content Requirement Provided Location: 7.1. Analytical studies Yes Page 48-76 7.1.1. Specimen types Yes Page 48-50 Annex XX The different specimen types that can be used with the product are Yes Page 48 identified The studies needed information for support of the specimen type are Yes Page 48-49 included The studies and needed information for support of claims made for Yes Page 49-50 specimen types are included 7.1.2. Analytical performance characteristics Yes Page 51-65 Annex XX 7.1.2.1. Accuracy of measurement Yes Page 51-53 7.1.2.1.1. Trueness of measurement Yes Page 51 The studies and information needed to establish trueness of Yes Page 51 measurement are provided 7.1.2.1.2. Precision of measurement Yes Page 51-53 7.1.2.1.2.1. Repeatability Yes Page 51-53 The studies and information needed to establish within-run variability Yes Page 51-53 are included If applicable, provide studies to establish repeatability undertaken by Yes Page 51-53 non-laboratory personnel 7.1.2.1.2.2 Reproducibility Yes Page 51-53 Studies and information to establish the appropriate types variability Yes Page 51-53 are included The use of specimens that represent the full range of expected analyte Yes Page 51-53 concentration are included If applicable, provide studies to establish repeatability undertaken by Yes Page 51-53 non-laboratory personnel 7.1.2.2. Analytical sensitivity Yes Page 53-58 The studies needed to establish analytical sensitivity are included with Yes Page 53-58 all needed information If applicable, the needed parameters are provided and there are details Yes Page 53-58 on their derivation 7.1.2.3. Analytical specificity Yes Page 59-63 There are studies and information included that evaluate the effects of Yes Page 59-63 potentially interfering and cross-reacting substances/agents on the assay 7.1.2.4. Metrological traceability of calibrators and control material Yes Page 63 values There is detailed information about the traceability of values assigned Yes Page 63 to calibrators and trueness control materials 7.1.2.5. Measuring range of the assay Yes Page 63 Studies and information that define the measuring range of the assay Yes Page 63 are included
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Dossier Content Requirement Provided Location: 7.1.2.6. Validation of assay cut-off Yes Page 63 Studies and information on how the assay cut-off time was determined Yes Page 63 are included 7.1.2.7. Validation of assay procedure-reading time Yes Page 63-65 Studies and information on how the reading time was determined are Yes Page 63-65 included 7.2. Stability (excluding specimen stability) Yes Page 66-69 The studies and information on stability are included Yes Page 66-69 When applicable, the manufacturer has looked to internationally Yes Page 66-69 accepted methods for determining stability of diagnostics and followed WHO recommendations for stability 7.2.1. Claimed shelf-life Yes Page 66-67 Ensure that testing is done on at least three different lots manufactured Yes Page 66-67 under conditions equivalent to routine production conditions The study protocol specifies acceptance criteria and testing intervals Yes Page 66-67 Accelerated studies/extrapolated data are acceptable for initial shelf Yes Not applicable life claim, but have been/will be followed up with real time stability studies If applicable, the method used for accelerated studies is identified Yes Not applicable The shelf life is derived from the lot with the shortest real time stability Yes Page 66-67 data The conclusions clearly identify claimed shelf life stability Yes Page 66-67 7.2.2. In use stability Yes Page 67-68 There are studies and information for each assay component’s in-use Yes Page 61-62 stability provided For each component, there is testing on at least one lot Yes Page 67-68 The studies reflect routine use of the device Yes Page 67-68 The study protocol specifies acceptance criteria and testing intervals Yes Page 67-68 If applicable, supporting data for calibration stability claims is provided Yes Page 67-68 Conclusions clearly identify the claimed in-use stability Yes Page 67-68 7.2.3.Shipping stability Yes Page 68-69 Information needed on shipping stability studies is included. These Yes Page 68-69 studies are of one lot to evaluate the tolerance of products to the anticipated shipping conditions Studies are done under real/simulated conditions that include variable Yes Page 68-69 conditions The studies reflect the environmental conditions of the countries of Yes Page 68-69 supply, along with justification The study protocol specifies acceptance criteria and testing intervals Yes Page 68-69
If applicable, the methods of simulated conditions must be identified Yes Page 68-69
The results and conclusions must clearly demonstrate that the product Yes Page 68-69 will be effective at the end of its claimed shelf life after being subjected to the stressed conditions
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Dossier Content Requirement Provided Location: 7.3. Robustness studies Yes Page 70-76 There is a summary of all evidence for the robustness study(ies) Yes Page 70-76 The test environment and its relation to the intended environment are Yes Page 70-76 stated There is a discussion of what tests were considered for the device and Yes Page 70-76 why they were/were not performed There is a discussion to support why the evidence presented is Yes Page 70-76 sufficient to support the application If applicable, there is reference to the studies and endpoints for Yes Page 70-76 performance studies that include human factors/usability end points 7.4. Clinical evidence (clinical or diagnostic sensitivity and specificity) Yes Page 76-96 7.4.1. Clinical evaluation - Part 1 Clinical performance evaluation - Yes Page 76-83 professional use All performance claims are supported by well-designed performance Yes Page 76-83 evaluations that have been carried out/coordinated by the manufacturer and these studies are included with all needed information 7.4.2. Clinical evaluation - Part 2: Qualification of Usability (Validation Yes Page 84-89 of labelling and device interpretation for self-testing) If applicable, publication details of the independent study(ies) is Yes Annex XX included Testimonials are not included as evidence of performance Not applicable 7.4.3. Clinical evaluation - Part 3: Establishing clinical performance for Yes Page 89-96 self-testing If applicable, publication details of the independent study(ies) is Yes Annex XX included Testimonials are not included as evidence of performance Not applicable 8. Labelling Yes Page 97-101 The product dossier contains a complete set of labelling associated with Yes Annex XX the product with all four needed inclusions 8.1. Labels Yes Page 97-99 Copies of all packaging labels for the assay are included and contain all Yes Page 97-99 needed information 8.2. Instructions for use Yes Page 100 Annex XX A copy of the current instructions for use are included and these Yes Annex XX instructions include all needed information 8.3. Instrument manual Yes Not applicable If applicable, there is a copy of the instrument manual/associated Yes Not applicable operator manuals included 8.4. Any other instructional materials provided to the user Yes Page 101 Annex XX If applicable, any other instructional material copies are provided Yes Annex XX 9. Commercial History Yes Page 102
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Dossier Content Requirement Provided Location: 9.1. Countries of supply Yes Page 102
There is a list of all countries in which the product under assessment is Yes Page 102 currently supplied and the year when supply started For each country, detailed information about the training and support Yes Page 102 network are provided with all needed information The minimum and maximum global price of supply for the product for Yes Page 102 the last financial year or included (quote in USD) 9.2. Adverse events and field safety corrective actions Yes Page 102
A list of all adverse events within the last five years, with details of the Yes Page 102 corrective and preventive action taken, is provided There is a list of all events within the last five years that required field Yes Page 102 safety corrective action 10. Regulatory History Yes Page 103 If applicable, include a list of National Regulatory Authorities that have Yes Page 103 provided current regulatory approval for the supply of the in vitro IVD under assessment, as well as the type of regulatory approval obtained, in the countries/regions of the product authority Current evidence of the regulatory approval, such as certified copies, Yes Page 103 must be included If applicable, there are details regarding any situations in which the Yes Page 103 product was rejected by a National Regulatory Authority, an application was withdrawn, or approval was withdrawn Information relating the export-only regulatory approvals are clearly Yes Page 103 identified 11. Quality Management System Yes Page 104 Annex VII 11.1. Quality manual system documents and procedures Yes Page 104 Annex XX There is a copy of the current version of the manufacturer’s quality Yes Annex VII manual and all needed points are addressed An organizational chart for the manufacturer is provided Yes Annex XX A complete list of all valid quality management systems documents, Yes Annex XX with needed information, is included Documented procedure/s for the control of design and development Yes Annex XX changes are included Documented procedure/s relevant to risk management planning and Yes Annex XX implementation are included Documented procedure/s relevant to control of non-conforming goods Yes Annex XX are included Documented procedure/s relevant to the control of the key suppliers Yes Annex XX are included 11.2. Quality management system documents Yes Annex XX If applicable, there is evidence of certification for the manufacturer of Yes Annex XX the product
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Dossier Content Requirement Provided Location: The two previous inspection reports issued by the certification body are Yes Annex XX included 14. Essential principles (EP) checklist Yes Annex I This checklist is filled in as per the description and examples provided in Yes Entire dossier the instructions
Manufacturer Declaration: 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 Programme 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: 14/December/2015
Please Note: The Checklist submitted to WHO must be signed and dated.
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1 5 The product 2 Insert intended use statement
3 5.1 Regulatory versions of this product 4 There are two regulatory versions of the SIMU™ self-test for HIV-12O. The ROW version, which 5 will be submitted for approval by WHO, has two product codes: 6 Y1234-B SIMU™ self-test for HIV-12O for use with whole blood, 7 Y1234-O SIMU™ self-test for HIV-12O for use with oral mucosal 8 transudate (OMT). 9 There is a version for Jordan (product code Y1222-B and Y1222-O) approved by the local agency 10 Jordan Food and Drug Administration. 11 The test device is presented in a single, waterproof primary package that contains all materials 12 necessary for testing: 13 Y1234-B SIMU™ self-test for HIV-12O for use with whole blood is supplied with a retractable safety 14 lancet, an alcohol swab and an adhesive bandage and an opaque, zip lock disposal bag for discrete 15 disposal. 16 Y1234-O SIMU™ self-test for HIV-12O for use with oral mucosal transudate is supplied with an oral 17 fluid collection device for oral mucosal transudate collection OMT (also known as gingival crevicular 18 fluid), and an opaque, zip lock disposal bag for discrete disposal. 19 Spare lancets are available at the point of distribution as an accessory pack (of 20 items) with 20 alcohol swab and adhesive bandage (product code A1234), if required for use in a supervised self- 21 testing service. 22 The device is shipped to distributors in secondary packaging of 100 units, as described in Section 8 23 of this dossier. 24 Unless stated otherwise, all data submitted in this application were generated using only the ROW 25 version of the product, with the finalised version of the method written and depicted in the 26 Instructions for Use (IFU) using reagents made to final validated scale on manufacturing equipment 27 that will be used for routine production. 28 There are no differences in design, specifications, materials or manufacturing processes between 29 the regulatory versions of the product. In-process controls use the same materials between the two 30 product versions. However, the version for sale in Jordan undergoes extra lot release testing using 31 specific specimens, and has particular labelling that is required by the local regulations. Aside from 32 extra regulatory testing and labelling there are no differences between the ROW and Jordan 33 versions of the product.
34 5.2 Product description including variants (configurations) and accessories
35 5.2.1 Product description 36 The product is comprised of a small moulded hand-held auto-transfer cassette and either a lancet 37 for fingerstick capillary blood release (Y1234-B) or a device for collecting oral mucosal transudate 38 (Y1234-O). See Figure 5.2–1 for an overview of the construction and components of the cassette.
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39 Figure 5.2–1: Components of the SIMU™ self-test for HIV-12O
40 The device is completely self-contained. It is prefilled with all required reagents and includes an 41 EDTA-coated chamber of defined volume. This design eliminates the need for a user to pipette a 42 specific volume of test fluid, whether whole blood or OMT. 43 Fingerstick blood is added by applying a hanging drop to the specimen port. OMT is collected from 44 gingival tissue using the oral fluid collection device provided. The collection device is then inserted 45 directly into the specimen port and squeezed to release fluid. 46 Adding specimen to the port will fill the specimen chamber. Addition of insufficient specimen 47 volume can be readily observed through the specimen chamber view (a dye included in the Y1234- 48 O cassette, which is also visible to visually impaired individuals, allows OMT to be observed). More 49 specimen can be added if required. However, only a small volume is needed and validation shows 50 that it is extremely unusual that the chamber does not fill on the first attempt (insufficient 51 specimen volume is most likely to occur as a result of intentional manipulation by the user). Once 52 the chamber has been filled the test is started by the user squeezing the end of the device until a 53 loud click is heard and the device changes shape (becomes shorter). Clicking the device prevents 54 not only the addition of more fluid but also the user coming into contact with any fluid in or around 55 the port. Once the test is started, excess specimen remains safely contained in the device. See 56 Figure 5.2–2.
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57 Figure 5.2–2: Operating the SIMU™ self-test for HIV-12O once loaded with specimen
58 5.2.2 Intended use 59 The SIMU™ self-test for HIV 12O is a qualitative in vitro diagnostic test for the detection of 60 antibodies to HIV-1 (Groups M and O) and HIV-2. Two different formats exist 61 Y1234-B SIMU™ self-test for HIV-12O for use with whole blood 62 (fingerstick or venepuncture), and
63 Y1234-O SIMU™ self-test for HIV-12O for use with oral mucosal 64 transudate. 65 The test is for use in adults and adolescents. It is a single use test and is suitable for self-use. This 66 test does not need to be used in a medical setting. 67 NOTE: This test should not be used for blood donor screening.
68 5.2.3 Intended users 69 The SIMU™ self-test for HIV 12O is intended for use by the adult and adolescent population (aged 70 11 years and above) as a triage test for antibodies to HIV-1 (Groups M and O) and HIV-2. When 71 used as a self-test, it should not be considered as a step in the testing algorithm.
72 5.2.4 Photographs of kit 73 Insert photographs of all kit configurations with all components and accessories 74 collectively and individual components and accessories, in and out of any packaging
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75 5.2.5 A general description of the principle of the assay method or instrument 76 principles of operation. 77 The mechanism of antibody detection is a third generation (antigen sandwich) lateral flow 78 (immunochromatographic) assay using both colour-augmented, nanoparticle-labelled recombinant 79 HIV antigens and a synthetic peptide in the flow path. The fixed capture reagents at the test line are 80 antigens of the same amino-acid sequences but cloned into a different host organism to prevent 81 anti-species false reactivity (see European patent Eur. Pat. 0307149 priority 1988). In addition, the 82 test line contains anti-human Ig (G, M, A) to act as a second capture system. This double capture 83 system overcomes the problems of a potential prozone effect with blood and of very low antibody 84 content in oral mucosal transudate (Parry, J.V., Ann. N.Y. Acad. Sci. 694 (1993) 216 – 233). The 85 control line, which contains the same mixture of capture reagents as the test line, acts as a stability 86 and functionality monitor. A third reagent line, between the test and control lines, contains a 87 monoclonal humanised antibody directed against the primary HIV-1 epitope. When labelled 88 antigens (regardless of whether the specimen is positive or negative) pass across this line they react 89 exactly as with a positive specimen, bind to the monoclonal antibody and are then captured at the 90 control line. This ensures that reagents in the system are active (stable) at the time of use, and that 91 the flow of liquid is sufficient to ensure a valid test. 92 Specimen (OMT or whole blood) is added to the device through the sample port. 93 Whole blood is entered by touching a drop of blood from fingerstick to the absorbent 94 material at the base of the port, 95 OMT is entered by squeezing the oral fluid collection device provided into the port, 96 where both the corrugations on the moulding and the absorbent material draw liquid 97 into the device. 98 Clicking the device opens the running fluid reservoir, forces the wicking system into the fluid and 99 moves a shutter across the specimen port, sealing the device and allowing it to be safely handled 100 and discarded (see Figure 5.2–2). After the reservoir is opened the fluid travels by capillary action 101 along the device membrane, allowing both HIV antibodies (if present) and labelled antigens to 102 migrate across the test capture line, the monoclonal humanised anti-HIV-1 antibody, the control 103 line and finally into the waste reservoir. A valid test, where the control is visible, gives a high 104 degree of assurance at the time a test is conducted that the antigens in both capture line and 105 conjugate are stable and functional. 106 In-built timing: Dye in the specimen chamber flows rather more slowly than the bulk liquid. This 107 occurs because of a combination of an intrinsic property of the dye and the manner in which it 108 interacts with the membrane. When the result window is completely clear of dye, the entire 109 specimen will have passed at an appropriate speed across the test and control lines and a result is 110 able to be read. With this design there is no need for a timing device, just observation of clearance 111 of the dye from the result window. 112 In-built volume control: The design of the specimen chamber provides assurance that a sufficient 113 volume of specimen has been provided for testing. Continuity of flow across the test and control 114 lines is demonstrated by complete clearance of the band of dye from the results window. 115 Timing is not critical once dye flow indicates that a test has been completed. The colour at the test 116 and control lines does not “develop” in the same way as for an enzymatic test – once the colour- 117 augmented nanoparticles are bound to a line it is coloured, with the intensity of colouration 118 dependent on the amount of specific antibody present. Once all the specimen has passed across 119 the test line and the test is valid (a visible control line indicating appropriate flow rate of functional
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120 reagents) and complete (dye has cleared the results window) the capture is maximal and both test 121 and control lines become colour-stable.
122 5.2.6 A description of the components of the assay 123 All reactive components of the assay are contained within the device. 124 The antigens in both the conjugate and the test line were engineered as fusion proteins from the 125 immunodominant regions of the envelope of HIV-1 and HIV-2 by THE Manufacturing Company. 126 Antigens used in the test and control lines are cloned and cultured in different species of micro- 127 organism. 128 The antibody used alongside the antigen as a capture reagent is from a commercial source. 129 The HIV-1 (O) peptide is synthesised by THE Manufacturing Company 130 The monoclonal humanised antibody used as part of the system to monitor stability and 131 functionality of the antigens (both capture and conjugate) at the time of use of the device was 132 developed and validated by THE Manufacturing Company. It is directed against the 133 immunodominant epitope of HIV-1 and cross-reacts to a large extent with that of HIV-2. 134 Competition experiments showed that it reacts with the same epitope structures as antibodies 135 from plasma at the time of HIV-1 seroconversion and so should be suitable for monitoring 136 functionality of the antigens in the device.
137 5.2.7 A description of the specimen collection and transport materials 138 provided with the product or descriptions of specifications 139 recommended for use. 140 Product code Y1234-B contains an auto-retractable lancet (1.5mm blade size) for 141 obtaining fingerstick blood, two alcohol swabs and a bandage. 142 Product code Y1234-O contains a device for collection of oral mucosal transudate. The 143 oral fluid collection device was developed by a national health protection agency. 144 As the device is intended for use in a private environment by relatively unskilled users, transport of 145 specimens is not a primary consideration. Nevertheless, the device has been validated for use with 146 venepuncture whole blood in EDTA anticoagulant and must be transported at 2–8°C and tested 147 within 24 hours of collection.
148 5.2.8 For instruments of automated assays: a description of the appropriate 149 assay characteristics or dedicated assays 150 Not applicable - there are no instruments required.
151 5.2.9 For automated assays: a description of the appropriate instrumentation 152 characteristics or dedicated instrumentation. 153 Not applicable.
154 5.2.10 If applicable, a description of any software to be used with the product. 155 Not applicable.
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156 5.2.11 If applicable, a description or complete list of the various configurations 157 or variants of product that will be made available 158 At present both configurations of the product are sold as a single pack only. THE Manufacturing 159 Company is considering the configuration of a two test pack. WHO will be notified of the new 160 configuration as per WHO PQDx_121 WHO Procedure of Changes to a WHO Prequalified in vitro 161 diagnostic, in which case this section of the dossier will be updated to reflect the new configuration 162 of a two test pack.
163 5.2.12 If applicable, a description of the accessories and other products that 164 are intended to be used in combination with the diagnostic 165 The kit comes fully equipped with all accessories listed above that are required to perform the test. 166 For professional or home use (as required) disposable gloves should be worn when collecting 167 specimen and using the test.
168 5.3 Essential principles (EP) check list 169 An EP checklist has been produced for the device and is provided in Annex I: Essential Principles 170 checklist 171 The evidence supporting performance requirements is submitted as Section 7 of this dossier and 172 other evidence of manufacturing and quality management is also provided throughout this dossier, 173 in agreement with GHTF/SG1/n046 and with Annex II of the proposal for a regulation on in vitro 174 diagnostic medical devices of the European Community (“the proposed IVD regulation”).
175 5.4 Risk analysis and control summary
176 5.4.1 Risk analysis policy 177 The risk management policy of THE Manufacturing Company is attached as Annex II: Risk 178 management policy. The SOPs lead to the FMEA output documents attached (
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179 Annex IV: Design inputs FMEA and Annex V: User and patient FMEA), and to the risk statement 180 (Annex III: Residual risk statement) which describes any residual risks and their control by warning 181 statements. The process and supplier management FMEA for this product, which are of the same 182 format as the submitted FMEAs for 'risk to users and patients', are kept on file but have not been 183 submitted with this dossier. 184 The design input FMEA is prepared before any R&D and is updated as work progresses and the 185 requirements are satisfied as is the risk FMEA for user and patient (usually the same individual with 186 a home self-test device but not always, since this device is also intended to be used in remote 187 clinics by health care workers). 188 A series of control measures arises from the risk assessment – these are listed in the spreadsheets 189 of the risk analyses and also shown on the flow diagram of the manufacturing process. The 190 effectiveness of the controls and changes in eliminating the identified risk is shown in the FMEA. 191 Some of the risks – such as instability arising from different factors, common- (but not specific-) 192 interfering agents are regarded as routine and evaluated as a matter of course. The data are 193 presented in Section 7 of this dossier. 194 Instability and allowable life-times are evaluated for OMT and fingerstick whole blood, for the shelf 195 life of the device itself using several independent manufactured lots, for the life of the materials 196 once taken out of the pouch, the length of time between adding the specimen to device and 197 reading, and for the length of time after adding specimen to device for which the result is valid.
198 5.4.2 Risk Categories
199 5.4.2.1 Erroneous test results 200 Various types of instability that could lead to erroneous test results have been evaluated, including 201 OMT and fingerstick whole blood, shipping conditions, shelf life of the device, life of the materials 202 once opened, and length of time after adding specimen to cartridge for which the result is valid. 203 Evaluations were performed with several independently manufactured lots of reagents and device 204 kits. The main risks to intended users stem from the potential for false reactive and false non- 205 reactive results. With self-test, untrained users are responsible for specimen collection, performing 206 the test, and interpreting the test result. False reactive results can cause emotional distress while 207 false non-reactive outcomes can result in delayed treatment or no treatment and risk of HIV 208 transmission to others. 209 Stability conditions are clearly described on labels and temperature indicators in the packaging 210 alert the user not to use the test if excursions outside of specified shipping or storage conditions 211 occurred, as this could cause inaccurate test results. Temperature indicators can, for example, 212 provide monitoring of shipping and storage conditions by changing colour to indicate an event 213 outside specified conditions has occurred and are available commercially for pharmaceutical and 214 medical product applications. In addition the device does not require any special storage 215 conditions, such as refrigeration. 216 Product labelling is also important for addressing the risks associated with use of the test and 217 includes language or illustrations and symbols describing the accuracy of the test, how to collect 218 specimen and apply it to the device, how to perform the test properly, how to interpret the test 219 correctly, what to do if the result is positive, what a positive and negative result mean and do not 220 mean, how often to test, and that a negative result does not validate risky behaviour. 221 Product labelling and language is easily readable (Flesch-Kincaid grade <6). In addition, the inherent 222 rate of incorrect results is very low when the test is performed by trained users and the test is
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223 designed to be easy and simple to use so that the intended use population (untrained users) will be 224 able to perform the test properly. 225 The labelling, language, symbols and illustrations used on the packaging, IFU and labelling of the 226 device have been qualified as part of the user studies in Section 7.4 to help clearly convey 227 information on how to use the test safely and effectively.
228 5.4.2.2 Interfering substances 229 Common interfering materials and specimen types are listed by CLSI in EP07 but the likely 230 interference arising specifically because of the analyte and intended use are addressed separately. 231 Examples of specific factors identified in the risk management documentation are: acute infection 232 with Epstein Barr Virus (EBV) and Hepatitis A, infection by malaria with its effects on red blood cell 233 haemolysis, infection by other diseases, HCV, high titres of anti-E. coli found in men who have sex 234 with men, pharmaceutical agents used for treatment of tropical and sexually transmitted disease 235 such as malaria, syphilis, HBV, HIV; carbonated sugar drinks, tooth pastes and mouth washes, and 236 chewing materials such as betel and tobacco. 237 While an extensive evaluation of the effect of interfering substances on assay performance was 238 performed (including endogenous and exogenous oral substances, medical conditions [such as 239 common co-infections and unrelated conditions], common medications, etc.; Section 7 of this 240 dossier), exhaustive evaluation of such factors is not practical and unanticipated factors may be 241 present in the intended use population in some regions. This risk was mitigated by conducting 242 clinical studies in as many countries or regions as possible to provide a broad representation of the 243 intended use populations. Evaluation of the assay by country/region demonstrated similar 244 performance, suggesting the assay is robust and the risk of interfering substances is minimal. No 245 impact on assay sensitivity was observed and assay specificity met the pre-established acceptance 246 criteria for the studies.
247 The manufacturer should add/remove discussion of other risk categories as 248 appropriate, such as those indicated below.
249 5.4.2.3 Testing process
250 The manufacturer should summarise the risks and mitigations related to the testing 251 process, such as the impact of improper timing on interpretation of the result, early 252 reading of the test result, various levels of competency for performing the test and 253 reading the instructions for use, the need for clear information regarding the 254 outcome of the test including advice to seek further testing and counselling etc.
255 5.4.2.4 Stability
256 The manufacturer should summarise the risks and mitigations related to stability, 257 such as impact of evaporation on sufficient reagent volume particularly for any low 258 volume reagents, storage temperature of the device on performance including 259 potential long term storage by the user after purchase before testing, etc.
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260 5.4.2.5 Specimen type 261 The test is intended to be used with OMT and fingerstick whole blood specimens. It was identified 262 during preliminary qualification of the IFU, during early product development, that the provision of 263 dual sampling methods (for whole blood and for OMT) was confusing to end users. 264 Hence it was decided that two versions for the product would be marketed individually:
265 Y1234-B SIMU™ self-test for HIV 12O for use with whole blood 266 Y1234-O SIMU™ self-test for HIV 12O for use with oral mucosal 267 Fingerstick specimens: A fingerstick specimen is applied to the test device by hanging drop. An 268 adhesive bandage is provided to cover the fingerstick after the specimen is collected. Specimen 269 added to the device remains contained within the device. Thus, biohazard disposal is minimized. 270 The lancets provided are auto-retractable and a zip lock disposal bag is provided for safe and 271 discrete disposal of the used test device and accessories. 272 Oral mucosal transudate specimens: An OMT specimen is collected using the oral fluid collection 273 device provided, which is inserted directly into the specimen port and squeezed to release the 274 specimen. A zip lock disposal bag is provided for safe and discrete disposal of both the used test 275 device and oral collection device. Used oral collection devices are not considered to be potentially 276 infectious for HIV but may pose a potential risk of transmission for other infectious diseases. Hence 277 it was decided that patients should be warned in the IFU to use the zip lock disposal bag provided 278 as part of the test kit.
279 5.4.3 Risk/Benefit 280 As described above, the main risks are related to erroneous test results, regardless of whether they 281 occur as a result of producing, distributing and/or using the test. In clinical performance study 282 (conducted in the intended use population; Section 7.4 of this dossier), it was established that the 283 rate of erroneous results <5% when used in the intended use population. Therefore, it is 284 anticipated that availability of the test will provide an individual health benefit by diagnosing new 285 HIV infections, primarily through increasing the number of individuals who get tested. Those 286 identified with HIV infection will benefit from early detection, intervention and treatment. In 287 addition, a public health benefit of the test is anticipated, as new transmissions by subjects with 288 positive test results can be prevented. In conclusion, the remaining risks posed by potential 289 erroneous results of the test are outweighed by the individual and public health benefits projected 290 from use of the test.
291 The Manufacturer should provide evidence that the risk analysis is part of the 292 manufacturer's risk management plan [inclusion of the relevant manufacturer’s 293 document]. 294 The Manufacturer should provide identification of specific standards or guidelines 295 recommended by WHO, when applicable [for example, ISO 14791:2007 (E) “Medical 296 devices -- Application of risk management to medical devices”]
297
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298 6 Design and manufacturing information
299 6.0 Design control 300 The R&D laboratory of THE Manufacturing Company (987 Somewhere Street, 301 Somewhere in Europe EU-1234, Europe) is responsible for the control of design of the 302 device. Manufacturing, up to and including devices for use, and design validation is 303 done in our main factory, where production for all our ROW products occurs. 304 Manufacturing of the Jordan version (product code Y1234-A) is also done in our main 305 factory. 306 The R&D department were responsible for all the design aspects and design validation 307 of the test device by the manufacturing site at company headquarters. Headquarters 308 manufacturing, apart developing the prototypes in conjunction with the R&D 309 department undertakes all aspects of manufacture for the test device for the ROW and 310 Jordan regulatory version. 311 A certified copy of ISO 13485:2003 Medical devices - Quality management systems is 312 attached as part of Section 11. The manufacturer also holds certification for the 313 environmental management system (ISO 14001:2015) for the design and manufacturing 314 site. THE Manufacturing Company is in compliance with ISO 14971:2007 Medical 315 devices - Application of risk management to medical devices. 316 The design control system is shown in Figure 6.1–1. It will be understood that product 317 design is iterative so although the process is shown as a linear flow each stage might be 318 repeated several times to optimise the whole design. 319 Design change control begins as soon as the customer requirements document is 320 authorised; changes to requirements documents undergo full change control, controlled 321 by SOP234AQ, changes during phase 1 are under R&D change control SOP234AQ – 322 which is different from full design change control only in that revalidation may 323 potentially be required. 324 All performance factors are obtained with product manufactured following authorised, 325 finalised documentation and QA parameters. 326 Data generated throughout the design input and R&D phases are collected as the design 327 history file, the finalised specifications as the device master record. Risk analyses are 328 initiated as shown and reviewed regularly with direction from SOP WE3. Design control 329 review meetings are also held regularly and the output of the meetings stored in the 330 design history file. 331 Training for manufacturing staff commences as soon as possible in the design phase, 332 and always during R&D phase 2 at the latest. Process SOPs are qualified in the factory by 333 manufacturing staff under R&D supervision. 334 Following the development phase there is a risk assessment followed by full staff 335 training, qualification of all the manufacturing processes, re-verification of device 336 performance against the specifications and revalidation of the QA release to market 337 requirements, all being completed before validating the device in a user’s hands in the 338 intended environment of use 339 The Instructions for Use are written according to ISO 18113 parts 1-4:2009 and printed 340 professionally, close to our factory, with translation where necessary from the 341 authorised English version by licenced scientific/medical translators and subsequent 342 approval by our local staff.
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343 Other labelling is controlled and printed locally. International symbols (IS0 15223 part 344 1:2012 and part 2:2010) are used wherever possible, other translation is by local 345 licenced scientific/medical translators. 346 A Universal Device Identifier (UDI) is applied according to IMDRF/UDIWG/N7FINAL:2013 347 and Article 22 of the proposed IVD regulation. Packing materials, vials and bottles are 348 sourced locally, QA-inspected for every lot and validated for use prior to acceptance of 349 the manufacturer. Any changes to packaging materials are evaluated by risk 350 assessment; any changes to packaging that is in immediate contact with product (e.g. 351 vials and bottles and/or their labels) require a revalidation of stability as described in 352 SOP St326. 353 Any changes to the design, including to labelling, are controlled within the change 354 control system and cascaded to all our factories, with risk evaluations and re- 355 qualifications as appropriate at each factory. 356 Changes to the design are notified in compliance with mandatory regulatory 357 requirements.
358 6.1 Product design
359 6.1.1 Design overview 360 Please see Section 5.2.1 , Product description, for a review of the product features, functioning and 361 general description of the ingredients.
362 Figure 6.1–1: Product design control: flow diagram 363 Key to type faces and colours in the flow diagram:
Reviews and risk evaluations: Design and development Phase of work: Design inputs Activity in the phase: User requirements collected Explanatory text: Design output validated against this 364
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
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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 Calibrators and internal controls developed and metrologically traceable Beginning of stability work for in-process intermediates and final device IFU initiated R&D phase 2 Transitioning to factory Under design change control as documents are finalised Instruments and material suppliers finalised and audited Instrumental PQ, OQ in the factory Pilot batches made, tested against putative QC Interfering substances evaluated Efficacy of anti-microbial agents proven Process documentation finalised and approved All aspects of device and specimen stability using devices made to approved specifications IFU finalised and approved Any changes to the IFU other than addition of performance data require in- depth evaluation and revalidation QA and QC specifications finalised 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, lot to 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 done in three user-labs with three independent lots of reagent IFU completed with data from validation work e.g. reproducibility, specificity
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Final risk analyses and production of risk declaration Manufacture Full scale manufacture under change control Market surveillance Review of scientific literature for independent clinical evaluations
365 6.1.2 Formulation and composition 366 The constituents and their source for critical reagents are shown in the table below
367 Formulation and composition information such as ingredients of buffers, amino acid 368 sequences for recombinant proteins etc. should be provided. Please note that WHO 369 will ensure that all proprietary information will be treated confidentially
370 Table 6.1–2: Constituents and sources of critical reagents Amount per Constituent Source litre as used Recombinant HIV-1 and -2 antigen 5 – 100ng In-house, clone, culture, purification, from E. coli used for conjugate Recombinant HIV-1 and -2 antigen used for capture at test and 100µg In-house, clone, culture, purification, from M. scarcii control lines In-house, synthetic, Fmoc chemistry, instrumental Peptide from HIV-1 (O) 75 µg control Humanised monoclonal antibody In-house, clone, culture in immortalised mouse cells, 50 µg used for control purification, Purchased from: Colour augmented nanoparticles We brighten your life Ltd.
for labelling the antigens 50 Aniline St, Henna, UK www.BrightAsDay.co.uk Purchased from: Antibody used for capture at test Colossal Health Limited Services and control line 100 µg 53 Some Street, Some Town, Europe product code: CHLS 123 www.CHLS.co.eu Purchased from: Nitrocellulose membrane Membranes for U, Long Road, Rooler, USA,www.mfurooler.com Purchased from: Plastic components Impossible Mouldings, Malleable Mansions, ConriceVille Aus8765 www.mouldy.com.au Purchased from: Pouching materials AlumStrip, The Mines, Canada www.wecanpack.ca Purchased from: Lancets VerySharp, Sore Point, Big Town, PRC Oral mucosal transudate Purchased from:
collection device Government Supplies Ltd, UK
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Amount per Constituent Source litre as used Purchased from: SuperPure chemicals Inc. General laboratory chemicals Somewhere, 5600001 www.cleanascanbe.com Printed materials (IFU, labels) and Purchased from:
translations IPrint Local street Small Town UK
371 Our local print shop is not quality-certified but is regularly inspected according to our supplier 372 management SOP 1234. The translators they employ are certified by national authorities. 373 All other suppliers have quality certification: ISO 9001:2015 is held by all, CHLS also has 374 ISO 13485:2003; Impossible Mouldings and We brighten your lives Ltd also have ISO 14001:2015. 375 Copies of the certifications are included as Annex XX
376 Biochemical information on the critical reagents is shown in Table 6.1 –3.
377 Table 6.1–3: Biochemical information of the critical reagents Constituent Information Immunodominant regions of gp41 of HIV-1 (C) and of gp36 of Recombinant HIV-1 and -2 proteins HIV-2 (A) expressed as a fusion protein with a connection / used for conjugate spacer sequence derived from B. rarus and cultured in E. coli Recombinant HIV-1 and -2 proteins used for capture at test and control As above but cultured in M. scarcii rather than E.coli lines A humanised mouse anti-gp4. [gp41 from HIV- (B)]. Proven to Humanised monoclonal antibody react at the immunodominant epitope detected by human used for control means antibodies at HIV-1 seroconversion Antibody used for capture at test A commercially sourced monoclonal antibody reacting with and control line the light chain, both κ and λ, of human Ig, hence reacting with product code: CHLS 123 IgG, IgM and IgA A phosphate-buffered saline solution (pH X.X) containing Wash solution contained within the detergents, synthetic saponins, an antimicrobial agent device (paraben) and proteins from E. coli
378 6.1.3 Biological safety 379 a) Recombinant antigens: cultured in minimal media with no identified risks from the media 380 or, later, from the host organisms and plasmids used. Recombinant HIV antigens are used 381 as part of the sandwich method for detecting the presence of HIV antibodies in the 382 specimen (e.g. they are cloned from the xxx region of the yyy protein and cultured in a zzz 383 (name of host) system). The antigens are purified by ion-exchange chromatography and 384 continuous flow gel electrophoresis. The recombinant antigens themselves are contained 385 within the device and although theoretically could, if injected, raise an immune response 386 this is regarded as extremely unlikely. A formal risk assessment of these components has 387 been undertaken (Refer to Residual Risk Report – Biological Safety Recombinant antigens – 388 DOC XXX held on file). 389 b) Monoclonal antibodies: Produced by in vitro continuous culture of modified mouse cells in 390 a medium containing biological additives. The monoclonal antibodies are purified by affinity
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391 chromatography preceded by concentration and buffer exchange and then ion-exchange 392 chromatography. Each culture is monitored to show freedom from bacterial, mycoplasma 393 and fungal contamination. The risk of any extraneous material being present is assessed as 394 exceedingly low (see the following paper for example “AR ter Avest et al. Purification 395 process monitoring in monoclonal antibody preparation: Contamination with viruses, DNA 396 and peptide growth factors. Biologicals (20) 177-186. 1992”. Refer also to Residual Risk 397 Report – Biological Safety Monoclonal Antibodies – DOC XXX, held on site). 398 c) Synthetic peptides corresponding to segments of the HIV genome: 399 d) Synthetic peptides are used as part of the sandwich method for detecting the presence of 400 HIV antibodies in the specimen. They are synthesised from purified individual amino acids 401 using a solid-phase support followed by purification using reverse-phase HPLC. A formal risk 402 assessment of this process has been undertaken (ANNEX X, Residual Risk Report – 403 Biological Safety Synthetics – DOC XXX) and demonstrates that when all factors are taken 404 into account, the risk of human infectivity from either the components or final product is 405 negligible. 406 e) Ruminant proteins: no ruminant (bovine, ovine, caprine) proteins are used in this device. 407 However, bovine albumin is used in other products from THE Manufacturing Company. All 408 bovine materials used originate from herds in countries declared free of transmissible 409 spongiform encephalopathies (TSE); e.g. bovine spongiform encephalopathy and chronic 410 wasting diseases of cervids) and are obtained from TSE-free certified manufacturers.
411 The Manufacturer should add/remove other components of the test as 412 appropriate. If a residual risk of any component is identified, provide information 413 on how users of the device will be informed of any residual risk.
414 6.1.4 Documentation of design changes 415 Change control has been described in Section 6.0 above. It is controlled by SOP234AQ. The change 416 control system notes the following changes: 417 a) Following further customer input a requirement for an in-built timing system was added 418 and the need validated through our distributor network. At the same time a requirement 419 that the packaging be light and discrete was added. (Change Y1234 – 1.) Date of change: 420 2010 11 02, phase of work: R&D phase 1, design change. 421 b) Problems found with auto-retractable lancets made it necessary to change supplier during 422 design verification. The new lancets and the new supplier were subject to the usual 423 supplier and incoming goods checks (SOP1234 and 6451) and the functioning of the lancets 424 validated during user evaluations of the device. (Change Y1234 – 2.) Date of change 2011 425 12 30 phase of work: Research and Development phase 3 (Not regarded as a design input 426 change, evaluated under manufacturing process risk management.) 427 c) Change to IFU after validation work. It was found that the readability of the detailed 428 method instructions could be clarified by changing the spacing of the text and adding a 429 small paragraph about disposal of the device after use. This was assessed and added to the 430 risks to users and patients FMEA and judged an improvement in both cases. The changed 431 text was revalidated in a small trial at Site XZY, the points having been suggested at centre 432 XYY. (Change Y1234 – 3.) Date of change 2012 03 13. Reference: QMCC Report XXX Phase 433 of work: after validation during Research and Development phase 4 but before first release
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434 to market of the product. (Not regarded as a design input change, evaluated under user 435 and patient risk management) (IFU to Version 2) 436 d) Change to the claimed shelf life of the product. On-going stability work with routinely 437 manufactured kits showed that the life could be extended from 2 years to 3 years with no 438 change to the performance of the product. This was verified in-house with end-of-life 439 testing of all the performance factors using four routine manufactured lots three years and 440 one month after their manufacture. This testing would have detected a 5% change in 441 characteristics, which was not found. The performance was judged unchanged from the 442 initial validation and verification work, the risk judged negligible. Change Y1234 – 4.) Phase 443 of work – post first release to market. Date of change 2013 03 06. Reference: QMCC Report 444 XXX. (Regarded as a design input change, evaluated under design input risk management.) 445 e) Change to IFU after launch. Added data on user repeatability of reading, obtained 446 independently (Fix, J and Bend, D, Journal of Reproducible results 121/2 (2014) 23 – 29) but 447 validated by THE Manufacturing Company. Date of change 2014 06 01 Reference QMCC 448 Report XXY (Not regarded as a design input change, evaluated under user and patient risk 449 management) (IFU to Version 3)
450 6.2 Manufacturing process
451 6.2.1 Overview of manufacture 452 The flow of product manufacture is shown below. 453 In-process quality checks are indicated in green – the reason for each of these checks can be traced 454 back either to a risk management document (section 5.4) or is a routine technical measurement for 455 the process concerned. Critical materials supplied to THE Manufacturing Company are marked in 456 red borders and their sources listed in Table 6.1–2. Incoming goods are checked against 457 specifications and functional testing is performed as decided from risk analyses and supplier 458 auditing.
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459 Figure 6.2–1: Flow of product manufacture
Liquid reagent preparation Recombinant growth Monoclonal growth Diluents continuous flow bioreactor continuous flow bioreactor Stabilisers pH, optical density, oxygen monitoring pH, optical density, oxygen monitoring
Microbiocides microbial testing Conductivity, pH, Same for both recombinants
Optical density measurements Recombinant purification Monoclonal purification Differential centrifugation, ion Proteins G & A purity, functionality measures Nanoparticles exchange gel filtration Purity, Western Blot Western Blot,
C & N terminal analysis, Affinity measurement, Functionality measures Capillary electrophoresis
Labelling of antigens Peptide synthesis Membrane roll: lining application Functionality measures XYZ peptide synthesiser Optical (instrument) monitor of spray
Titration of each conjugate onto Mass spectrometry (composition) density and bandwidth test-striped membranes
Conjugate roll: spray application Optical (instrument) monitor of spray
density and bandwidth
Lamination to backing strip, addition of wick and waste absorbent Wick, pad, backing continuous mechanical application Optical mechanical flaw detection
Cut continuous rolls to size (3.5mm) Mechanical guillotine Optical mechanical flaw detection, automatic
rejection of non-conforming material Functionality test prior to main assembly
Fill buffer reservoir and seal Automated Weight check in-line
Device assembly Lancets, oral fluid collection device, Automated process IFU Moulded parts Within batch homogeneity check
ASTM sampling process Limited functionality testing Collection pack Assemble, flow wrap Weight check in line Dessicant units
Pouch material
Pouching, labelling Automated process, flow wrapping Weight check of each 100packs
Release testing
Functionality, Pack conformity Part and label reconciliation Batch history file review
Release to warehouse
Package for shipment
460
461 6.2.1.1 Batch release criteria/Final lot release 462 The final product is inspected to meet the final requirements outlined in the Quality Specifications 463 for SIMU™ self-test for HIV 12O. The specifications are provided in Annex XX.
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464 6.2.2 Sites of manufacture 465 The entire device, including all antigen and antibody production is made in the European factory, 466 THE Manufacturing Company, 987 Somewhere Street, Somewhere in Europe, EU-1234, Europe. A 467 number of other devices are made at this site under the same design control and quality systems. 468 Some are made using a very similar process. There are devices for detection of:
469 Malaria antigens 470 HIV – antibody-antigen 471 Hepatitis C – antibody-antigen 472 Syphilis antibodies 473 Hepatitis B surface antigen 474 CD-4 cell counting 475 A site plan for the factory is included below.
476 Insert a diagram of the Site Plan here. 477 It must be labelled with functions for each area.
478 The company has 96 full-time staff and 23 part-time staff. A structure chart is included in the 479 Quality Manual, appended as
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480 Annex VII: THE Manufacturing Company Quality Manual.
481 6.2.3 Key suppliers 482 Key suppliers of critical materials have been listed in Table 6.2–2, a listing of other suppliers 483 providing essential but non-critical material is:
484 Table 6.2–2: Key suppliers Certification (certified copy Material Supplier Control of incoming goods provided in Annex XX) Tissue culture media We Grow Better ISO 9001 SOP e453 – Microbial Main Road, Nowhere Else contamination testing – see Q1234 http://www.lgcstandards- www.growth.com.au atcc.org/en/Documents for methods used Packaging for shipment Bags of Boxes ISO 9001 and SOP e460 : visual inspection Long Way, Forest Ville 14001 Europe www.moreWords.com Instrumentation for Unbelievable Systems Inc. ISO 9001 SOP e451 – full functional IQ automatic device Make and Mend Road, OQ PQ and performance assembly Buzzville USA testing www.nochance.com Desiccant sachets Drybyzones Ltd ISO 9001 SOPe460: visual, opened Drought Road Somewhere sachets, plus water content CH www.DrybyzonesLtd.co.ch 485
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486 7 Product performance specifications and associated 487 validation and verification studies. 488 WARNING: Please read the following important notes about the information 489 provided in this section. 490 NOTE 1. For the purposes of this Sample Product Dossier, validation studies have 491 been presented in varying levels of detail in order to illustrate the reporting 492 requirements. When submitting a dossier for WHO Prequalification assessment, the 493 following should be provided either in the main dossier or as annexes for EACH 494 PERFORMANCE CLAIM: 495 • The complete study protocol 496 • The methods of data analysis 497 • The complete study report (signed and dated), including the study conclusion. For 498 each study presented, the site(s) and principal investigator(s) should be identified. 499 Similarly, the date each study was performed, the lot numbers used, and a 500 description of the study design along with the statistical analysis, results and 501 conclusions should be provided. 502 NOTE 2. The studies presented in this section should not be taken as representing a 503 complete list of studies that are expected to be performed and submitted; they are 504 provided as an illustrative sample of the type of information that should be 505 submitted. For each claim (including, but not limited to: specimen type to be used, 506 testing population, stability and other performance characteristics) one or more 507 validation studies must be performed to support that claim. 508 NOTE 3. The data provided in this section must be produced on using the final 509 version of the assay product submitted for prequalification. Where this has not 510 occurred, the version used should be stated and a justification for the inclusion of 511 the data provided. Depending on the nature of differences between product 512 versions, additional validation evidence may be required. 513 NOTE 4. Where possible, internationally accepted standards should be used to guide 514 not only the design of each study, but also the formulation of criteria for judging the 515 acceptance of study and inform on the acceptance of the outcomes. These are 516 comprehensively noted in the Essential Principle Checklist (Refer to Section 5.3 of 517 this dossier).
518
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519 Summary of studies 520 The results of all analytical and clinical performance testing, submitted in this dossier were 521 conducted on the final version of SIMU™ self-test for HIV 12O device. Earlier tests with prototype 522 systems and procedures have not been included, but the data are retained in design history files, 523 held on site at THE Manufacturing Company. 524 The results of both verification studies1 (performed by the manufacturer) and validation studies2 525 (performed on behalf of the manufacturer in the setting of intended use) have been submitted in 526 support of the performance of the assay. 527 All efforts were undertaken to eliminate potentials for bias, including but not limited to, blinding of 528 known HIV status, randomization of procedures that may have unfairly influenced the result 529 outcome, and careful selection of reference testing. In addition, validation studies were designed 530 and executed in a manner to avoid the potentials for conflicts of interest. 531 In accordance with the requirements of ISO 13485 THE Manufacturing Company associates all 532 plans and protocols with a risk evaluation. For all plans and protocols provide in this section the 533 risk assessments are available on file at the company. Each assessment is prepared by the initiating 534 department in association with any other departments affected by the plan (with input from 535 medical experts and R&D and including a literature review if relevant). This is especially important 536 for plans related to changes in design or manufacture and to all stages of development in R&D. 537 Analytical performance studies were undertaken for professional use and self-testing. Clinical 538 performances studies were performed in three parts:
539 Part 1: Establishing clinical performance of SIMU™ self-test for HIV 12O device for 540 professional use. 541 Part 2: Qualification of the usability of SIMU™ self-test for HIV 12O device for self- 542 testing 543 Part 1: Establishing clinical performance of SIMU™ self-test for HIV 12O device for self- 544 testing 545 546 ______
547 1 ISO 9000:2005 Definition of Verification “confirmation, through the provision of objective evidence, that specified requirements 548 have been fulfilled” 549 2 ISO 9000:2005 Definition of Validation “confirmation, through the provision of objective evidence, that the requirements for a 550 specific intended use or application have been fulfilled.” 551
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552 7.0 QC panel for SIMU™ self-test for HIV 12O Product Codes: Y1234-B 553 and Y1234-O
554 NOTE : The studies in Section 7.0 are not a requirement for submission within a 555 product dossier for WHO Prequalification. However, given the importance of 556 appropriate panels for test method validation, the following studies have been 557 included for demonstration purposes.
558 7.0.1 Validation of the QC calibrator scale for use in stability studies and at 559 release-to-sale 560 QC Calibrator scale 0 1 2 3 4 5 6 7 8 9 10 561 562 Scale version 1.00 January 2008
563 7.0.1.1 Introduction 564 The QC calibration scale is used to produce a quantitative result or read-out for a qualitative test. 565 Validated densitometry readings would be preferable but were not available at the time this work 566 was initiated at THE Manufacturing Company. Validation of densitometry is currently ongoing, but 567 all the data in this dossier was obtained using the QC calibrator scale, as validated in this study. 568 Results obtained using the QC calibrator scale are not considered the same as interpreting a 569 specimen as positive or negative as per the IFU. The scale functions as a validation step that allows 570 any unacceptable changes during stability studies and from lot to lot variation in manufacture to be 571 detected.
572 7.0.1.2 Study objective 573 To verify that readings from the QC calibrator scale will reflect any changes of practical significance 574 in the function of the device. 575 Readings from selected QC panel members will be used during stability studies (as the stability 576 testing panel) and at release to sale of finished devices (final batch release testing). It is essential to 577 validate that the readings obtained will reflect any changes that might have occurred in the ability 578 of the device to meet performance claims: seroconversion detection, HIV-1 and -2 analytical 579 sensitivity and specificity, among other critical parameters. 580 581 Study protocol: AP XXX. Protocol risk assessment P123 – on file. 582 Full Report: AR XXX 583 Study Dates: 1 May 2010 – 23 July 2010 584 Specimens (see “QC panel members, their criteria, and rationale for inclusion in the panel.”) 585 QC 123, QC 124, QC 302 586 Lot numbers: Special R&D lots made with varying amount of conjugate and test and control 587 reagents as described
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588 IFU version: v1.0 589 Conducted by: Ann French, Peter Jones, John Lewis, David Brown, Tom Keen. All QC Dept., THE 590 Manufacturing Company. 591 Testing: Performed on site, QC Dept., under condition of standardised lighting
592 7.0.1.3 Study design and planning 593 1. The QC calibration scale and the QC panel members together must be able to detect 594 changes in the functionality of the device. 595 2. During the development of an appropriate QC panel, the weakest HIV -1 seroconversion 596 specimen evaluated (seroconversion series 234, bleed 5) was found to give a reading of 597 between 2 and 3 on the calibration scale when tested using newly-made devices. A loss of 598 10% in signal would result in the user of the device reading the specimen result at, at best, 599 borderline reactive/negative and at worst usually negative. Similarly, for the HIV-2 600 analytical sensitivity: a 10% loss would invalidate the claim. 601 3. Thus, since the seroconversion specimen is not available for testing at release to sale (as 602 too little volume is available) and titrations of HIV-1 do not necessarily mimic 603 seroconversion, the QC calibration scale and the QC panel members together must be able 604 to detect changes in the functionality of the device of at least 10%. 605 4. It is not possible to mimic all possible failures of the device. The risk assessment concluded 606 that modifying both the amount of conjugate applied to the device (by modifying volume 607 and/or concentration) and the concentration of the reagents in the test and control lines 608 should be sufficient to cover any foreseeable risks. 609 5. To ensure that the study had sufficient power and could meet the stated objectives, 610 assistance in the design of the study protocol (and subsequent analysis of results) was 611 provided by staff at THE Manufacturing Company with expertise in statistical analysis.
612 Study summary protocol 613 1. Devices were read by a total of five trained and experienced QC staff members under 614 conditions of standardised lighting exactly as used in the QC department bays used for 615 product release to sale. Each device was read by all the nominated staff members who 616 were blinded to: 617 the experimental situation of the device, 618 the true status of samples being tested, and 619 results recorded by other readers. 620 2. The readers were asked to estimate to 1 decimal place the point reading against the scale 621 (e.g. giving a reading of 2.3 not 2 nor 3) 622 3. The results were evaluated between several readers and varying experimental conditions 623 on multiple QC panel members. The study size was required to validate the panel and 624 calibrator and to give information on the readability of the device. The data were analysed 625 by ANOVA. 626 4. Fifteen devices were made for each of the following conditions: 627 Conjugate concentration: 85%, 90%, 95%, 100%, 110% of normal. Routine volume 628 Conjugate volume: 85%, 90%, 95%, 100%, 110% of normal. Routine concentration 629 Test & control line concentrations: 85%, 90%, 95%, 100%, and 110% of normal. 630 Routine volume
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631 5. Five devices at each experimental condition were loaded and used with each of the 632 nominated QC panel members, with the following exceptions: Due to the low volume 633 available of these rare but critical specimens, only four devices were used to test QC 302 634 (false reactive) and only one with seroconversion series 234, bleed 5 – the weakest claimed 635 positive. However, the results were still considered of use, even if these specimens could 636 not be tested in all circumstances.
637 Results 638 In this section THE Manufacturing Company presented the raw data (Table 7.0 - 1) and between- 639 concentration (Table 7.0 -2) and between-reader (Table 7.0 – 3) differences for testing specimen 640 QC124 with devices of varying concentration of conjugate.
A sample of test results are shown here for illustrative purposes. Manufacturers are expected to present all summary and raw data relevant to performance claims in their product dossiers.
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Table 7.0–1: Raw data Table 7.0–2: Analysis for concentration
difference
Concn 1 Concn 2 Concn Diff. Mean SE Prob.
Concentration Device A Reader B Reader C Reader D Reader E Reader 90% -0.200 0.018 0.000 85 1 2.6 2.6 2.4 2.5 2.6 95% -0.259 0.018 0.000 85 2 2.6 2.6 2.5 2.8 2.7 85% 100% -0.489 0.018 0.000 85 3 2.6 2.7 2.7 2.5 2.7 110% -0.613 0.018 0.000 85 4 2.7 2.6 2.6 2.4 2.5 95% -0.059 0.018 0.023 85 5 2.4 2.7 2.7 2.5 2.7 90% 100% -0.288 0.018 0.000 90 1 2.7 2.7 3.2 2.9 3.1 110% -0.413 0.018 0.000 90 2 2.8 2.8 3.0 2.8 2.9 100% -0.229 0.018 0.000 90 3 2.9 3.1 2.7 3.1 2.9 95% 110% -0.354 0.018 0.000 90 4 2.7 2.6 2.8 2.9 2.7 100% 110% -0.124 0.018 0.000 90 5 3.0 2.8 2.9 2.9 2.9 95 1 2.9 3.2 2.8 2.9 3.0 Table 7.0–3: Analysis of reader differences
95 2 3.0 3.1 2.9 2.7 3.0
95 3 2.9 3.0 3.1 2.9 3.0
95 4 2.9 2.9 3.0 3.0 2.8
Reader 2 Reader Diff. Mean SE Prob. 95 5 3.1 3.0 2.8 3.1 3.1 Reader 100 1 3.3 3.2 3.2 3.2 3.3 B -0.034 0.018 0.543 100 2 3.4 3.3 3.3 3.1 3.1 C -0.019 0.018 0.746 A 100 3 3.4 3.4 3.3 3.1 3.5 D -0.008 0.018 0.760 100 4 3.4 3.4 3.2 3.2 3.5 E -0.066 0.018 0.083 100 5 3.1 3.2 3.1 3.5 3.2 C 0.015 0.018 0.546 110 1 3.4 3.3 3.5 3.3 3.5 B D 0.026 0.018 0.560 110 2 3.3 3.4 3.4 3.5 3.6 E -0.032 0.018 0.218 110 3 3.3 3.5 3.3 3.5 3.5 D 0.011 0.018 0.672 110 4 3.1 3.5 3.4 3.5 3.7 C
E -0.047 0.018 0.160 D E -0.058 0.018 0.112
641 Statistical analysis – whole of study 642 From the analysis of the whole study, it could be seen that:
643 With the false positive QC specimen (QC 302) - a 10% increase in reading could be 644 detected, and a 5% decrease in HIV-2 reading. 645 With the QC specimen (QC 124) – a 10% decrease in sensitivity could be detected. This 646 confirms that QC specimen QC 124 may act as a mimic of seroconversion.
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647 The criteria for assigning a grading is as follows: 648 o If the grading is within the bounds marked 1 (1.1 – 1.9), the result will be assigned 649 a value of 1, not assigned into the region marked as 2, even if it were near the 1 - 2 650 boundary (e.g. a true reading of 1.9 would be assigned to a grading of 1, not 2). 651 Original decimalised results are stored for review purposes. 652 o Analysis of device to device variability showed that readings of triplicate devices 653 would allow 80% assurance of correctly assigning a grading in the grading range 1 654 – 6 on the calibration scale 655 o If the reading is within +/- 10 % of a boundary then the result could be assigned 656 either way.
657 Conclusion 658 The QC calibrator scale is valid for use in stability work and at release to sale/final batch release 659 testing and will detect any changes of more than 10% in the performance of the device, if readings 660 are made in triplicate.
661 7.0.2 QC panel members, criteria, rationale
662 7.0.2.1 QC panel for SIMU™ self-test for HIV 12O Product Codes: Y1234-B and Y1234-O
663 Statistical process control using QC panel: QA SOP T&T 01 664 Aliquot and storage of panel members: see QA SOP P01 665 Replacement of panel members from existing validated stocks of sera or plasma: see SOP QA P 02 666 Dilution into saliva pool (QC 501) of QC 121 and 123: see QA SOP P03 667 Replacement of panel members from new sera or plasma: see “SOP R&D Panel replacement” (R&D 668 only)
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669 Acceptance criteria 670 See “SOP R&D Setting criteria for panel members” below. If these criteria are met, the device lots 671 are validated to meet the design input requirements and intended use claims.
672 Table 7.0–4: Setting criteria for panel members QC # Description Role in panel Criteria QC 120 Negative serum Serves as a blank, little utility 0 Dilution of HIV-1 (B), from clinical late Monitor detection of late disease stages, 3 - 5 QC 121 stage of disease diluted in serum stability of epitopes for IgG Monitor detection of late stages, Dilution of HIV-1 (E), from clinical late stability of epitopes for IgG: readings QC 122 3 - 5 stage of disease diluted in serum found not to correlate well with QC 121 on stress testing Dilution of HIV-2 (A), from clinical late Monitor detection of HIV-2, stability of QC 123 2 - 4 stage of disease diluted in serum epitopes for IgG Monitor detection of HIV-2, stability of Dilution of HIV-2 (E) found in field work QC 123a epitopes for IgG: found not to correlate 2 - 4 in West Africa well with QC 123 on stress testing Monitor seroconversion sensitivity: found to correlate well with readings Dilution from an early stage of HIV-1 (B) QC 124 from seroconversion specimens, found 1 - 3 infection, in plasma to be predominantly IgM anti-HIV on HIV-1 Western blots with IgM detection Monitor this specific source of false reaction, specimen found during R&D, QC 302 False reactive, undiluted 0 - 1 plasma pack purchased (ethically sourced) As diluent for the source serum for panels QC 121 and 123, to mimic anti- ~HIV in saliva. Because of the extra OMT stock pool, collected weekly from variability introduced by this dilution and ±1 wrt QC 501 local volunteers, stored under validated changes in the diluent pool the dilutions reference conditions are estimated against a specified reference lot of devices (not the previous lot)
673 In addition, five normal negative whole venous blood samples in EDTA were collected from the 674 local blood service tested less than 5 hours after donation. Their role is to monitor gross problems 675 in linearity of flow, haemolysis, and red-cell capture. These specimens must all give a negative 676 result (0); all must flow completely beyond the window and during flow must run evenly (not 677 diagonal flow, no streaks). The bleed numbers are recorded separately on the QC lot release 678 documentation.
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679 Figure 7.0–5: Process control chart for QC 122, calibrator scale estimated to nearest 0.1
680 COMMENT: the criteria for this specimen being 3 – 5, the devices currently appear to be running 681 low but in specification.
682 Last lot released: SIMU™ self-test for HIV 12O Product Code: Y1234-B Lot number: NPQ 683 Check of in-process manufacturing documentation: specifications all met 684 In-process low pressure rupture test on seals of 100 pouches: specifications all met 685 Weight of 100 device secondary carton: 1.35kg specifications all met
686 Table 7.0–6: Test of QC panel at release to sale QC # Description Criteria Reading QC 120 Negative serum 0 0 QC 121 Dilution of HIV-1 (B), 3 - 5 3.9 QC 122 Dilution of HIV-1 (E) 3 - 5 3.3 QC 123 Dilution of HIV-2 (A) 2 - 4 3.1 QC 123a Dilution of HIV-2 (E) 2 - 4 3 QC 124 Dilution from an early stage of HIV-1 (B) infection 1 - 3 2.8 QC 302 False reactive 0 - 1 0
687 Record of whole blood used: specifications all met 688 Blood tube # 100234 – 100239. Five recent EDTA venous whole blood specimens: all negative, clear 689 result windows, even flow. 690 All requirements met 691 Signed: Pete Brown, Head QA Date: 2015-11-17 692
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693 7.1 Analytical studies 694 Comprehensive analytical studies were undertaken before commencing the clinical evaluation 695 studies. The majority of the analytical studies were undertaken using serum and plasma (collected 696 in EDTA) although neither of these specimen types are the ultimate intended specimen type. This 697 approach was taken due to the non-availability of panels for seroconversion, interference etc. with 698 OMT and capillary whole blood. This was considered appropriate as initial studies were undertaken 699 to demonstrate relative equivalency between OMT, capillary whole blood and EDTA plasma and 700 serum. However comprehensive testing of both OMT and capillary whole blood was undertaken in 701 clinical performance studies.
702 7.1.1 Specimen types
703 7.1.1.1 Specimen type equivalence 704 SIMU™ self-test for HIV 12O device has been evaluated with plasma using EDTA as anticoagulant. 705 Furthermore, it has been evaluated with OMT using the oral collection device and capillary whole 706 blood that was collected with retractable safety lancets from fingerstick puncture, described in 707 Section 7.4 “Clinical Evidence” of this dossier. Use of whole blood collected in other anticoagulants 708 has not been evaluated. Summaries of specimen equivalency (OMT and fingerstick whole blood vs. 709 plasma and serum) and stability of OMT specimens are provided below.
710 Study protocol 711 Protocol: AP XXX - refer ANNEX XXX Specimen type study protocol
712 Study Summary Report: SIMU™ self-test for HIV 12O Specimen Equivalency 713 Protocol: AP XXX 714 Full Report: AR XXX – refer Annex XXX Specimen type study full report May 2012 715 Study Dates: April 2012 – May 2012 716 Lot number: 12345 717 Expiry date: 14 October 2012 718 IFU version: v1.0 719 Conducted by: P Lallement, Research and Development Dept., THE Manufacturing Company 720 Testing: Performed on site, Headquarters
721 Study objective 722 The purpose of this study was to evaluate the equivalence of OMT and capillary whole blood 723 fingerstick specimens compared to plasma and serum for the detection of HIV with the SIMU™ 724 self-test for HIV 12O.
725 Acceptance criterion 726 The acceptance criterion was defined as demonstration of acceptable assay performance to 727 support recommended specimen types. Acceptable assay performance was defined as agreement 728 with expected results of >95% with the lower bound of the 95% CI of >90%.
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729 Study design 730 Four specimen types (plasma using EDTA as anticoagulant, serum, OMT and fingerstick capillary 731 whole blood) were collected from individuals known to be positive for HIV (n=50) and from 732 individuals negative for HIV (n=50). Plasma and serum samples were collected via venepuncture; 733 OMT was collected using the SIMU™ self-test for HIV 12O device OMT collection device and 734 fingerstick specimens were collected directly on to the SIMU™ self-test for HIV 12O device. Each 735 specimen type was tested once with the SIMU™ self-test for HIV 12O. 736 Although test results are reported qualitatively, for the purposes of this study, the results were also 737 interpreted and recorded quantitatively using THE Manufacturing Company reading scale where 738 the intensity of the test line was graded between 0-10.
739 Statistical analysis 740 Reactivity of specimens was recorded and agreement between specimen types and with expected 741 results was calculated. Mean reactivity of positive antibody panels members were determined and 742 95% CI calculated for the mean reading scale value.
743 Results - See full study results in Annex XXX Specimen type study full report May 2012 744 The results demonstrated 100% agreement between specimen types and with expected results in 745 known positive HIV specimens and in negative HIV specimens. Mean reactivity demonstrated no 746 more than a -7.5% difference from baseline for positive specimens.
747 Conclusion 748 These results demonstrate that OMT and fingerstick specimens are equivalent to plasma and serum 749 specimens for detection of HIV when tested with the SIMU™ self-test for HIV 12O.
750 7.1.1.2 Specimen stability
751 Study protocol 752 Protocol: AP XXX - refer ANNEX XXX SIMU™ self-test for HIV 12O Specimen Stability for OMT
753 Study Summary Report: SIMU™ self-test for HIV 12O Specimen Stability 754 Protocol: AP XXX - refer ANNEX XXX Protocol for SIMU™ self-test for HIV 12O OMT Specimen 755 Stability 756 Full Report: AR XXX – refer ANNEX XXX Study report SIMU™ self-test for HIV 12O OMT Specimen 757 Stability 758 Study Dates: June 2012 – July 2012 759 Lot number: 12345 760 Expiry date: October 2012 761 IFU version: v1.0 762 Conducted by: A Blog, Research and Development Dept., THE Manufacturing Company 763 Testing: Performed on site, Headquarters
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764 Study objective 765 The purpose of this study was to evaluate the effect of OMT specimen handling conditions on the 766 performance of the SIMU™ self-test for HIV 12O.
767 Acceptance criterion 768 The acceptance criterion was defined as demonstration of acceptable assay performance to 769 support recommended specimen handling conditions for OMT specimens. Acceptable assay 770 performance was defined as a detection rate of >95% in HIV positive samples.
771 Study design 772 As OMT specimens are self-collected by the intended user, there is a risk that the specimens could 773 be stored at uncontrolled conditions prior to testing. To evaluate the effect of OMT specimen 774 handling conditions on assay performance, saliva spiked with HIV was used to prepare test samples. 775 Because of the volume required, saliva was used in place of OMT. Preliminary studies by the R&D 776 department supported this change. The reference to this work“2011 Feb 19 OMT Stability” is held 777 at THE Manufacturing Company in the records department in R&D. Expectorated saliva was 778 collected from HIV negative individuals and spiked with saline (negative) or with HIV (positive) to a 779 final concentration that achieved low levels of reactivity. Sufficient volume of saliva was prepared 780 to support testing of all aliquots at all time points in the study. Aliquots of this mixture were 781 processed with the oral collection device from the SIMU™ self-test for HIV 12O device to simulate 782 actual OMT collection. Aliquots were tested in triplicate at baseline and after being stored at (1) 783 ambient temperature for 5 minutes, 10 minutes, 15 minutes, 30 minutes, 60 minutes and 70 784 minutes, and (2) 42±2°C for 5 minutes, 10 minutes, 15 minutes, 30 minutes, 60 minutes and 70 785 minutes. 786 Although test results are reported qualitatively, for the purposes of this study, the results were 787 recorded quantitatively using THE Manufacturing Company reading scale where the intensity of 788 the test line was graded between 0-10. 789 Similar studies with capillary whole blood collected with retractable safety lancets from fingersticks 790 were not performed as this specimen is transferred immediately onto the device obviating any risk 791 of storage before testing is performed.
792 Statistical analysis 793 Reactivity of samples was recorded. Mean reactivity of positive antibody panels members were 794 determined and 95% CI calculated for the mean reading scale value.
795 Results and discussion 796 Full study results are in Annex XXX Study report SIMU™ self-test for HIV 12O OMT Specimen 797 Stability. 798 The results demonstrated 100% reactivity of positive HIV samples at all time points evaluated in the 799 study. All negative samples were nonreactive. Mean reactivity demonstrated no more than a - 800 5.5% difference from baseline for positive specimens.
801 Conclusion 802 These results support that accurate test results are obtained with OMT specimens exposed to 803 temperatures to 42±2°C for up to 1 hour after collection prior to testing.
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804 7.1.2 Analytical performance characteristics
805 7.1.2.1 Accuracy of measurement
806 7.1.2.1.1 Trueness of measurement 807 Trueness measures apply only when a reference method is available. 808 As a result, the trueness of SIMU™ self-test for HIV 12O device can be found in studies where sero- 809 status of specimens has been established using reference methods and validated testing 810 algorithms’. This includes genotype studies, seroconversion studies, studies using commercial mixed 811 titre standards, WHO international standards (e.g. WHO 1st international reference standard for HIV 812 2006) and clinical evaluation studies.
813 7.1.2.1.2 Precision of measurement: Reproducibility and repeatability 814 The SIMU™ self-test for HIV 12O device reproducibility and repeatability was first established in 815 plasma. Given the significant difference in specimen nature, the same study design was used to 816 investigate precision when the specimen type was OMT as well as in whole blood. Reproducibility 817 assessed the inter-assay variability between operators and lots; repeatability assessed intra-assay 818 variability between replicates of panel members tested with the same lot and operator.
819 Study Summary Report: SIMU™ self-test for HIV 12O Reproducibility and repeatability in plasma 820 Protocol: AP XXX - refer Annex XXX Study protocol for SIMU™ self-test for HIV 12O reproducibility 821 and repeatability in plasma 822 Full Report: AR XXX – refer Annex XXX Study report for SIMU™ self-test for HIV 12O 823 reproducibility and repeatability in plasma 824 Study Dates: 12–14 June 2012 825 Lot number: 12345, 13455, 14555 826 Expiry date: October 2012, November 2012, December 2012 827 IFU version: v1.0 828 Conducted by: A Blog, Research and Development Dept., THE Manufacturing Company 829 Testing: Performed on site, Headquarters.
830 Study objective 831 The purpose of this study was to establish the reproducibility and repeatability of the SIMU™ self- 832 test for HIV 12O device according to the CLSI EP05-A2 Evaluation of Precision Performance of 833 Quantitative Measurement Methods; Approved Guideline - Second Edition (2004) in the hands of 834 trained users.
835 NOTE: There is now a more recent version of this guidance available from CLSI. EP05- 836 A3 Evaluation of Precision Performance of Quantitative Measurement Methods; 837 Approved Guideline - Third Edition (2014)
838
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839 Acceptance criterion 840 Overall reproducibility acceptance criterion was >95% agreement with expected results. The 841 acceptance criteria for each panel member is summarized below.
842 Table 7.1.2–0: Acceptance criteria for reproducibility panel members Panel Member Number of Expected results - Acceptance criteria samples Reading scale HIV-1/2 antibody negative 2 0 100% results reading of 0 HIV-1 antibody (low reactive) 1 1-3 95% results falling within the mean HIV-2 antibody (low reactive) 1 1-3 95% results falling within the mean HIV-1 antibody (high reactive) 1 7-9 95% results falling within the mean No results reading 0-3 HIV-2 antibody (high reactive) 1 7-9 95% results falling within the mean No results reading 0-3
843 Study design 844 Reproducibility of the SIMU™ self-test for HIV 12O device was established by testing multiple 845 replicates of panel members. Panels were prepared as follows. Negative plasma samples were 846 combined to create bulk pools to support replicate testing. Positive panel members were created 847 by spiking negative samples. Panels contained samples negative (not spiked) for HIV-1 and HIV-2 848 antibody, HIV-1 samples with antibody positivity graded between 1 to 9 on the reading scale, HIV-2 849 samples with antibody positivity graded between 1 to 9 on the reading scale, samples with greater 850 than 95% positivity for HIV-1 antibody, and samples with greater than 95% positivity for HIV-2 851 antibody. Although the test results are typically reported qualitatively, for the purposes of 852 evaluating reproducibility and repeatability, the results were also recorded quantitatively using 853 THE Manufacturing Company reading scale where the intensity of the test line was graded 854 between 0—10. 855 Testing was performed using three independent device lots on three separate days by three 856 testers. The 6-member panel included two nonreactive sample, one HIV-1 high reactive, one HIV-2 857 high reactive, one HIV-1 low reactive and one HIV-2 low reactive sample. Five replicates of each 858 panel member were de-identified and randomized to avoid reader bias and tested each day by each 859 tester. Study parameters are summarized below.
860 Table 7.1.2–1: Reproducibility study parameters Parameters Criteria Inter-Day 5 days Inter-operator 3 operators Inter-lot 3 lots Within-run 5 replicates per day x 5 days
861 Statistical analysis 862 Positivity of each panel member was determined and 95% CIs were calculated. Mean reactivity of 863 positive antibody panels members were determined and 95% CI calculated for the mean reading 864 scale value.
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865 Results and discussion 866 Full results can be found in Annex XXX Study report for SIMU™ self-test for HIV 12O 867 reproducibility and repeatability in plasma. 868 A total of 405 test results were generated. Overall reproducibility was calculated as 405/405 = 869 100% (95% CI 99.1-100%). Mean reactivity demonstrated no more than a -10.5% difference from 870 baseline for positive specimens.
871 Conclusion 872 The SIMU™ self-test for HIV 12O device demonstrated acceptable reproducibility and 873 repeatability when used by trained professionals.
874 7.1.2.1.2.1 Repeatability studies 875 Repeatability was addressed within the reproducibility study (Section 7.1.2.1.2).
876 The Manufacturer should in addition provide summaries of related studies 877 performed to demonstrate reproducibility of the assay when performed by 878 untrained users.
879
880 7.1.2.2 Analytical sensitivity
881 7.1.2.2.1 Analytical sensitivity of SIMU™ self-test for HIV 12O for HIV-2 in whole blood
882 Study Protocol: AP XXX Protocol for analytical sensitivity of SIMU™ self-test for HIV 12O for HIV-2 883 in whole blood. 884 Protocol risk assessment P128 – on file
885 Protocol: AP XXX Protocol for analytical sensitivity of SIMU™ self-test for HIV 12O for HIV-2 in 886 whole blood. 887 Full Report: AR XXX Study report for analytical sensitivity of SIMU™ self-test for HIV 12O for HIV-2 888 in whole blood. 889 Study Dates: 1 May 2014 – 2 June 2014 890 Lot number: AAA Made to the final manufacturing specification. 891 Expiry date: October 2015 892 Comparator kit lot: Product code K 1460, expiry: end 2015-01 from A Very Good Manufacturer™ 893 IFU version: v1.0 894 Conducted by: Don. Camillo, R&D Dept., THE Manufacturing Company. 895 Testing: Performed on site, R&D Dept., 896 Specimens: Source packs of QC 123 (specimen 1 in the tables below) and 123a (specimen 7 in the 897 tables), HIV-2 groups A and E respectively, plus 8 other un-sequenced HIV-2 from a 898 commercial supplier. Source pack of QC 120 (negative, diluent for the other specimens)
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899 Acceptance criterion 900 From the design input requirements: the product must be as sensitive as state of the art CE marked 901 HIV 1+2 assays in routine use in European transfusion centres.
902 Study design and planning 903 Rationale: Measurement of sensitivity by comparing dilutions of a single specimen is 904 inappropriate as each specimen will have a different spectrum of antibody types (IgG 1- 905 4, IgM etc.), antibody affinities, and antibody concentration and possibly vary in subtype 906 of the infecting virus. In addition, each device will have a different response depending 907 on the subtype (or precise sequence) of the recombinant proteins or peptides used 908 (HIV-2 A, B etc.), the epitopes used and conformation adopted and the assay format 909 (antigen sandwich, protein A, L capture etc.). 910 For these reasons it is essential to compare devices using several dilution series of 911 specimens as geographically diverse as possible so as to avoid possible bias from 912 specimen choice. The strength of signal is not important – the study objective is to study 913 the sensitivity of detection using dilutions (positive or negative). 914 The negative specimen used as diluent to make the dilution series must be shown to be 915 “flat” negative on each of the devices used (i.e. in the centre of the distribution of 916 negative specimens tested for assays with numerical read-out). This is so as not to 917 distort the result by being atypical. It must also be included in replicate in the assay 918 work to ensure a true background for the comparisons. 919 Only one lot of SIMU™ self-test for HIV 12O needs to be used. The risk evaluation 920 concluded that QA control was sufficient with one lot (two HIV-2 specimens in the panel 921 with rationale and defined criteria) to ensure lot-to-lot reproducibility. 922 Analysis by χ2 of the relative numbers of positive dilutions over the whole experiment. 923 Any obviously discrepant specimens should be evaluated individually.
924 Results 925 1 = reactive, 0 = negative
926 Figure 7.1.2.2–1: Results for sensitivity of Assay A for HIV-2: Specimen 1 2 3 4 5 6 7 8 9 10 Dilution 1:50 1 1 1 1 1 1 1 1 1 1 1:100 1 1 1 1 1 1 1 1 1 1 1:200 1 1 1 1 1 1 1 1 0 1 1:400 1 1 1 1 0 1 1 1 0 1 1:800 1 1 0 1 0 1 0 1 0 1 1:1600 1 1 0 1 0 0 0 1 0 0 1:3200 1 0 0 1 0 0 0 1 0 0 1:6400 1 0 0 1 0 0 0 0 0 0 1:12800 0 0 0 1 0 0 0 0 0 0 1:25600 0 0 0 0 0 0 0 0 0 0 Diluent 0 0 0 0 0 0 0 0 0 0
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Specimen 1 2 3 4 5 6 7 8 9 10 Dilution Number positive 8 6 4 9 3 5 4 7 2 5
927 Figure 7.1.2.2–2: Results for sensitivity of Comparator Assay B for HIV-2 Specimen 1 2 3 4 5 6 7 8 9 10 Dilution 1:50 1 1 1 1 1 1 1 1 1 1 1:100 1 1 1 1 1 1 1 1 1 1 1:200 1 1 1 1 1 1 1 1 1 1 1:400 1 1 1 1 0 1 0 1 0 1 1:800 1 1 0 1 0 1 0 1 0 1 1:1600 1 1 0 1 0 0 0 1 0 0 1:3200 1 0 0 1 0 0 0 1 0 0 1:6400 1 0 0 1 0 0 0 1 0 0 1:12800 1 0 0 1 0 0 0 0 0 0 1:25600 0 0 0 0 0 0 0 0 0 0 Diluent 0 0 0 0 0 0 0 0 0 0 Number positive 9 6 4 9 3 5 3 8 3 5
928 Figure 7.1.2.2–3: Results of difference between Assay A and Comparator Assay B Specimen: 1 2 3 4 5 6 7 8 9 10 Difference A-B -1 0 0 0 0 0 1 -1 -1 0
929 A plot of this data is in the figure below:
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930 Figure 7.1.2.2–4: Results plotted difference between Assay A and Comparator Assay B
931 The overall analysis of this data by χ2 (= 0.08) shows the assays are not statistically significantly 932 different with these 10 specimens and there is no particular difference in detectability of the 933 various specimens.
934 Conclusion 935 The assays are not statistically different in ability to detect end-point dilutions of HIV-2 from a 936 variety of sources. The analytical sensitivity of the SIMU assay meets the specifications in the 937 design input documentation and is satisfactory for full-scale evaluation by users.
938 7.1.2.2.2 Performance in HIV 1 seroconversion panels 939 The reactivity of the SIMU™ self-test for HIV 12O has been evaluated in seroconversion panels 940 consisting of plasma specimens obtained from individuals during seroconversion.
941 Study Summary Report: Reactivity of the SIMU™ self-test for HIV 12O in Seroconversion Panels 942 Protocol: AP XXX - refer ANNEX XXX Protocol Reactivity of the SIMU™ self-test for HIV 12O in 943 Seroconversion Panels. 944 Full Report: AR XXX – refer ANNEX XXX Study Report Reactivity of the SIMU™ self-test for HIV 12O 945 in Seroconversion Panels 946 Study Dates: 1 June 2012 – 30 June 2012 947 Lot number: 12345 948 IFU version: v1.0 949 Conducted by: A Blog, Research and Development Dept., THE Manufacturing Company 950 Testing: Performed on site, Headquarters.
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951 Study objective 952 The purpose of the study was to evaluate assay sensitivity in seroconversion panels compared to 953 Enzyme immunoassays (EIAs) considered state of the art in Europe.
954 Acceptance criterion 955 HIV-1 956 As per the Common Technical Specifications for IVDs required for the European Union, the 957 acceptance criterion for assay sensitivity in seroconversion panels was defined as demonstration of 958 similar ability to detect antibodies to HIV-1 during seroconversion compared to the reference test - 959 Results should conform to the state of the art for antibody only detection i.e. 3rd Generation HIV 960 assays. 961 All seroconversion HIV samples shall be identified as reactive whereby seroconversion HIV samples 962 mean p24 antigen and/or HIV RNA positive, and, recognised by all of the antibody screening tests, 963 and positive or indeterminate confirmatory assays, 964 At least 40 early seroconversion HIV samples shall be tested. Results should conform to the state of 965 the art. Early seroconversion HIV samples mean p24 antigen and/or HIV RNA positive, and not 966 recognised by all of the antibody screening tests, and indeterminate or negative confirmatory 967 assays.
968 Study design 969 Twenty commercially acquired seroconversion panels, each consisting of sequential plasma 970 specimen collections from individuals who seroconverted, were tested. Seroconversion panels 971 should start with a negative bleed(s) and should have narrow bleeding intervals. The table below 972 shows days elapsed from initial specimen collection. Results of testing with EIAs and the SIMU™ 973 self-test for HIV 12O are shown. Seroconversion panels were not available for OMT specimens.
974 Results 975 Of the 20 seroconversion panels tested, the SIMU™ self-test for HIV 12O detected antibodies to 976 HIV-1 as early as EIA in 17 panels and later than EIA in 3 panels. Reactivity in seroconversion panels 977 is shown below. However, no seroconversion specimens were not detected, only early 978 seroconverting panel members.
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979 Table 7.1.2.2–1: Detection of HIV-1 antibody in seroconversion panels Panel Relative day of SIMU™ self- 3rd Generation 3rd HIV RNA/p24 specimen test for HIV 1st Result™ GenerationGood antigen/Western blot collection 12O HIV 1 2 EIA asGold™ HIV 1 2 Cat no. 2233 EIA Cat no. 22222 001-001 0 NR NR NR NR/NR/NR 4 NR NR NR R/NR/NR 15 NR NR NR R/R/NR 26 R RR RR R/R/IND 35 R RR RR R/R/POS 001-002 0 NR NR NR NR/NR/NR 10 NR NR NR R/NR/NR 22 NR NR NR R/NR/NR 31 R NR RR R/NR/NR 44 R RR RR R/R/NR etc. 980 NR: nonreactive R: reactive RR: repeatedly reactive
981 Conclusion 982 The SIMU™ SELF-TEST FOR HIV 12O assay demonstrated similar ability to detect antibodies to 983 HIV-1 in plasma specimens compared to 3rd generation state of the art EIAs.
984 The Manufacturer is also expected to provide full study protocol and results of 985 additional similar sensitivity studies, such as those listed below.
986 7.1.2.2.3 Sensitivity in HIV-1 low titre panels 987 Low titre panels are available commercially. Similar studies should be performed for HIV-2, if 988 applicable to the assay.
989 7.1.2.2.4 Sensitivity in HIV-1 specimens from diverse geographic regions representing various HIV- 990 1 subtypes and genotypes 991 Worldwide specimens should be tested. Both clinical specimens and commercial panels may be 992 used. A significant number of non-subtype B should be tested. All known non-B subtypes: A1, A2, C, 993 D, F, G, H, J, K, O and recombinant AE should be represented with a minimum of 3 subtypes. The 994 number of specimens from each different subtype tested should be guided by a risk analysis of the 995 setting (countries) of intended use.
996 7.1.2.2.5 Sensitivity in HIV-2 specimens 997 Studies similar to those performed for HIV-1 should be performed for HIV-2 if applicable to the 998 assay.
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999 7.1.2.3 Analytical specificity - Effect of interfering substances and unrelated medical 1000 conditions 1001 The guiding documents for these types of studies are:
1002 CLSI EP07-A2 Interference Testing in Clinical Chemistry Approved Guideline - Second 1003 Edition [2005]. 1004 European common technical specifications for in vitro-diagnostic medical devices, 3 1005 February 2009 [testing of 100 potentially interfering specimens] 1006 GHTF/SG1/N68:2012 Essential Principles of Safety and Performance of Medical Devices 1007 CLSI EP14-A3 Evaluation of Commutability of Processed Samples; Approved Guideline - 1008 Third Edition [2014] 1009 Guidance for Industry and FDA Staff; In Vitro Diagnostic (IVD) Device Studies -Frequently 1010 Asked Questions.
1011 Study Report Effect of Interfering Substances and Unrelated Medical Conditions in whole blood and 1012 OMT on SIMU™ self-test for HIV 12O 1013 Protocol: AP XXX Protocol on the effect of interfering substances and unrelated medical conditions 1014 in whole blood and OMT on SIMU™ self-test for HIV 12O 1015 Full Report: AR XXX Report of the effect of interfering substances and unrelated medical conditions 1016 in whole blood and OMT on SIMU™ self-test for HIV 12O; Risk assessment document TMC-risk 1017 Y1234-P15-1. 1018 Study Dates: January - August 2010 1019 Lot number: lot codes AAR (Y1234-B) and BDE (Y1234-O) were used for this study and were made 1020 from two independent lots to final specifications at validated scale by manufacturing staff. 1021 IFU version: v1.0 1022 Conducted by: A Blog, on site in the Research and Development Dept., or in the clinical evaluation 1023 centres or by the Clinical trials group conducted the clinical evaluation studies 1024 Testing: Performed on site in the Research and Development Dept., in local STI clinic, in local 1025 clinical evaluation centre or in the blood centre
1026 Study objective 1027 The purpose of the study was to evaluate any effect of potentially interfering substances or the 1028 presence of unrelated medical conditions on device performance.
1029 Risk evaluation 1030 Risk assessment document TMC-risk Y1234-P15-1 summarises the findings of an analysis of the risk 1031 of potentially interfering substances on performance of the device. Substances and unrelated 1032 infections/medical conditions identified in this assessment and their likely impact on device 1033 performance were addressed in this study.
1034 Acceptance criterion 1035 Interference from any potentially interfering substances, unrelated infections or medical 1036 conditions, or cross-reacting antibodies should be < 5%.
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1037 Study design 1038 The testing panel consisted of XXX fingerstick whole blood and XXX OMT/synthetic 1039 mucopolysacharride matrix specimens. Approximately half of the specimens for each sample type 1040 (whole blood or OMT) were confirmed HIV antibody positive, the other half HIV antibody negative. 1041 For each sample type this resulted in a total of: 1042 XX HIV-1 antibody positive specimens; XXX HIV-1 antibody negative specimens, 1043 XX HIV-2 antibody positive specimens; XXX HIV-2 antibody negative specimens, and 1044 XX HIV-1 Group O antibody positive specimens*; XXX HIV-1 Group O antibody negative 1045 specimens 1046 * Because of the difficulty in acquiring sufficient numbers of Group O specimens, the panel of HIV-1 1047 Group O specimens were generated by spiking HIV-negative whole blood with HIV-1 Group O 1048 antibody positive plasma purchased from commercial vendors. 1049 Each member of the testing panel was was used to spike each of the materials listed in Table 1050 7.1.2.3-1. The amounts/concentrations of each potentially interfering factor were targeted to 1051 mimic conditions likely to be encountered during routine use of the device as identified in the risk 1052 analysis. 1053 The effects of smoking, recent tooth-brushing or alcohol (as recently-used mouthwash) as well as 1054 the chewing of betel nut, tobacco or coca were evaluated in OMT specimens in validation study XX- 1055 XXX provided in Section X.x.x.2 1056 Genuine lipaemic, hypergammaglobulinaemic and icteric specimens were sourced to assess the 1057 effect of lipaemia, haemolysis, icteric specimens, and heterophile antibodies. This was required as 1058 an output of the risk assessment because of flow and reading implications: the use of spiked 1059 samples would not be valid for this device.
1060 Routine interfering factors (common consumer products, therapeutic and pharmacological agents) 1061 were used to spike, at concentrations summarised in Table 7.1.2.3-1, both HIV antibody negative 1062 and HIV antibody positive fingerstick whole blood or OMT/synthetic mucopolysacharride matrix 1063 specimens. Specimens used for spiking were acquired according to protocol SOP XXXX. Cross- 1064 reacting viruses and antibodies were evaluated on commercial specimens, which were selected and 1065 acquired according to protocol SOP XXXX. These included Epstein Barr virus and hepatitis A virus 1066 IgM positive specimens as acute infection with these viruses is known to induce a polyclonal B-cell 1067 activation and hence the potential for false positive results.
1068 Table 7.1.2.3–1: Interfering factors and medical conditions 1069 This table is provided as an example of the kinds of potentially interfering substances 1070 and unrelated infections and medical conditions that a manufacturer may need to 1071 address in a product dossier. This list is not intended to be either exhaustive or a 1072 checklist of what factors must be tested. The kinds of substances and conditions that 1073 a device is likely to be exposed to during normal use should arise from a risk 1074 assessment of the device, which would then be used to design a study of potentially 1075 interfering substances.
2 Manufacturers are reminded that any such references to supporting validation studies must be included in full in the corresponding section(s) of the product dossier.
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Potentially Interfering Factor Dose/Concentration Elevated Bilirubin X.xx mg/dL Elevated Haemoglobin etc Elevated Triglycerides Elevated Protein Bacterially Contaminated Visual Haemolysis (haemolytic) Human antimouse antibodies (HAMA) Sodium Heparin EDTA Sodium Citrate ACD Solution A Aspirin Paracetamol/acetaminophen Caffeine Consumer oral products (alcohol, toothpaste, tobacco, etc.) Therapeutic goods and pharmacological agents likely to have been taken by a user of the device Unrelated Infections and Medical conditions Cytomegalovirus (CMV) (acute) Epstein Barr virus (EBV) (acute) Hepatitis A virus (HAV) Hepatitis B virus (HBV) Hepatitis C virus (HCV) Human T-cell Lymphotropic virus Type I (HTLV-1) Human T-cell Lymphotropic virus Type II (HTLV-11) Rubella lgG gammopathies lgM gammopathies Rheumatoid factor Lupus Anti-nuclear antibody (ANA) Anti-DNA antibody Toxoplasmosis Tuberculosis Influenza Multiple transfusions Haemophiliac Herpes Simplex virus Cirrhosis Colon cancer Breast cancer Chlamydia Syphilis Gonorrhoea Multiparous women
1076 Results 1077 In this section are presented the summary results data (Table 7.1.2.3.-5) for the investigation of 1078 potential interference from unrelated infections and medical conditions. Full study results are 1079 provided in Section X.xx and are also available on site in the R&D department, Design history file, 1080 laboratory notebooks ZMRI 105 – 108.
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A sample of test results from one section of this sample study is shown here for illustrative purposes. Manufacturers are expected to present all summary and raw data relevant to performance claims in each section of their product dossiers.
1081 Table 7.1.2.3-2 Potential interference from unrelated infections and medical conditions from 1082 professional and user clinical evaluations in centres A and B #tested, SIMU result true HIV result SIMU result from reference lab Fingerstick OMT Infection Positive Negative Positive Negative Positive Negative
HIV-1 panel
HCV XX XX XX XX* XX XX HBV XX XX XX XX XX* XX Etc… ... … … … … … HIV-2 panel HCV XX XX XX XX XX XX HBV XX XX XX XX XX XX Etc… ... … … … … … HIV-1 O panel HCV XX XX XX XX XX XX HBV XX XX XX XX XX XX Etc… ... … … … … … 1083 *An effect was a change in >1 scale point on the QA calibrator scale, see Section 7.0, read by 1084 company staff. 1085 One HIV-1 spiked whole blood specimen, positive for X. Xxxxx antibodies, was falsely negative on 1086 the device when compared with the confirmed reference result. One HIV-1 spiked Xxxx-positive 1087 OMT specimen, was observed to be a common false positive between the test used at the STI 1088 centre and SIMU™ HIV 12O self-test. Further work at the reference centre showed it to be HIV 1089 negative but false reactive on a number of tests. The number of specimens tested in this study is 1090 too small to make statistically-rigorous conclusions. Despite this limitation, the single false negative 1091 whole blood specimen and the single common false-positive are each likely to fall outside the 1092 acceptance criterion for this study (1 false result = xx/XX = 2.3% but with a lower one-sided 1093 confidence limit of 7%)3. Summary results, illustrating the potential impact on device performance 1094 will be communicated to the user in the IFU.
3 NB: values provided here are for illustrative purposes only and do not necessarily reflect actual values and/or sample sizes expected to be provided to WHO. It is a manufacturer’s responsibility to establish sample sizes and acceptance criteria that are suitable for their validations.
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1095 Conclusion 1096 Verification work on potentially interfering substances shows that the SIMU™ HIV 12O self-test is 1097 not affected by most of the tested materials within the pre-assigned criteria from the design input 1098 specifications. Several discrepancies were noted and the potential for impact on device 1099 performance will be reflected in the IFU. 1100 The work by R&D staff leads to the conclusion that it is secure to proceed to validation work – the 1101 device is expected to meet user needs in these respects.
1102 7.1.2.3.1 Impact on sensitivity in the presence of unrelated medical conditions 1103 […]
1104 7.1.2.4 Traceability of calibrators and control material values 1105 […]
1106 7.1.2.5 Measuring range of the assay
1107 WHO expect that measuring range studies are submitted which include testing of 1108 mixed titre panels and investigation for hook effect (prozone phenomena).
1109 7.1.2.6 Validation of assay cut-off
1110 7.1.2.7. Validation of assay procedure – reading time 1111 A specific design input (4.1.1 f) required that use of the device must not require timing at any 1112 stage. The design accommodates this by a visual system – when the window is clear of dye the 1113 assay can be read and the reagents chosen give a stable result for a long period. The system was 1114 evaluated in this respect as follows.
1115 Study Summary Report: Time dependences of the HIV 120 Self-Test 1116 Protocol: AP XXX - refer ANNEX X; Protocol risk assessment P125 – on file. 1117 Full Report: AR XXX – refer ANNEX X. 1118 Study Dates: 1 September 2012 – 30September 2012 1119 Lot numbers: ABC, DEF, and PQR. These were made to final protocol and manufacturing scale and 1120 contain independent critical reagents, in particular different lots of membrane, dye and buffer. 1121 IFU version: v1.0 1122 Conducted by: Joe White and Pete Sloe, Research and Development Dept., THE Manufacturing 1123 Company 1124 Testing: Performed on site, Headquarters. 1125 QC specimens (see section 7.0 QC panel members, criteria, rationale.) 1126 QC 123 QC 124 QC 302 plus five normal negative whole venous bloods from the local blood service 1127 tested less than 5 hours after donation.
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1128 Study Objective 1129 To ensure that the device did not require timing by the user. This protocol is to verify the device 1130 against the specification – timing with use of fingerstick specimens and oral fluid is validated during 1131 professional evaluation see section 7.4
1132 Acceptance Criteria 1133 That the device gives clear, stable (at least 12 hours) results once the dye has cleared the window. 1134 Although each of the QC specimens have criteria with a validated range, for this protocol the 1135 criteria are increased so that the signal, while required to be in the range, must also not change 1136 consistently by more than 1 point against the QC calibration scale over the time periods involved.
1137 Study Design 1138 Each specimen was run in duplicate on devices from each specified lot exactly according to the IFU. 1139 A reading was made as soon as the dye had flowed past the control line, a second as soon as the 1140 reading window had been cleared of dye and then 1, 3, 6 and 24 hours later. Each reading was 1141 confirmed by a second observer, blinded to the earlier results by randomizing the order of 1142 presentation of devices. The times for each reading after starting the run (by clicking the device) 1143 were noted accurately for the first two readings 1144 Two separate replications of the whole experiment were performed. The devices were equilibrated 1145 to 10°C or to 47°C to accommodate the IFU claim that the device can be operated between 6 and 1146 45°C.
1147 Results 1148 Each specimen met its QC requirement on each occasion. There was no change of more than 1 1149 point against the QC calibrated scale in the signal over the complete period for any specimen. A 1150 sample of the result collection form is given below, a summary of the full results and raw data is 1151 available on file.
1152 Table 7.1.2.6–1: Results of reading time by reader 1, experiment at 10°C Reading Exact Exact 1 (when Reading time time 24 Lot # QC # control 2 (dye 1 hour 3 hour 6 hour after after hour line cleared) start start visible) ABC QC123 1 3”25 1 7’36” 1 1 1 1 ABC QC123 1 3’12” 1 7’05” 1 1 1 1 DEF QC123 1 4’02” 1 7’58” 1 1 1 1 DEF QC123 1 3’52” 1 7’39” 1 1 1 1 …. DEF QC124 2 3’16” 2 7’13” 2 2 3 2 PQR QC124 3 3’48” 3 7’52” 3 2 3 3 1153 Over all the lots and devices the time for the dye to completely pass the control line varied from 1154 2’58” (two minutes 58 seconds) to 4’09” and for the dye to clear from the window from 7’05” to 1155 8’02”. 1156 There were no invalid results and the negative whole venous blood flowed within criteria.
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1157 The timings and readings show the device is robust against early reading (the control line is visible 1158 approximately four minutes before device is allowed to be read according to the IFU) which is after 1159 approximately seven and a half minutes from starting the flow.
1160 Conclusion 1161 Readings from the SIMU™ SELF-TEST FOR HIV 12O are not sensitive to time once the dye has 1162 cleared the viewing window and are not degraded by early reading, in a professional environment. 1163 The device meets its input product requirement: 5.10.1. 1164
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1165 7.2 Stability (excluding specimen stability) 1166 Stability studies were performed with SIMU™ self-test for HIV 12O in order to determine shelf-life, 1167 in-use stability, and storage and transport conditions.
1168 7.2.1 Claimed shelf life
1169 Study Summary Report: SIMU™ self-test for HIV 12O Device Real-Time Stability 1170 Protocol: AP XXX. 1171 Full Report: AR XXX – refer ANNEX XXX Study report SIMU™ self-test for HIV 12O Device Real- 1172 Time Stability. 1173 Study Dates: July 2014 – ongoing 1174 Lot number: 12345, 13345, 14345 1175 IFU version: v1.0 1176 Conducted by: L Pasteur, Research and Development Dept., THE Manufacturing Company 1177 Testing: Performed on site, Headquarters.
1178 Study Objective 1179 The objective was to follow the stability of the device over at least 13 months and determine shelf 1180 life of the device. Testing beyond 13 months would allow an understanding of when, in real-time, 1181 the device is likely to ‘fail’ and may allow an extension of the proposed shelf-life. There is currently 1182 stability data for 13 months.
1183 Acceptance Criterion 1184 The acceptance criterion was defined as demonstration of acceptable assay performance to 1185 support recommended storage conditions. Acceptable assay performance was defined as a 1186 detection rate of >95% in HIV positive stability panel samples.
1187 Study Design 1188 Stability studies for the SIMU™ self-test for HIV 12O evaluated shelf life when stored at 6–45°C. 1189 Stability panels containing HIV were prepared by spiking plasma with HIV from a known positive 1190 sample to low levels of reactivity (see section 7.0). Sufficient volume of each stability panel member 1191 for the duration of the testing schedule was prepared. Testing was performed in triplicate for each 1192 panel member for each condition. Three kit lots, from three independent production lots, using a 1193 predetermined sampling protocol SOP 199 were tested. At least 10% overage was allowed for 1194 unexpected requirements and re-testing. 1195 Kits were divided into two groups and stored at either 6±5°C or 45±5°C. Testing was conducted at 1196 0, 3, 6, 9, 12 and 13 months. At each time point, kits were brought to room temperature (20 ± 5°C) 1197 and used to test the stability panel.
1198 Results 1199 Full study results in Annex XXX Study report SIMU™ self-test for HIV 12O device real-time stability.
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1200 Stability data is available through 13 months. Acceptable assay performance was demonstrated 1201 through the 13 month time point for kits stored at 45±5°C and 6±5°C. These results suggest 12 1202 month kit storage stability at 6–45°C.
1203 Conclusion 1204 The device is stable to 13 months and the current shelf life is 12 months; study is ongoing.
1205 7.2.2 In-use stability and stability of result
1206 Study Summary Report: SIMU™ self-test for HIV 12O In-Use Stability 1207 Protocol: AP XXX. 1208 Full Report: AR XXX – refer ANNEX XXX Study report SIMU™ self-test for HIV 12O In-Use Stability 1209 Study Dates: July 2014 1210 Lot number: 12345 1211 IFU version: v1.0 1212 Conducted by: J. Snow, Research and Development Dept., THE Manufacturing Company 1213 Testing: Performed on site, Headquarters.
1214 Study Objective 1215 The objective was to determine the stability of the device after removing from packaging. The 1216 intended use population is untrained users and the device could be subjected to uncontrolled 1217 conditions during testing.
1218 Acceptance Criterion 1219 The acceptance criterion was defined as demonstration of acceptable assay performance to 1220 support recommended in-use conditions. Acceptable assay performance was defined as a 1221 detection rate of >95% in HIV positive stability panel samples.
1222 Study Design 1223 In-use stability studies for the SIMU™ self-test for HIV 12O evaluated use immediately upon 1224 opening and after at 20 ±5°C and 45±5°C for 1, 2, 6, and 25 hours at 15% humidity and 80% 1225 humidity. Stability panels containing HIV were prepared by spiking plasma with HIV from a known 1226 positive sample to low levels of reactivity (see section 7.0). Sufficient volume of each stability 1227 testing panel member for the duration of the testing schedule was prepared. Testing was 1228 performed in triplicate for each panel member for each condition. Three kit lots, from three 1229 independent production lots, using a predetermined sampling protocol (SOP 199) were tested. At 1230 least 10% overage was allowed for unexpected requirements and re-testing. 1231 Kits were divided into two groups and placed at either 20 ± 5°C or 45±5°C. Kits from both groups 1232 were sampled at 0, 1, 2, 6, and 25 hours with the stability panel.
1233 Results 1234 Full study results are in annex XXX Study report SIMU™ self-test for HIV 12O In-Use Stability 1235 Acceptable assay performance was demonstrated through the 24 hour time point for kits stored at
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1236 20 ± 5°C and 45±5°C at both 15% humidity and 80% humidity. These results demonstrate in-use 1237 stability at 20–45°C. 1238 Conclusion 1239 The device can be used for testing up to 24 hours after opening at 20–45°C at low and high 1240 humidity.
1241 7.2.3 Shipping stability
1242 Study Summary Report: SIMU™ self-test for HIV 12O Device Transportation Stability study 1243 Protocol: AP XXX - refer ANNEX XX 1244 Full Report: AR XXX – refer ANNEX XXX Study report SIMU™ self-test for HIV 12O Device 1245 transportation stability 1246 Study Dates: July 2012 – August 2013 1247 Lot number: 12345 1248 IFU version: v1.0 1249 Conducted by: A Cochrane, Research and Development Dept., THE Manufacturing Company 1250 Testing: Performed on site, Headquarters.
1251 Study Objective 1252 The purpose of the study was to evaluate the impact of temperature and humidity extremes on 1253 device performance in real-time using simulated transport conditions and to define device storage 1254 and transport conditions. The transportation challenge preceded the real-time determination of 1255 shelf-life This served to determine that transportation conditions do not reduce the shelf-life of the 1256 SIMU™ self-test for HIV 12O device.
1257 Acceptance Criterion 1258 The acceptance criterion was defined as demonstration of acceptable assay performance to 1259 support recommended shipping conditions. Acceptable assay performance was defined as a 1260 detection rate of >95% in HIV positive stability panel samples. 1261 The stability was taken as the time point prior to last time point to have met the acceptance 1262 criteria, e.g. if the device was stable to 13 months, the stability will be deemed to be 12 months. 1263 The stability after transportation should be identical to the claimed shelf-life of the device, i.e. the 1264 extremes of possible conditions to which the device is likely to subjected during transport must not 1265 affect the shelf-life of the device.
1266 Study Design 1267 Shipping studies for the SIMU™ self-test for HIV 12O evaluated shelf life prior to shipping (45±5°C, 1268 the other at 6±5°C ), and shipping conditions including a freeze-thaw cycle (-20°C to 2-8°C), and 1269 temperature cycling from IFU to 55°C under variable humidity conditions. Stability panels 1270 containing HIV were prepared by spiking plasma with HIV from a known positive sample to low 1271 levels of reactivity (see section 7.0). Sufficient volume of each stability panel member for the 1272 duration of the testing schedule was prepared. Testing was performed in triplicate for each panel
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1273 member for each condition. Three kit lots, from three independent production lots, using a 1274 predetermined sampling protocol (SOP 199) were tested. At least 10% overage was allowed for 1275 unexpected requirements and re-testing. 1276 Prior to temperature cycling conditions, kits were divided into two groups; one group was stored at 1277 45±5°C, the other at 6±5°C. Testing was conducted at 0, 3, 6, 9, 12 and 13 months. At each of 1278 these time points, kits were removed from storage and subjected to a freeze-thaw cycle (-20°C to 2- 1279 8°C). After the freeze-thaw cycle, kits were subjected to the following temperature and humidity 1280 sequence: 1281 Ambient humidity (60% RH) 1282 Put at IFU storage temperature for 24±4 hours followed by 1283 55 ± 2°C for 24±4 hours, followed by 1284 IFU storage temperature for 24±4 hours 1285 Followed by: 1286 Desert humidity (30% RH) 1287 Put at IFU storage temperature for 24±4 hours followed by 1288 55 ± 2°C for 24±4 hours, followed by 1289 IFU storage temperature for 24±4 hours 1290 Followed by: 1291 Tropical humidity (85% RH) 1292 Put at IFU storage temperature for 24±4 hours followed by 1293 55 ± 2°C for 72±4 hours, followed by 1294 IFU storage temperature for 24±4 hours 1295 Followed by: 1296 Ambient humidity (60% RH) 1297 IFU storage temperature for 24±4 hours 1298 1299 The above complete sequence was used as opposed to separate kits held at individual 1300 temperatures. At each time point, kits were brought to room temperature (20 ± 2°C) and used to 1301 test the stability panel.
1302 Results 1303 Acceptable assay performance was demonstrated under all temperature and humidity conditions 1304 tested through the 9 month time point for kits stored at 45±5°C, and through the 13 month time 1305 point for kits stored at 6±5°C. These results suggest 6 month kit storage stability at 45°C and 12 1306 month kit storage stability at 6°C.
1307 Conclusions 1308 Recommended conditions are kit storage at 6°C prior to shipping at IFU temperature and humidity.
1309 The Manufacturer should refer to the WHO TGS-2 document “Establishing stability of 1310 an in vitro diagnostic for WHO Prequalification” for further information. 1311 http://www.who.int/diagnostics_laboratory/guidance/en/
1312
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1313 7.3 Robustness studies 1314 Robustness studies conducted over a range of conditions to mimic or exceed what 1315 the device may be exposed to may include, but are not limited to, assessment of the 1316 following: 1317 - presence of endogenous or exogenous factors in the oral cavity prior to collecting 1318 specimens 1319 - median and extreme temperatures 1320 - median and extreme humidity 1321 - variations in sample collection technique 1322 - other human factors 1323 See WHO PQDx-018 “Instructions for Compilation of a Product Dossier” for 1324 additional factors to consider. 1325 http://www.who.int/diagnostics_laboratory/evaluations/PQDxInfo/en/ 1326 The Manufacturer is expected to provide summaries of all studies conducted to 1327 demonstrate product robustness.
1328 Studies were conducted to demonstrate insensitivity of the SIMU™ self-test for HIV 12O to a 1329 range of conditions that could occur with self-testing. The effects of exogenous factors are 1330 described in Section 7.1.2.2.2; temperature and humidity extremes are summarized in Section 7.2; 1331 human factors associated with performing the test (such as variation in sample collection) are 1332 captured in untrained user studies (Sections 7.4), and environmental factors are described in 1333 Section 7.2. The results of these studies are summarized below.
1334 Table 7.3–1: Summary of Studies to Evaluate Robustness Factor Study report Summary of the Test environment Conclusion reference evidence and relation to intended use environment Operator error Part 2 Qualification Operator variability Test environment Device was of usability in self did not impact the was untrained insensitive to testing population accuracy of the device users and observed operator errors or the interpretation untrained users; evaluated. of the result. intended use environment is unobserved untrained users Specimen Effect of Interfering The presence of Test environment Device was integrity and Substances and potentially interfering was trained users insensitive to handling Unrelated Medical substances and (interfering endogenous factors, Conditions; SIMU™ specimen handling substances and which are not self-test for HIV 12O outside specimen stability) impacted by user Specimen Stability; recommended and observed proficiency. Device Part 2 Observed user conditions did not untrained users was also insensitive study impact the accuracy (Part 2 study). to specimen handling of the device result. Intended use is variations by trained untrained users. or untrained users.
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Environmental Claimed Shelf life, In- Temperature and Real time storage Conditions under factors Use and Shipping humidity extremes did and simulated end which the device Stability studies not impact device of life shipping accuracy is accuracy. stability conditions. insensitive were defined. 1335
1336 7.3.1 Robustness to volume variation 1337 Protocol: AP XXX Protocol Robustness of SIMU™ self-test for HIV 12O to volume variation
1338 Protocol risk assessment P126 – on file.
1339 Full report: AR XXX Study report Robustness of SIMU™ self-test for HIV 12O to volume variation
1340 Study dates: July 2014 1341 Lots: BCD, FGH, PRQ (Y1234-B) and CDB, HGF, QPR (Y1234-O) made to the final manufacturing 1342 specification except as noted for particular experimental purposes in the protocol 1343 IFU version: v1.0 1344 Conducted by: A Blogs, Research and Development Dept., THE Manufacturing Company 1345 Testing: Performed on site, Headquarters. 1346 Specimens: (see Section 7.0 “QC panel members, their criteria, and rationale for inclusion in the 1347 panel.”) 1348 QC 123, QC 124, QC 302 and five recent negative whole blood specimens 1349 QC 506, QC 507 (HIV-1 and -2 spiked OMT) and QC 500 (negative OMT)
1350 Study Objective 1351 To verify that the device will function according to the intended use and the documented claims 1352 with respect to the volume of specimen likely to be provided by unobserved untrained users.
1353 Acceptance Criterion 1354 From the design input requirements: the readings must be stable for at least 12 hours after 1355 starting, the device must not be sensitive to changes in applied specimen volume (nor wash buffer 1356 volume) within acceptable limits. 1357 Study planning
1358 A “designed experiment” statistical approach was followed to verify that the device will 1359 function as intended and claimed when used with the range of volumes likely to be present 1360 in the reservoir and the specimen chamber, using critical QC panel members. 1361 Ethical clearance was received by the ethical committees of all institutions concerned with 1362 the study (Note that in compliance with World Medical Association Declaration of Helsinki 1363 on Ethical Principles for Medical Research Involving Human Subjects (1964-2008) we are 1364 not allowed to evaluate devices using our own staff as subjects). A requirement during this 1365 study with experimental devices was that no indication of the subjects’ HIV status should 1366 be obtained.
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1367 Experimental devices were manufactured to ensure that no indication of the subject’s HIV 1368 status was obtained. The test and control lines on the membrane were coated with a fish 1369 protein, not the active components of a normal device in order to give no result. The same 1370 retractable safety lancets and oral collection device was used as provided with the SIMU™ 1371 HIV 12O self-test device. 1372 The reproducibility of the volume of wash buffer in the device in routine manufacture was 1373 ascertained. It was shown that under routine manufacture, the filling machine had an error 1374 of ± 3% at the required fill volume of 250µL of wash buffer. It was decided to evaluate the 1375 system with nominal 235, 250 and 265 µL fill volumes to mimic the intended and extreme 1376 fill volumes. 1377 The likely volumes of fingerstick blood and OMT loaded into the device by untrained users 1378 was ascertained. Untrained users were accessed at the local diabetes clinics and in the local 1379 anti-coagulant testing clinic and were used to collect fingerstick blood and OMT volumes as 1380 specified in the IFU. 1381 o The devices were weighed before and after the addition of the drop of blood and 1382 the weight converted to a volume on the basis that 1µL of whole blood weigh 1.06 1383 mg. The average drop size, estimated from 100 individuals, was 35 ± 4 µL. It was 1384 decided to verify the devices using 20 and 55µL of QC specimen to cover the 1385 expected blood volumes, and also 90µL to cover two drops of blood being used. 1386 o The average volume of OMT collected, estimated from 100 individuals and 1387 assuming a density of 1mg/µL, was 500 ± 15 µL. On this basis it was decided to 1388 verify the performance of the device using 450, 500 and 550µL of OMT. 1389 Study protocol summary 1390 QC specimen panels were used at the following volumes: 1391 1. Fingerstick: 20, 55 and 90 µL 1392 2. OMT: 450, 500 and 550µL 1393 The devices were equilibrated at either 10 or 47°C to cover the claimed temperature range of use 1394 (12 – 45°C). The test was performed according to the IFU except that QC specimens were added by 1395 pipette. Each specimen was run on each lot, in duplicate at each temperature. The result on each 1396 device was interpreted against the QC calibration scale independently by two trained readers 1397 (readers were blinded to both the status of the specimen being tested and to the other reader’s 1398 result at the time of reading). In case of a difference of opinion of more than ±1 point on the scale 1399 a third reader, unaware of previous results, gave a reading. The recorded outcome was the median 1400 of the two or three values for each device. 1401 Results: 1402 The specimen addition chamber of the device was inspected immediately after the volume was 1403 added to evaluate whether sufficient specimen had been added. All volumes collected were 1404 sufficient to clear the indicator dye in the specimen addition chamber. 1405 Summary of test results: QC 124 tested on lot BCD at 47°C 1406 The results for QC 124 tested using lot BCD at 47°C are summarised in Table 7.3-2.
1407 Table 7.3–2: Result with panel member QC 124, Lot BCD, 47°C Wash Specimen Response Duplicate Average Experiment # volume volume 1 response response 1 235 20 2 3 2.5 2 250 55 3 2 2.5
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Wash Specimen Response Duplicate Average Experiment # volume volume 1 response response 3 265 90 3 3 3 4 265 20 3 3 3 5 235 90 2 2 2 6 250 55 3 3 3 1408 Analysis shows that over this range, neither wash volume nor specimen volume has a consistent 1409 statistically significant effect on the reading from this QC panel member, although in this particular 1410 case the effect of specimen volume approached significance.
1411 A sample of test results from one section of this sample study is shown here for 1412 illustrative purposes.
1413 Summary of all test results 1414 The results of all testing at both temperatures and for each device lot suggest that QC panel 1415 members are not affected by either the specimen or wash volume ranges investigated in this study. 1416 Raw data for testing presented in this study are provided in Appendix XXX and are also held on file 1417 at THE Manufacturing Company, in the R&D department, Design history file, laboratory notebooks 1418 ZXBI 110 – 1284.
1419 Stability of reading 1420 Each device was stored on the work bench at the temperature of use and the result re-read at 12 1421 and 24 hours after the initial use by operators unaware of the previous results. There was no 1422 statistically consistent change in the result from any device, supporting the result in section 7.1.2.7. 1423 Both summary results are raw data are provided in Appendix XX4.
1424 Conclusion 1425 The device is not sensitive to variable input specimen volume (for either sample type) over a wide 1426 range of volumes likely to encompass those provided by untrained, unobserved users. In addition 1427 the in-built volume monitor (dye in the specimen chamber) is verified as indicating when 1428 insufficient volume has been added. Thus, design input requirement 5.2 has been verified as being 1429 met and suitable for validation by clinical performance evaluation. 1430
4 Manufacturers are expected to present all summary and raw data relevant to performance claims in each section of their product dossiers
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1431 7.3.2 Robustness to environment: temperature, humidity, time out of pouch 1432 Protocol: AP XXX Protocol Robustness of SIMU™ self-test for HIV 12O to environment 1433 Protocol risk assessment P127 – on file 1434 Full report: AR XXX Study report Robustness of SIMU™ self-test for HIV 12O to environment 1435 Study dates: July 2014 1436 Lots: AAA, FGH, PRQ (Y1234-B), BBB, HGF, QRP (Y1234-O). Lot AAA was a lot used for stability 1437 evaluation and was at the end of its assigned life. All lots are made to finalised documentation and 1438 validated scale by the manufacturing department. 1439 IFU version: v1.0 1440 Conducted by: Joe White and Dave Fastings, Research and Development Dept., THE Manufacturing 1441 Company 1442 Testing: Performed on site, Headquarters company environmental chambers. 1443 Specimens (see “QC panel members, their criteria, and rationale for inclusion in the panel”.) 1444 QC 123, QC 124, QC 302 and 10 recent negative whole blood specimens 1445 QC 506, QC 507 (HIV-1 and -2 spiked OMT) and QC 500 (negative oral fluid)
1446 Study objective 1447 To verify that the device will function according to the intended use and the documented claims 1448 with respect to the temperature and humidity of the environment and to the time between 1449 opening the pouch and starting the assay. (Design input requirement 4.1.1 and Essential Principle 1450 B 5.2.3) 1451 Planning 1452 This is a large study, covering many variables and a statistically designed experiment was followed. 1453 The planning risk evaluation also found “one-at-a-time” experimentation unlikely to be able to fully 1454 explore interactions between the variables. 1455 The experimental design covers temperature, humidity and time out of the pouch as the variables 1456 using expected specimen volume. In addition, for fingerstick blood (as mimicked by the QC 1457 specimens) twice the expected volume was used to ensure a “worst case” for potential back-flow. 1458 The design has the power to detect a change of 0.5 of a calibration scale unit. 1459 From the design input risk assessment: 1460 1. The device is likely to be used in environments of high and low humidity and extremes of 1461 temperature. The study is to evaluate if the device is usable at 6– 45°C and humidity range 1462 from 20 to 90%. Although the instructions for use indicate the device must be used 1463 immediately the pouch is opened, risk assessment and preliminary work showed that a 1464 naïve user is likely to take between 10 to 40 minutes before adding specimen to the device 1465 and activating the flow. 1466 2. Published information indicates that devices using cassette format should be subjected to 1467 the follow investigation: failure to flow to completion, back-flow after apparent completion 1468 owing to evaporation from the absorbent materials, skew flow, and failure to clear 1469 haemoglobin from the reading area
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1470 3. The risk assessment for this procedure found that the age of the device might affect the 1471 outcome. A lot already used in stability studies (i.e. pre-stressed and then stored at 45°C for 1472 24 months) was incorporated into this study. 1473 Study protocol summary 1474 Sufficient devices for each experiment were equilibrated in the environmental chambers at THE 1475 Manufacturing Company. The devices were used according to the IFU but with specimen being 1476 added by pipette. The results were read as soon as the dye cleared the result window and again 1477 after 12 and 24 hours. Each reading was confirmed by a second observer, unaware of earlier 1478 results. 1479 Results 1480 1481 Summary of test results: QC 124 tested on lot AAA 1482 The results for testing QC 124 on lot AAA under the conditions described above are summarised in 1483 Table 7.3.2.1-1.
1484 A sample of test results from one section of this sample study is shown here for 1485 illustrative purposes.
1486 Table 7.3.2–1: Results for panel member QC 124: Lot AAA Humidity Temp. Time pouch open Reader 1 Reader 2 Signal Exp # % °C min 1 90 10 40 3 3 3 2 20 47 40 2 3 2.5 3 90 10 2 2 3 2.5 4 90 47 40 3 3 3 5 20 10 2 3 2 2.5 6 20 10 40 3 3 3 7 20 47 2 3 2 2.5 8 90 47 2 2 2 2 1487 The analysis of results for QC 124 on lot AAA shows a slight effect from the time the pouch was 1488 opened, but no effect from humidity or temperature and no interactions:
1489 Table 7.3.2–2: Analysis showing change in signal once pouch opened Signal = b0 + b1*Pouch Confidence range P value Standard Error -95.00% 95.00% t Stat b0 2.3 0.00 0.13 2.0 2.7 17.8 b1 0.01 0.03 0.005 0.002 0.025 2.8 ANOVA Source SS SS% MS F F Significant df Regression 0.5 57.0 0.5 8.0 0.03 1.0 Residual 0.4 43.0 0.1 6.0 Total 0.9 100.0 7.0 1490 1491 Although there is a slight statistical effect from the time after opening of the pouch, it is not of 1492 practical importance. This effect was not seen with any other QC panel members regardless of the
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1493 lot used for testing. Full data on file at THE Manufacturing Company. The analysis of results in this 1494 study suggest that there was no indication of back-flow nor of skew flow.
1495 Conclusion 1496 There is no impairment of function under these conditions with neither new nor aged lots, nor with 1497 whole blood specimens. The result is stable for at least 24 hours after use. Thus the input 1498 requirements (5.8.6, 5.10.1), have been verified and the device is suitable for validation in clinical 1499 evaluation trial under expected user conditions.
1500 References to designed experimentation: 1501 Understanding industrial designed experiments Schmidt, SR & Launsby, R.G. Air 1502 Academy Press 1503 Design and Analysis of Experiments Montgomery, DC Wiley 1504 NIST/SEMATECH e-Handbook of Statistical Methods, 1505 http://www.itl.nist.gov/div898/handbook/ accessed 2015-11-15 1506
1507 7.4 Establishing clinical performance of SIMU™ self-test for HIV 12O 1508 device for professional use and self-testing 1509 COMMENT 1510 Studies to support claims for self-testing may be established concurrently with those 1511 being undertaken for professional purposes. However, it is highly recommended that 1512 qualification of usability is undertaken before embarking on clinical performance 1513 studies for self-use, to ensure that the product and its labelling are “fit for purpose”.
1514 7.4.1 Part 1: Clinical performance evaluation - professional use
1515 Summary of protocol 1516 Refer Protocol: AP XXX
1517 Objective 1518 The objective of the study is to evaluate the device performance when testing is undertaken by 1519 professional users for all validated specimen types. 1520 One group of intended users for this device is healthcare workers (nurses, counsellors, laboratory 1521 technicians) in rural locations. These users are considered a realistic representation of professional 1522 users. In this study the professional user will obtain the specimen, load and run the device and 1523 interpret the result.
1524 For WHO Prequalification, performance must be established with each specimen 1525 type claimed in the IFU. It is not acceptable that comparison evaluations are 1526 performed only on a small number of specimens, apart from initial testing to 1527 establish analytical claims.
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1528 In this study, the performance of both configurations of the device will be evaluated for both 1529 fingerstick blood and OMT, respectively. Ideally both specimen types will be obtained from the 1530 same individuals at the same visit, but this is not a study requirement. 1531 Validation of the device for its intended use will be performed after verification of the device and 1532 before clinical validation for self-testing.
1533 Planning 1534 Clinical Performance Study Sites: The device will be evaluated in:
1535 Four primary care centres in resource limited settings in two countries on different 1536 continents. The primary care centres will be chosen based on a high prevalence of HIV and 1537 familiarity with rapid tests as a means of diagnosing HIV. 1538 One sexually transmitted infection (STI) clinic, representing a high risk group, 1539 One blood bank where specimens represent a low risk group. 1540 1541 The sites themselves will be selected to meet the requirements of identifying patients with varying 1542 levels of education, proportion of HIV infected patients, different ethnicity etc., as outlined in 1543 protocol AP XXX.. 1544 Reference standard: For each patient tested, a venous blood specimen will also be collected for 1545 testing using the reference standard (the comparator assay in a validated algorithm). Testing of this 1546 specimen will take place in at THE Manufacturing Company. As the STARD Statement 1547 (http://www.equator-network.org/reporting-guidelines/stard/) refers to the reference standard as 1548 “the best available method for establishing the presence or absence of the target condition”, all 1549 venous blood specimens will be tested initially using a CE marked HIV 1.2 (O) “fourth generation” 1550 EIA with proven performance in international External Quality Assurance Schemes. Reactive results 1551 will then be subject to a validated testing algorithm. 1552 Participants: Consent for participation in the study will be obtained from participants on their 1553 arrival at the clinic. Participants will be unselected.
1554 HIV testing. The study participants will provide consent to undergo additional HIV 1555 testing with both the index test (the SIMU™ self-test) and the reference standard, in 1556 addition to the routine, standard of care routinely used at the clinic for HIV testing. 1557 Blood donor patients. A consenting local blood bank population will be evaluated to 1558 obtain an estimate of specificity on a low risk population. In addition to routine blood 1559 bank testing for haemoglobin using capillary blood, a second fingerstick drop and an 1560 OMT specimen will be obtained for the SIMU™ self-test . 1561 The test will also be evaluated on 450 known HIV-1 positive individuals and at least 50 1562 with infection with HIV-2 when recalled for testing, using both OMT and fingerstick 1563 blood, simultaneously in three of the four primary care centres involved. For sufficient 1564 clinical evidence to make a claim relating to detection of HIV-2 antibodies, a further 50 1565 stored positive HIV-2 positive specimens will be tested.
1566 Materials used 1567 The study will use three lots of each configuration of the device (Y1234-B and Y1234-O) that will be 1568 made with independent critical materials (antigens and monoclonal antibodies from separate 1569 growths; purchased nanoparticles, biologicals and membranes of different lots) to maximise 1570 differences between the lots and ensure any likely variability in sensitivity and particularly 1571 specificity is detected.
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1572 The lots will be manufactured to validated scale, on finalised instruments and to finalised 1573 documentation. 1574 Different sites will receive different lots. 1575 Testing will be conducted using a finalised pictorial guide (job aid) as well as an IFU that has been 1576 finalised except for performance data. No training will be given to participants beyond the written 1577 documentation provided with the devices.
1578 Interpreting results 1579 Invalid results will be recorded and reported at all centres. 1580 Any questions regarding the interpretation of the IFU by the user will be recorded and reported. 1581 Reactive results: Participants who have a specimen (whole blood or OMT) that is reactive in either 1582 the index test (the SIMU™ self-test for HIV 12O) and/or the 4th generation EIA will be further 1583 tested using the venous blood specimen to enable full characterization using a validated testing 1584 algorithm. 1585 For any specimens that are non-reactive with OMT, but reactive on the reference standard, the 1586 venous blood specimen will be further tested for evidence of anti-retroviral therapy, known to 1587 repress antibody expression in oral fluid. 1588 When possible, any specimens with discrepant results will have the index test repeated on all lots, 1589 and both configurations of the device.
1590 Criteria 1591 To meet the WHO PQ requirements of sensitivity and specificity for professional use (lower bound 1592 of the 95% confidence limit to be greater than 99% for sensitivity and greater than 98% for 1593 specificity).
1594 Study summary report: SIMU™ self-test for HIV 12O Clinical Performance – Professional Use Protocol AP XXX Full Report AR XXX – refer Annex XXX Clinical Performance – Professional Use Full Report December 2013 Study Dates September 2012 – November 2013 Lots Y1234-B AAA expiry end 12/14 SIMU™ self-test for HIV-12O for use ACR expiry end 4/15 with whole blood NRT expiry end 02/16 IFU version v 1.0 pictorial guide v 2.0 Y1234-O AAA (a) expiry end 12/14 SIMU™ self-test for HIV-12O for use ACR (a) expiry end 4/15 with oral mucosal transudate NRT(a) expiry end 02/16 IFU version v 1.0 pictorial guide v 2.0
Conducted by A Blog, Research and Development Dept., THE Manufacturing Co™
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Testing On site, Headquarters
1595 Composition of each lot: 1596 Evidence of different composition (i.e. independent) lots, refer following figure:
1597 Table 7.4.1–1: Lot composition Material Manufacturer's lot Used in SIMU lot Comment 123 AAA Membrane 456 ACR 789 NRT HIV-1/2 fusion 01/03/2010 AAA In-house culture and purification Lot protein 03/10/2012 ACR 01/03/2010 was approaching the end (recombinant) 01/01/2012 NRT of its validated shelf life B-432 AAA Nano-particles B-502 ACR B-111 NRT 04/02/2008 AAA HIV-1 (O) 03/09/2010 ACR In-house FMOC synthesis peptide 03/05/2010 NRT 31/08/2011 AAA In-house culture and purification. Lot Monoclonal 06/03/2012 ACR 31/08/2011 was approaching the end 03/01/2013 NRT of its validated shelf life K-1134-2 AAA Indicator dye K-1134-9 ACR K-1134-13 NRT
1598 Clinical Performance Study Sites 1599 WHO expects result sheets, submitted in a form readable in Excel, from studies 1600 conducted in at least two geographically distinct sites. These sites should be 1601 representative of countries where this IVD is likely to be used in large volumes e.g. 1602 Sub-Saharan Africa.
1603 Leading investigators: see returned agreement sheets and result sheets
1604 Results 1605 A sample of study results have been included in this section and are shown here to 1606 illustrate the kinds of information and the detail of analyses that might be required 1607 for a product dossier. Manufacturers are expected to present all summary and raw 1608 data relevant to performance claims in their product dossiers.
1609 Table 7.4.1–2: Results from blood bank testing of fingerstick blood Blood Bank: Testing of Fingerstick Blood Results of SIMU™ self-test for HIV 12O vs Reference Standard
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Lot # tested Simu Simu Simu Simu Sensitivity Specificity (95% CI) number Reactive reactive/ reactive/ Negative True False positive positive AAA 400 2* 1 1* 398 100%** 99.7 (99.3-100) % ACR 400 0 0 0 400 - 100.0(100–100) % NRT 406 2 0 2* 404 99.5 (98.8–100)% Overall 1206 4 1 3 1202 100%** 99.8 (99.5–100)% 1610 * Re-testing the reactive specimens on all lots gave exactly the same results, there was no lot to lot difference noted. 1611 ** The sample size (n=1) is too small to make this a statistically meaningful estimation of sensitivity. 1612 There were no invalid runs recorded. 1613 A total of 4 whole blood specimens were reactive in the SIMU™ self-test for HIV 12O. Three of 1614 these specimens were negative for HIV antibodies according to the reference standard. The 1615 remaining specimen was confirmed as a true HIV antibody positive specimen and was removed 1616 from the calculation of specificity.
1617 Table 7.4.1–3: Results from blood bank testing of OMT Blood Bank: testing of Oral Mucosal Transudate Results of SIMU™ self-test for HIV 12O vs Reference Standard Lot # tested Simu Simu Simu Simu Sensitivity Specificity (95% CI) number Reactive reactive/ reactive/ Negative True False positive positive AAA 400 2* 1* 1* 398 100%** 99.7 (99.3-100) % ACR 400 1* 1* 399 - 99.8 (99.3-100) % NRT 406 2* 2* 404 99.5 (98.8–100)% Overallǂ 1206 5 1 4 1201 100%** 99.6 (99.2–99.9)% 1618 * Re-testing the reactive specimens on all lots gave exactly the same results, there was no lot to lot difference noted. 1619 ** The sample size (n=1) is too small to make this a statistically meaningful estimation of sensitivity. 1620 There were no invalid runs recorded. 1621 A total of 5 OMT specimens were reactive in the SIMU™ self-test for HIV 12O. Four of these 1622 specimens were non-reactive according to the reference standard. The remaining specimen was 1623 confirmed as a true HIV antibody positive specimen and was removed from the calculation of 1624 specificity. With one exception, all paired specimens agreed (i.e. the matching fingerstick blood 1625 specimen results and the OMT results, from the same donor).Only one OMT specimen that was 1626 initially identified on lot ACR gave a false reactive result on OMT but was non-reactive on the 1627 matching fingerstick blood specimen.
1628
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1629 Table 7.4.1–4: Results from STI centre testing of OMT STI Centre: Testing of Oral Mucosal Transudate Results of SIMU™ self-test for HIV 12O vs Reference Standard Simu Simu Simu Sensitivity* Lot reactive/ reactive/ Simu # tested non reactive/ * Specificity (95% CI) number True False Negative False negative (95% CI) positiveǂ positive ACR 200 6* 1* 0 193 100%** 99.5 (97.2-99.9) % NRT 450 7* 2* 1*** 441 87.5 99.7 (98.7–99.9)% (47-97)% 1*** 92.8 Overall 650 13 3 634 99.5 (98.6–99.8)% (66-98)% ** 1630 ** The sample sizes are too small to make these statistically meaningful estimates of sensitivity. 1631 ǂ True HIV status determined according to the reference standard. 1632 *** All but one OMT specimens were reactive in the SIMU™ self-test for HIV 12O. The single non-reactive specimen was 1633 obtained on a patient at his initial presentation to the clinic. It was his first HIV test. The results were repeatedly reactive 1634 on both the reference test and on the whole blood version of the assay. Further testing revealed the patient was 1635 positive to HIV-1 IgM on Western Blot and HIV-1 antigen positive. The specimen was also negative on other whole blood 1636 rapid assays from two other manufacturers (data on file) and biochemical assays did not detect evidence of ART. The 1637 patient was classified as a seroconvertor. HIV antibodies are unlikely to be detected by the SIMU™ self-test for HIV 1638 12O when testing in OMT from seroconverting subjects. Information reflecting this limitation of the test will include in 1639 the final version of (both) the IFU (and job aid). Follow up testing of this patient was conducted 5 days later using OMT, 1640 fingerstick and venepuncture specimens. The OMT specimen was reactive on all lots of the device and again reactive 1641 using the reference standard. This reinforced the conclusion that the patient was seroconverting at the time of the 1642 initial visit. The specimen retested on recall was negative on another manufacturer’s OMT-validated EIA, implying that 1643 the SIMU™ HIV 12O self-test is state of the art for oral mucosal transudate 1644 Insert table with the following results: 1645 “STI Centre: Testing of Fingerstick Blood 1646 Results of Simu self-test for HIV 120 vs Reference Standard”
1647 1648 Comparison of results between testing using fingerstick blood with OMT revealed that identical 1649 results were obtained on all lots of device with the single exception discussed above. 1650 The OMT discrepant results were identical on all lots of the device, i.e. both had the same false 1651 negative and false positives. The false positives were common between fingerstick and OMT, and 1652 the false positive specimens were also positive on other lots of the product when tested using the 1653 venous specimen collected for reference testing. 1654 There was one invalid result recorded on a fingerstick specimen on lot ACR. The patient was 1655 retested in duplicate and found (true) negative on both occasions on lots ACC, ACR and NRT. The 1656 cause of this problem was not identified, and no other invalid results were reported on lot ACR in 1657 the approximately 2,500 occasions for which data was available (collated and on file in QA at THE 1658 Manufacturing Company ).
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1659 Table 7.4.1–5: Results from primary care centres (PCCs) in Africa for fingerstick blood in known 1660 HIV-1 positive patients
1661 Results of Simu self-test for HIV 120 vs Reference Standard Sensitivity Site # tested True Positiveǂ False negative (95% CI) 100 PCC1 180 180 0 (98.0–9.9)% 100 PCC2 70 70 0 (94.9–9.9)% PCC3 200 200 0 100 (……..) % 100 Overall 450 450 0 (98.5–99.9) % 1662 ǂ True HIV status determined according to the reference standard.
1663 Insert table with the following results: 1664 “Results from primary care centres (PCCs) in Africa for Fingerstick Blood in known 1665 HIV-2 positive patients 1666 Results of Simu self-test for HIV 120 vs Reference Standard”
1667 1668 Insert table with the following results: 1669 “Results from primary care centres (PCCs) in Africa for Oral Mucosal Transudate in 1670 known HIV-1 positive patients 1671 Results of Simu self-test for HIV 120 vs Reference Standard”
1672 1673 NOTE: Insert table with the following results: 1674 “Results from primary care centres (PCCs) in Africa for Oral Mucosal Transudate in 1675 known HIV-2 positive patients 1676 Results of Simu self-test for HIV 120 vs Reference Standard”
1677
1678 Table 7.4.1–6: Overall Summary Professional clinical performance study, by site and by lot Site Lot # # Positive False False Negative Sensitivity Specificity tested reactive negative (95% CI) (95% CI) Fingerstick AAA DATA DATA DATA DATA DATA DATA DATA Blood ACR DATA DATA DATA DATA DATA DATA DATA Bank NRT DATA DATA DATA DATA DATA DATA DATA
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Site Lot # # Positive False False Negative Sensitivity Specificity tested reactive negative (95% CI) (95% CI) Overall DATA DATA DATA DATA DATA DATA DATA AAA DATA DATA DATA DATA DATA DATA DATA ACR DATA DATA DATA DATA DATA DATA DATA STI clinic NRT DATA DATA DATA DATA DATA DATA DATA Overall DATA DATA DATA DATA DATA DATA DATA Site A AAA DATA DATA DATA DATA DATA DATA DATA Site B ACR DATA DATA DATA DATA DATA DATA DATA Site C NRT DATA DATA DATA DATA DATA DATA DATA TOTAL DATA DATA DATA DATA DATA DATA DATA Oral mucosal transudate AAA DATA DATA DATA DATA DATA DATA DATA Blood ACR DATA DATA DATA DATA DATA DATA DATA Bank NRT DATA DATA DATA DATA DATA DATA DATA Overall DATA DATA DATA DATA DATA DATA DATA AAA DATA DATA DATA DATA DATA DATA DATA ACR DATA DATA DATA DATA DATA DATA DATA STI clinic NRT DATA DATA DATA DATA DATA DATA DATA Overall DATA DATA DATA DATA DATA DATA DATA Site A AAA DATA DATA DATA DATA DATA DATA DATA Site B NRT DATA DATA DATA DATA DATA DATA DATA Site C NRT DATA DATA DATA DATA DATA DATA DATA TOTAL DATA DATA DATA DATA DATA DATA DATA
1679 Comments: 1680 All true HIV antibody-positive specimens from non-seroconverting subjects were found to be 1681 reactive on all the lots of the device. All reactive initially specimens were confirmed by use of the 1682 validated algorithm THE Manufacturing Company . 1683 There is strong evidence that the single falsely-negative OMT specimen arose from a 1684 seroconverting patient. 1685 Only one of 3588 test runs was invalid. Its origin is unclear but no further invalid runs were found 1686 on the implicated lot, nor on any of the other lots used in this trial.
1687 Conclusion 1688 The Y1234-B SIMU™ self-test for HIV-12O device when used with fingerstick blood meets the 1689 requirements for professional use as defined in the design input requirements, and the WHO 1690 requirements. 1691 The Y1234-O SIMU™ self-test for HIV-12O was not as sensitive using OMT since early 1692 seroconversion was not detected on two specimens; however, 100% of non-seroconversion 1693 specimens were detected with OMT as the specimen. Information reflecting the limitation of the 1694 device for seroconverting users will be reflected in the final version of [both] the IFU [and job aid].
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1695 7.4.2 Part 2: Qualification of Usability (Validation of labelling and device 1696 interpretation for self-testing; Observed self-testing in trained and 1697 untrained users) 1698 NOTE: For the purposes of this sample dossier; apart from the user of the device, the 1699 design, composition and operation of the SIMU™ self-test for HIV 12O device is 1700 identical as that used for professional use. 1701 PURPOSE 1702 The purpose of this section of a product dossier is to assess product design, IFU and 1703 usability of devices intended for self-testing. Three main areas of investigation are 1704 expected to be undertaken (summarized below). Each of these studies (either alone 1705 or in combination) may prompt design changes (in device and/or IFU, etc.), making it 1706 likely this would be a process of iterative refinement and one best conducted well in 1707 advance of clinical testing. 1708 - Comprehension of labelling. Questionnaire, or similar, testing undertaken to 1709 assess the ability of users to correctly comprehend key messages from all device 1710 packaging and labelling (including IFU and/or job aid). Participants would be 1711 expected to be representative of intended users of the device and include those 1712 with different levels of education and socioeconomic status. 1713 - Interpretation of results. Testing with non-functional devices (or a simulation) 1714 that are modified to display contrived results to assess the ability of untrained 1715 users to correctly interpret results (e.g. non-reactive, weakly-reactive, etc). 1716 Participants would be expected to be representative of intended users of the 1717 device and include those with different levels of education and socioeconomic 1718 status. 1719 - Observation of untrained users. Self-test-aware professionals (e.g. health care 1720 workers, etc) are used to conduct self-testing on their own specimens. 1721 Consideration of medical ethics may require that the participants in such a study 1722 not be provided a true HIV result, in which case a modified device (provides 1723 control line, but no test line) would be used. A second group of healthcare 1724 workers would be used as observers to assess the progress of self-testing as well 1725 as compliance with IFU and other instructional materials. 1726 - The usability of the finalized device (and finalized labelling) must also be 1727 assessed in a clinical setting, preferably in a study that includes a high-risk, high- 1728 prevalence population (to ensure adequate representation of HIV negative and 1729 positive subjects).
1730 The assay is intended to be used by untrained individuals, unfamiliar with how to perform a test 1731 and possibly with little knowledge of the languages used in the IFU (See Annex IV Design input 1732 FMEA 3.3.2 and Annex V User and patient FMEA). 1733 1734 The job aid was designed by taking into account not only similar materials used for other common 1735 self-test products but also advice from relevant behavioural scientists. Validation of device usability 1736 was conducted in three (potentially) interactive stages: 1737 Questionnaire study
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1738 Pre-made cassette (contrived results) study 1739 Observation of trained users 1740 It was anticipated that these studies might result in changes being made to either the design of the 1741 device or the job aid, etc. Consequently, these studies were conducted prior to commencement of 1742 investigation of clinical performance of the finalised device when used for self-testing by (observed) 1743 untrained participants.
1744 7.4.2.1 Part 2-a: Validation of label comprehension for finger stick and OMT job aid and 1745 IFU 1746 Study objective 1747 To validate the job aid and IFUs provided for self-testing in either fingerstick whole blood or OMT. 1748 Study design 1749 Subjects involved in this validation will be members of the general public selected to be a 1750 representative cross-section of intended users of the device. Participants will and have a range of 1751 educational attainments, including approximately equal proportions with graduate, high school, 1752 and elementary school education and those with no functional literacy. The educational level will 1753 be recorded on the worksheet along with the testing results and, so far as possible, a range of other 1754 information about the patient. Participants will also represent a range of socioeconomic statuses 1755 and demographies. 1756 1757 Participants were divided into two groups of approximately equal sizes. One group asked to 1758 complete the finger stick whole blood questionnaire (TMC-X-XXX-X 1234-B); the other group asked 1759 to complete the OMT questionnaire ((TMC-X-XXX-X 1234-O). Both questionnaires comprised 1760 several questions designed to assess participants’ comprehension of key messages in device 1761 labelling. The questions set in both questionnaires and summarized in Tables 7.4.X.X and 7.4.X.X, 1762 respectively. 1763 1764 It is a Manufacturer’s responsibility to formulate usability questions for a study 1765 of this type in a way that is directly relevant to validating that device. A useful 1766 source is the FDA document 1767 http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/A 1768 pprovedProducts/PremarketApprovalsPMAs/UCM312534.pdf .
1769 1770 Study results 1771 Manufacturers are expected to provide both summary results and full study data 1772 in their product dossiers.
1773 1774 Acceptance criteria 1775 Observed comprehension scores for either configuration of the device must be greater than XX%. 1776 Study conclusion
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1777 Overall comprehension scores were observed to be XX%. The labelling for both configurations of 1778 the device appears to be suitable for self-testing in the intended population of users. 1779
1780 7.4.2.2 Part 2-b: Validation of result interpretation of results from pre-made Y1234-B/O 1781 cassettes 1782 Study objective 1783 The study will aimed to evaluate the ability of potential self-testers to interpret the results on non- 1784 functional devices pre-prepared with the following results: 1785 Reactive results (3 prepared devices each read by 200 subjects), 1786 Non-reactive results (5 prepared devices each read by 200 subjects), 1787 Invalid results (2 prepared devices each read by 200 subjects), and 1788 Reactive results with Test lines approaching non-reactive/weak test line (3 prepared 1789 devices each read by 200 subjects). These cassettes were developed by the R&D group to 1790 simulate very early whole blood seroconversion specimens 1791 1792 Study design 1793 The same participants recruited for study TMC-X-XXX-XXXXX-X (Validation of label comprehension 1794 for finger stick and OMT) will be used in this study. Interpretation of the result will be recorded by 1795 the subjects on a simple form (TMC-X-XXX-XXX-1234B/O), which will include the number of the 1796 device (to enable collation of expected and recorded results) and a set of check boxes, positive, 1797 negative, invalid, (in line with the pictorial guide) plus “don’t know”:
1798 Figure 7.4.2–2: Form for recording results of prepared devices THE Manufacturing Company Form for recording results of prepared devices Record your interpretation of the result of each device: Use the pictorial guide for examples of each possible result Note the number written on the device, and then: Tick the box corresponding to your interpretation for that device – or tick the “don’t know” box
Don’t Device # Positive Negative Invalid know
1 □ □ □ □
2 □ □ □ □
1799 Results of this study 1800 Carton and Pouch labelling 1801 Carton
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1802 The carton is required to be discrete (design input 3.3.1 e) and has only a small amount of text. 1803 There were no recorded problems with opening this box. Users commented that it was discrete 1804 and gave no indication of the purpose of its contents. 1805 Pouch 1806 Of the 100 European subjects: 1807 95% opened the pouch correctly 1808 100% were able to extract the materials 1809 80% reviewed the pictorial guide before starting 1810 The 20% who did not were still able to collect the sample, load and start the device as they 1811 moved step by step through the procedure, 1812 10% of all subjects collected the specimen incorrectly. 1813 100% interpreted the result as required after flow was complete. 1814 The observers noted that in all cases the Control line was clearly visible, with no invalid 1815 results being obtained. 1816 Of the 100 non-European subjects: 1817 98% opened the pouch correctly 1818 100% were able to extract the materials 1819 95% reviewed the pictorial guide before starting 1820 15% failed to obtain or load specimen appropriately… 1821 Conclusions 1822 Conclusions on labelling 1823 The study showed the labelling to be appropriate. Failure to obtain the specimen appropriately 1824 was found to be due to the diagrams which were not sufficiently clear on lancet use (clearer 1825 instruction required for user to puncture the finger from the side, not directly into the finger pad) 1826 and on the method of obtaining oral mucosal transudate (clearer instruction required to show that 1827 the OMT collection device should be rolled, not brushed). 1828 The job aid/pictorial guide was modified with this information and re-evaluated on a small set of 1829 new subjects in Africa. In this study (50 subjects) all collected the specimen correctly. All reported 1830 work up to this point was against the IFU v1.0 which remained unchanged. 1831 Conclusions on interpretation of results on pre-made cassettes 1832 All clear positive, negative and invalid results were interpreted correctly. 1833 The borderline positive result was interpreted as positive on 94.5% of the readings by the 200 1834 subjects and invalid by zero. There was no statistical difference between the devices – each was 1835 equally likely to be misinterpreted. There was a difference between subjects – some 6%, (12 1836 individuals) being less able to resolve the devices as positive. (ANOVA data, on file) 1837 Overall conclusion on this study 1838 The overall conclusion is that health-care workers with exposure to self-testing but no exposure to 1839 self-testing with OMT specimens or with cassette devices can follow the job aid (version 1.0) 1840 adequately and can interpret results. It was within the design of the experiment that some 5 - 10 % 1841 of the subjects would not be able to correctly visualise the prepared very weak specimen 1842 results. The cassettes with these weak Test bands were developed to have a detectability of 1843 around 19 times from 20 readings by people with normal vision. Thus, the 6% found to have 1844 difficulty was as expected. 1845 A similar set of studies were undertaken to validate the IFU. See Attachment XYZ.
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1846 7.4.2.3 Part 2-c Validation of device usability by observed self-testing in trained users 1847 Study objective 1848 To evaluate device performance (including collection materials, IFU and job aid, test result and 1849 result interpretation) in professional, trained testers conducting observed self-testing. 1850 Study design 1851 The following population will be chosen for this evaluation: 1852 Health-care workers, including nurses and counsellors, and laboratory technicians 1853 Individuals who had used self-test but not with OMT in cassette-format 1854 10 to 30 individuals at each of 10 sites geographically dispersed (STI or primary care 1855 centres in Europe, Africa and Asia) 1856 Manipulated devices will be used (devices manufactured to complete, finalised manufacturing 1857 documentation with the exception that the components of the Test line will be replaced with fish- 1858 protein) as the status of the assay at this stage of development was Research Use Only, hence no 1859 HIV result will be provided to the subjects. An effectively run assay will result in a reaction at the 1860 control line, as in a non-manipulated device. The manipulated device will be packaged with the 1861 OMT collection device, the zip lock bag for disposal of used materials and job aid. IFU will not be 1862 included. 1863 1864 For WHO Prequalification, validation of device usability must be established with 1865 each specimen type claimed in the IFU.
1866 Observers 1867 Observers will be health-care workers, selected for their appropriate training and given further 1868 training in subject observation and data recording. 1869 Ethics approval will be sought from all institutions concerned. 1870 Study protocol 1871 The subjects will be given the boxed device, asked to conduct a test using their own specimen. The 1872 subjects will be given no further instruction and will be observed during the process. 1873 The subjects of these evaluations will be asked to note their observations on a prepared comment 1874 sheet (see below) written in the local language and provided immediately after the device has been 1875 used. 1876 The observers of these evaluations will make notes discreetly, while appearing to attend to other 1877 activities, without interacting with subjects. This may cause some bias but is deemed necessary as 1878 an output of the pre-study risk assessment and evaluation. 1879 Acceptance criteria 1880 The subjects will be expected carry out the following steps correctly in the following order: 1881 1. to open the carton, the pouch containing the OMT collection device at the correct end, and 1882 then open the pouch containing the cassette at the correct end, 1883 2. find the pictorial guide, 1884 3. with the materials before them the subjects should study the guide, collect the specimen, 1885 load it into the device, check for the correct volume by observing the dye in the chamber, 1886 then start the test. 1887 4. finally they should wait until the dye had cleared from the result window and check the 1888 result.
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1889 The following is a selection of aspects the observers will be asked to monitor: 1890 Observers will be asked to note particularly whether the subjects studied the whole guide 1891 before starting or if they looked at the guide as they performed each step without first 1892 reviewing the whole of the guide. 1893 The observers will be asked to record how the subjects obtained the oral mucosal 1894 transudate, according to the job aid or in some other way. 1895 The observers will also be asked to record whether the subjects read the result (the Control 1896 line in this case) after at the correct time – when flow was complete, not before.
1897 Figure 7.4.2–1: Extract of the form for recording comments and observations THE Manufacturing Company. – Extract of the form for recording comments and observations Question Yes No Comments / observations Did the carton or opening the pouch present any
problems? □ □ … Were you able to understand the diagram explaining how to use the sponge to obtain oral □ □ mucosal transudate? Did you roll the sponge along the tooth-gum line
or did you use it like a tooth-brush? □ □ Were you able to transfer the sponge to the loading port of the device and then rotate the □ □ sponge to squeeze out the fluid? Did you check the blue dye in the window? □ □ Was the window clear of dye after you rotated
the sponge? □ □ … Could you easily decide when to read the result? □ □ … 1898 Study results 1899 The results of this study would indicate the appropriateness of the job aid for use with patients who 1900 have difficulty reading a classic IFU. 1901 Note: If this, or other studies indicate improvements to the job aid are required, studies will be 1902 repeated until the job aid is determined to be effective in this group of professional subjects. 1903
1904 7.4.3 Part 3: Clinical performance evaluation – self testing 1905 Study objective 1906 The device is intended for self-testing by untrained individuals in resource limited settings. The 1907 design input documents require that the devices for OMT and for fingerstick blood, both must 1908 meet WHO performance validation criteria, in addition to meeting all the other input requirements.
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1909 Validation in self-testing population is to take place after validation for professional use and 1910 subsequent to validation of labelling (including instructions for use, IFU) and device interpretation 1911 by these intended users. 1912 Planning 1913 Location: Risk assessment of this aspect of device validation at THE Manufacturing Company found 1914 that it would be preferable to use those centres (at least two centres on each of two continents) 1915 that took part in the earlier evaluation of the device with professional users. They would already 1916 have an understanding of its attributes and be able to interpret the result from the device after the 1917 untrained user had completed judgement but before a reference result had been issued. 1918 The study was approved by the ethical committee of THE Manufacturing Company and of all the 1919 institutions involved. The institutions received financial support to perform the work; the 1920 untrained subjects, hence forth referred to as “patients” for convenience, all gave informed 1921 consent prior to the study and did not receive any financial inducement. 1922 Reference test: The centres chosen routinely use 4th generation EIAs that perform well in 1923 international EQAS programmes. Reactive results are subjected to a validated testing algorithm. 1924 Participants: The study patients will be consented on arrival at the clinic. Patients are unselected, 1925 with the exception of the need to provide matched specimens (see below) and tested in order of 1926 registration at the centre. 1927 Each centre will test at least 250 patients, of whom ~25% are a risk group for HIV infection. 1928 The patients involved in this validation will be a representative cross-section of those 1929 attending the centre, and have a range of educational attainments, including approximately 1930 equal proportions with graduate, high school, and elementary school education and those 1931 with no functional literacy. The educational level will be recorded on the worksheet along 1932 with the testing results and, so far as possible, a range of other information about the 1933 patient. 1934 Only patients with matched specimens (OMT, fingerstick blood and venous whole blood for 1935 reference testing) will be enrolled. 1936 The patients will be observed by a health care worker (HCW) who will in no manner 1937 intervene until after the patient has declared that they have completed the procedure and 1938 interpreted the outcome. Only at this point with the HCW record any non-adherence to the 1939 IFU or any adverse event. 1940 Materials used: 1941 Three lots of the device made with independent critical materials (antigens and monoclonal 1942 antibodies from separate growths; purchased nanoparticles, biologicals and membranes of 1943 different lots) to ensure maximum differences between the lots to ensure any likely 1944 variability in sensitivity and particularly specificity is estimated. 1945 The lots are to be manufactured to validated scale, on finalised instruments and to finalised 1946 documentation. 1947 IFU to be finalised except for performance data, job aid to be finalised. No additional 1948 training to be given. 1949 Each centre (at least two centres on each of two continents) will use at least two 1950 independent lots of the device on roughly equal number of patients per lot. 1951 Recording and interpreting results: 1952 Confirmation of test results: Results will be presented showing the performance relative to the 1953 true result – the antibody status of the patient. The true result for the patient is either the 1954 confirmed positive result from the centre’s confirmatory testing of the patient, or the reference 1955 centre’s evaluation of any discrepant specimens. Confirmation of the status of donors of
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1956 specimens found negative on the SIMU™ self-test for HIV-12O and the centre’s routine test are 1957 unlikely to be evaluated further. In the case of patients who have been long term on ART and who 1958 give negative HIV antibody test results during this study, the confirmed result by the reference 1959 centre shall be taken as the true result. 1960 The SIMU™ self-test for HIV-12O device will be evaluated on both OMT and fingerstick specimens 1961 from the same user. The OMT result will be obtained first and interpreted by the patient and 1962 privately by the health professional before progressing to the fingerstick. Any invalid runs will be 1963 recorded along with as much information as possible about the cause of the invalidity. 1964 Discrepant results: Any patients whose results are discrepant between any of OMT, fingerstick or 1965 the centre’s routine results will be re-evaluated by the healthcare worker in duplicate on both OMT 1966 and fingerstick using SIMU™ HIV 12O self-tests from each lot provided and recorded on the 1967 supplementary work sheet. Any remaining discrepancy will be resolved at the local reference 1968 centre, by following a validated testing algorithm. Results that are discrepant between the 1969 interpretation by the healthcare worker and the patient will be evaluated by a second healthcare 1970 worker unaware of the previous results; the results to be recorded on the supplementary 1971 worksheet. 1972 Criteria 1973 Greater than 95% concordance between patient and healthcare workers’ interpretation of result. 1974 >98% specificity and >99% sensitivity for fingerstick, from the healthcare workers’ readings, 1975 relative to confirmed true patient status. 1976 For OMT and fingerstick whole blood of known HIV positive patients, there must be >99% 1977 sensitivity unless the patient can be shown to be either pharmacologically immunosuppressed or to 1978 be seroconverting to HIV antibody positive (i.e. HIV antigen positive, HIV IgM positive). 1979 There must be no practical difference between lots (judged to be that results must be exactly 1980 concordant for positive specimens for all lots, and that when more than 500 true negative 1981 specimens are tested each lot must meet the >98% specificity requirement individually, not as part 1982 of an overall pool of specificity result). 1983 The overall invalidity rate must be < 1% 1984 Lot and centre information 1985 Lots used: AAB expiry end 12/15, ACS, expiry end 4/16 NRU expiry end 02/16 for fingerstick 1986 specimens, product code Y1234-B. 1987 Lot numbers AAB (a), ACS (a) and NRU (a) product code Y1234-O with the same expiry dates as 1988 above for oral mucosal transudate specimens. 1989 IFU version v 1.0: pictorial guide v 2.0
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1990 Table 7.4.2–3: Lot information Material Manufacturer's lot Used in SIMU lot Comment 155 AAB Membrane 444 ACS 987 NRU HIV-1/2 fusion 01/06/2010 AAB protein 30/08/2012 ACS In-house culture and purification (recombinant) 12/05/2012 NRU B-444 AAB Nano particles B-522 ACS B-114 NRU 04/07/2008 AAB HIV-1 (O) 13/02/2010 ACS In-house FMOC synthesis peptide 20/09/2010 NRU 03/07/2011 AAB Monoclonal 09/09/2012 ACS In-house culture and purification. 06/05/2013 NRU K-1177-2 AAB Indicator dye K-1777-9 ACS K-1177-13 NRU
1991 Table 7.4.2–4: Centres involved Centre Address Comparator device (s) (T1) Test lot Product Lot Expiry Manufacturer Code number date Blood bank DB Good Devices 1234 W23-14 3/16 AAB NRU STI A FR Good Choice ABC 1234 12/15 NRU ACS Ante-natal CA Fast Results 780 A-12-13 11/15 ACS AAB Remote A Narniar Good Maker 123 K123 5/16 AAB ACS Good Maker 123 K124 9/16 AAB ACS Remote B Bellasis Not As Good 2345614 RD-1-13 15/3/17 ACS NRU 1992 Dates of work: see returned result sheets for individual centres, overall from January 2013 to 1993 November 2014.
1994 WHO expects to see result sheets in a form readable in Excel from at least two 1995 geographically distinct centres representing a cross section of the centre attendees.
1996 Leading investigators: see returned agreement sheets and result sheets 1997 Example work sheets
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1998 Figure 7.4.2–5: Example result sheet 1999 In this sheet ST = self-test = patient, HCW = healthcare worker. 2000 The columns with those headings represent the result of interpretation (Reactive or Negative, + or -).
Centre: Address:
Date Patient # Oral mucosal transudate Fingerstick Comparator result True result HUST HCW STHU HCW
2001 Figure 7.4.2–6: Discrepancies: supplementary sheet Centre: Address
Repeat lot A Repeat lot B Patient # Initial discrepancy found Oral Finger Oral Finger Text describing the situation
2002 Figure 7.4.2–7: Patient information sheet Centre: Address:
Date Patient # Age Education Gender Pregnant/ Prior HIV ART Other disease Treatments Observations # of status children
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2003 Results
2004 Figure 7.4.2–8: Summaries, result sheets on file at THE Manufacturing Company Centre: Remote B Address: West Africa
Lot # # Prior HIV False False True Sensitivity Specificity Gender Pregnant Positive Negative Fingerstick tested status reactive negative Negative* (95% CI) (95% CI) 99.5 Male 130 36 Pos - 53 1* 0 76 77 100% ACS (97.2-99.9) % Female 205 2 Pos 121 12 0 0 193 193 100% 99.7 Male 108 12 Pos - 41 0 0 67 67 100% NRU (98.7–99.9)% Female 122 1 Pos 75 5 1* 0 116 117 100% 100 99.6 Overall 565 51 196 111 2 0 452 454 (97-100)% (98.4–99.9)% 2005
Centre: Remote B Address: West Africa
Lot # Gender # Prior HIV Pregnant Positive False False Negative True Sensitivity Specificity OMT tested status reactive negative Negative* (95% CI) (95% CI) Male Data Data - Data Data Data Data Data Data Data ACS Female Data Data Data Data Data Data Data Data Data Data Male Data Data - Data Data Data Data Data Data Data NRU Female Data Data Data Data Data Data Data Data Data Data Overall - Data Data Data Data Data Data Data Data Data Data
2006 All the newly discovered reactive specimens were evaluated at the local reference centre. The false reactive results were only found on fingerstick 2007 devices, not from the oral mucosal transudate of the same patient and were repeatable on both lots of the device at the testing centre and were
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2008 confirmed as false results at the local reference centre. All the donors of the other reactive specimens were confirmed as positive by PCR, and with the 2009 exception of 3 by Western blot. Those three were antigen positive and PCR positive. 2010 The age range for males 16 – 61, median age 25, average age 30; for females 18 – 61 median 22, average 26. 2011 The number of children per female ranged from 0 to 5, median 3 and average 2.2 2012 WHO expects to see the complete result, discrepancies and patient sheets from at least one centre in a form suitable for analysis in Excel.
2013 There should also be summary tables from each of the test centres in a form suitable for analysis in Excel, along with a commented analysis of the results, 2014 plus an overall summary
2015 Figure 7.4.2–9: Overall Summary for OMT
# Prior HIV False False True Sensitivity Specificity Centre Lot # Gender Pregnant Positive tested status reactive negative Negative (95% CI) (95% CI) A Male Data Data Data Data Data Data Data Data Data A A Female Data Data Data Data Data Data Data Data Data B Male Data Data Data Data Data Data Data Data Data A B Female Data Data Data Data Data Data Data Data Data A Male Data Data Data Data Data Data Data Data Data B A Female Data Data Data Data Data Data Data Data Data C Male Data Data Data Data Data Data Data Data Data B C Female Data Data Data Data Data Data Data Data Data And so forth Data Data Data Data Data Data Data Data Data Data Data Data Data Data Data Data Data Data Overall Data Data Data Data Data Data Data Data Data 2016 2017 A similar table for fingerstick whole blood results is in Annex XX.
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2018 If necessary further summary tables showing results from patients being treated with ART, 2019 antimalarial drugs, patients with recent immunisation, patients with concurrent disease (malaria, 2020 Chagas’ trypanosomiasis ,,, ) 2021 Of the known HIV-1 positive patients, Y specimens were found non-reactive on oral mucosal 2022 transudate , with variable reactivities on the routine assays at centre A, but reactive on matched 2023 fingerstick blood specimens, all were patients on long term ART. They had low antibody responses 2024 by S/CO ratio on EIA from A Very Good Company when evaluated at the reference centre and 2025 Western Blot patterns consistent with treatment. Of X OMT false negatives from patients of 2026 previously unknown HIV status, all were positive on matched fingerstick blood specimens and 2027 reference testing. All X were shown to be seroconversion specimens. 2028 The results were all concordant between OMT, fingerstick and reference testing for patients being 2029 treated with pharmacological agents (other than those on ART), with concurrent infections or with 2030 multiple children. 2031 For the SIMU™ self-test for HIV 12O, there were no practical differences between lots, the false 2032 reactive rates being 1.1±0.2, 0.8±0.4 and 1.2±0.15, all meeting the greater than 98% specificity with 2033 95% confidence requirement. 2034 The invalid rate was 0.5±0.1%, not different between lots, but the power of statistical discrimination 2035 was low with this small number and overall variability. 2036 There were no statistical differences between professional and patient use of the device, the 2037 numbers of specimens tested were such as to give adequate statistical resolving power within the 2038 requirements – a 1% difference in overall sensitivity or specificity would have been detected. 2039 Conclusion 2040 The SIMU™ self-test for HIV 12O performed as expected from the device verification activities. All 2041 the criteria derived from the design input specifications were met in terms of performance and 2042 labelling. Thus, the design is to be regarded as validated and suitable for the intended use and 2043 users. 2044
2045
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2046 8 Labelling
2047 8.0 Packaging
2048 8.0.1 Shipping packaging 2049 The wholesale (shipment) packaging for the device contains 100 units. It is 2050 packed in the box shown in Figure XXX and labelled as shown in Figure XXY 2051 (standard “folding cardboard” internally reinforced with corrugated cardboard). 2052 Temperature logger tags are included on the box. This allows THE 2053 Manufacturing Company to monitor shipments and storage as well as to trace 2054 and correct errors.
2055 Shipping packaging design and dimensions: L = xx cm, W = xx cm, H = xx cm (100 2056 device pack).
2057 8.0.2 Outer packaging for single test kit 2058 The outer packaging for the single test kit is standard “folding cardboard”. 2059 The packaging is water resistant by lamination.
2060 A closing system has been designed. After the box is folded, a sticker is place 2061 over the outermost flaps to prevent tampering with the box. No information is 2062 printed on the tape/sticker itself, since it becomes unreadable when the 2063 tape/sticker is broken
2064 Outer packaging design and dimensions: L = xx cm, W = xx cm, H = xx cm
2065 8.0.3 Pouch 2066 The retail pack for the device contains a single unit. 2067 The materials used are waterproof metallised wrapping which is heat sealable
2068 The packaging has an indentation to allow easy opening of the device packaging 2069 without the need for scissors. 2070 Pouch packaging design and dimensions: L = xx cm, W = xx cm, H = xx cm (single 2071 device pack)
2072 8.1 Labelling
2073 8.1.1 Outer packaging for single test kit labelling 2074 Well-fixed water resistant label (applied with water resistant glue) and 2075 permanent printing are utilized.
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2076 Figure 8.1–1: Outer packaging for single test kit Y1234-O (To be inserted)
2077
2078
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2079 8.1.2 Pouch 2080 Well-fixed water resistant label (applied with water resistant glue) and permanent printing are 2081 utilized. 2082 Figure 8.1-2: Pouch packaging for single test kit Y1234-O (To be inserted)
2083 2084
2085
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2086 8.2 Instructions for Use 2087 We have submitted a comprehensive IFU and a pictorial job aid for the following product codes: 2088 Product code Y1234-B (Fingerstick blood) version number: Version 3 date: 01 January 2089 2015 2090 Product code Y1234-O (OMT) version number: Version 3 date: 01 January 2015 2091 A comprehensive IFU was developed and qualified by THE Manufacturing Company in compliance 2092 with the following regulatory requirements, standards and guidance documents:
2093 ISO 18113-1:2009. In Vitro Diagnostic Medical Devices - Information Supplied by the 2094 Manufacturer (Labelling) - Part 1: Terms, Definitions and General Requirements. 2095 ISO 18113-4:2009. In Vitro Diagnostic Medical Devices – Information Supplied by the 2096 Manufacturer (Labelling) – Part 4: In Vitro Diagnostic Reagents for Self-Testing. 2097 GHTF/SG1/N70:2011: Label and Instructions for Use for Medical Devices. 2098 WHO TGS 3 Instructions for use. 2099 WHO FIND Generic job aid v1.0. 2100 FDA Write it Right: Recommendations for Developing User Instruction Manuals for 2101 Medical Devices Used in Home Health Care. 1993. 2102 FDA 1128: Guidance on Medical Device Patient Labeling; Final Guidance for Industry and 2103 FDA Reviewers. 2001. 2104 FDA 2003D-0383: Use of Symbols on Labels and in Labelling of In Vitro Diagnostic Devices 2105 Intended for Professional Use. 2004. 2106 MHRA guidance for notified bodies on the regulation of IVDs for self-testing. 2012. 2107 The IFU was qualified for use in the intended population during the clinical studies “Interpretation 2108 and use of labelling” as outlined in Section 7.
2109 WHO expects that the manufacturer will qualify all instructional material for self- 2110 testing. If it is observed that the current testing instructions are inadequate during 2111 these qualification studies, the manufacturer may need to re-evaluate many factors 2112 such as design and the relevance to other studies that have already been undertaken. 2113 For example, if qualification of the IFU indicates that a self-testing user cannot obtain 2114 the volume of blood required to perform the test, there may be a need for re- 2115 designing of the assay. This would result in all testing undertaken to date to be 2116 repeated. 2117 The IFU should include relevant end-user studies for reproducibility, repeatability and 2118 clinical performance. Studies presented in the IFU should be relevant to the final and 2119 qualified version of the IFU.
2120 8.3 Instrument manual 2121 Not applicable
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2122 8.4 Any other instructional materials provided to the user
2123 8.4.1 Job aid 2124 Special consideration was given to the development of a pictorial job aid for use with the self-test. 2125 The job aid followed the example given in the generic job aid for malarial rapid tests published by 2126 FIND/WHO and was qualified during the study mentioned above.
2127 8.4.2 Other material – pre- and post-testing information and instructional 2128 video 2129 Other instructional material will be developed on request by national programmes to meet specific 2130 user needs. These will be submitted for review to WHO PQ via the Change Notification process. This 2131 additional instructional material will comply with the general principles of labelling (as stated in the 2132 reference documents listed above). Planned materials to be developed include information on pre- 2133 and post-test counselling and an instructional video available on-line.
2134
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2135 9 Commercial history
2136 9.1 Countries of supply
2137 9.1.1 List of countries where product is currently supplied 2138 The SIMU™ self-test for HIV 12O has been supplied in several countries since late 201X: South 2139 Africa (201X), China (PRC) (201X), Republic of Korea (201X), Kuwait (201X), Jordan, Saudi Arabia 2140 (201X) and Peru (201X). A total of 1,470,000 tests have been supplied. A number of tests 2141 (approximately 20,000) were donated to Nigeria for performance evaluation.
2142 9.1.2 Minimum and maximum price in 2014 2143 The price per test varies between USD 1.50 and USD 2.50. The majority of tests sold have been at 2144 the USD 1.50 price.
2145 9.1.3 Training and support network 2146 The IFU incorporates a job aid which can, on request to THE Manufacturing Company, be printed in 2147 local language (noting that a fee may apply). The utility of both these instructions have been 2148 subjected to intense testing by THE Manufacturing Company, as part of our risk analysis for 2149 instructions to users and qualified as part of the performance studies listed in Section 7 of the 2150 dossier. The goal was that these instructions would prove sufficient to a range of self-test users with 2151 varying skills levels, acknowledging the fact that the product will be used in a variety of settings. 2152 A customer hotline has been set up for users to contact the manufacturer for further information 2153 and trouble shooting. The customer hotline is manned by a customer support team who are trained 2154 in self-testing, pre-testing and post-testing counselling requirements. The customer hotline also 2155 maintains a current list of HIV testing centres in all countries where the product is supplied. 2156 Technical support is provided by the local distributor as required.
2157 9.2 Adverse events and field safety corrective actions 2158 One field safety corrective action has been undertaken since the product has been marketed.
2159 Table 9.1–1: Table of adverse event reports QA Type of event Country of Determined cause Action taken reference event 2013-001 Increased number of Kenya Temperature New transport agent has been falsely reactive test incursion during identified for transportation with results reported transportation from temperature controlled vehicles. shipping container to New programme for temperature central medical monitoring implemented using stores temperature monitoring devices.
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2160 10 Regulatory history 2161 Certified copies of the Import Medical Device Registration Certificate, issued by the China Food and 2162 Drug Administration, Kenya and the Korea Licence Holder Certificate, are also provided in ANNEX 2163 XXX. 2164 The version for the Jordan (product code Y1234-A) has approval by the local regulatory agency (JFDA) 2165 since 2013 (Annex XXX).
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2166 11 Quality Management System
2167 11.1 Quality manual 2168 Refer to Annex VII
2169 11.1.1 Quality manual system documents 2170 Manufacture to insert a complete list of all valid quality management system documents with 2171 document title and number relevant to the product under prequalification assessment
2172 11.1.2 Quality manual system procedures 2173 Refer Annex XXX for documented procedures for the following areas: 2174 1. Control of design and development changes (SOP 12333) 2175 2. Risk management planning and implementation (SOP 123444) 2176 3. Control of non-conforming goods (SOP 123555) 2177 4. Corrective and preventative actions (SOP 123666) 2178 5. Recalls procedure (SOP 123777) 2179 6. Control of key suppliers (SOP 123888)
2180 11.2 Quality manual system certification 2181 THE Manufacturing Company holds ISO 13485:2003 Medical devices – Quality management 2182 systems – Requirements for regulatory purposes certification for the manufacture of the product 2183 under assessment which is valid until 23 May 2018. A certified copy of the certificate is attached in 2184 Annex XX in addition to the two previous inspection reports issued by the certification. 2185
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2186 Annex I: Essential Principles checklist Check list of Essential Principles of GHTF/SG1/N068 for: SIMU™ self-test for HIV 12O SIMU™ SELF-TEST FOR HIV 12O Product CodesY1234-B and Y1234-O
Document version # 02 Document date: Written by: Approved by: Agreed by: signatures date QA R&D signature date signature date Regulatory affairs Manufacturing signature date signature date Changes from earlier versions: Version Item modified Modification 01 Date 2011 01 01 N/A Document created according to SOP XXX 02 Date 2011 09 15 8 C 3.1 SOP for control of risk from vCJD added 03 Date 2011 09 15 8 A1 Addition of reference to REACH regulation 2187
2188 The checklist submitted to WHO must include dates and signatures
2189
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THE Manufacturing Company – SIMU™ self-test for HIV 12O Product Codes Y1234-B & Y1234-O A/NA = Applicable/Not Applicable No. Essential Principles A/ Method(s) and references used to Reference -to supporting controlled documents NA demonstrate conformity of Manufacturer A GENERAL PRINCIPLES A1 Medical devices should be designed and A Application of recognised Standards: ISO 13485 certificate held by QA department, manufactured in such a way that, when used ISO 13485:2003 Medical Devices- certified copy submitted for Section 11.2 of this under the conditions and for the purposes Quality Management Systems- dossier intended and, where applicable, by virtue of the Requirements for Regulatory Purposes “SIMU™ self-test for HIV 12O Risk Management technical knowledge, experience, education or ISO 14971:2007 Medical devices – and Control Report” held by QA training, and the medical and physical conditions Application of risk management to Risk analysis output documents “SIMU™ self- of intended users, they will perform as intended medical devices test for HIV 12O - design risk”, “SIMU™ self-test by the manufacturer and not compromise the for HIV 12O risk - processes”, “SIMU™ self-test clinical condition or the safety of patients, or the EN 13641:2002 Elimination or for HIV 12O risk-users” safety and health of users or, where applicable, reduction of risk of infection related to other persons, provided that any risks which may in vitro diagnostic medical devices SIMU™ self-test for HIV 12O Residual Risk be associated with their use constitute acceptable Statement risks when weighed against the benefits to the Design history file, design input specification and patient and are compatible with a high level of design validation documentation (held by QA protection of health and safety. 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 A2 The solutions adopted by the manufacturer for the A Application of recognised Standards: Risk management policy document “Policy XXX” design and manufacture of the devices should ISO 13485:2003 Medical Devices- and risk analysis SOPs “SOP XXX”, “SOP XXXX” conform to safety principles, taking account of the Quality Management Systems- held by QM Department generally acknowledged state of the art. -When Requirements for Regulatory Purposes Risk analysis output documents “SIMU™ self- risk reduction is required, the manufacturer ISO 14971:2007 Medical devices – test for HIV 12O -risk-design”, “SIMU™ self-test should control the risks so that the residual risk Application of risk management to for HIV 12O risk - processes”, “SIMU™ self-test
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THE Manufacturing Company – SIMU™ self-test for HIV 12O Product Codes Y1234-B & Y1234-O A/NA = Applicable/Not Applicable No. Essential Principles A/ Method(s) and references used to Reference -to supporting controlled documents NA demonstrate conformity of Manufacturer associated with each hazard is judged acceptable. - medical devices for HIV 12O risk-users” The manufacturer should apply the following ISO 18113:2009 In vitro diagnostic “SIMU™ self-test for HIV 12O Risk Management principles in the priority order listed: medical devices – Information and Control Report” held by QA – identify known or foreseeable hazards and supplied by the manufacturer SIMU™ self-test for HIV 12O Instructions for estimate the associated risks arising from the (labelling) – Parts 1 and 4 Use intended use and foreseeable misuse; SIMU™ self-test for HIV 12O Job aid – 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 A3 Medical devices should achieve the performance A Application of recognised standards Risk management policy document “Policy XXX” intended by the manufacturer and be designed Verification and Validation -Studies and risk analysis SOPs “SOP XXX”, “SOP XXXX” and manufactured in such a way that, during held by QM Department Section 7 ISO 13485:2003 Medical normal conditions of use, they are suitable for Devices - Quality Management Risk analysis output documents “SIMU™ self- their intended purpose. Systems-Requirements for Regulatory test for HIV 12O -risk-design”, “SIMU™ self-test Purposes for HIV 12O risk - processes”, “SIMU™ self-test for HIV 12O risk-users” ISO 14971:2007 Medical devices – Application of risk management to “SIMU™ self-test for HIV 12O Risk Management medical devices and Control Report” held by QA EN 13612:2002 Performance All verification and validation studies (refer evaluation of in vitro diagnostic Section 7 of this dossier). - medical devices Traceability of SIMU™ self-test for HIV 12O GHTF/SG5/N6:2012 Clinical Evidence Control Cells.
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THE Manufacturing Company – SIMU™ self-test for HIV 12O Product Codes Y1234-B & Y1234-O A/NA = Applicable/Not Applicable No. Essential Principles A/ Method(s) and references used to Reference -to supporting controlled documents NA demonstrate conformity of Manufacturer 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 A4 The characteristics and performances referred to A Application of recognised standards All verification and validation studies (refer in Clauses A1, A2 and A3 should not be adversely Stability and (user) Validation -Studies Section 7 of this dossier) including Stability affected to such a degree that the health or safety studies (Section 7.2) ISO 18113:2009 In vitro diagnostic of the patient or the user and, where applicable, of medical devices – Information Risk management policy document “Policy XXX” other persons are compromised during the supplied by the manufacturer and risk analysis SOPs “SOP XXX”, “SOP XXXX” lifetime of the device, as indicated by the (labelling) – Parts 1 and 4 held by QM Department manufacturer, when the device is subjected to the Risk analysis output documents “SIMU™ self- stresses which can occur during normal conditions ISO 14971:2007 Medical devices – test for HIV 12O -risk-design”, “SIMU™ self-test of use and has been properly maintained in Application of risk management to for HIV 12O risk - processes”, “SIMU™ self-test accordance with the manufacturer’s instructions. medical devices for HIV 12O risk-users” ISO 23640:2011 In vitro diagnostic medical devices -- Evaluation of “SIMU™ self-test for HIV 12O Risk Management stability of in vitro diagnostic reagents and Control Report” held by QA CLSI EP25A:2009 Evaluation of Stability SIMU™ self-test for HIV 12O Instructions for of In Vitro Diagnostic Reagents; Use Approved Guideline A5 Medical devices should be designed, Application of recognised standards Stability studies (Section 7.2 of this dossier) manufactured and packaged in such a way that Stability Studies Risk management policy document “Policy XXX” their characteristics and performances during their ISO 18113:2009 In vitro diagnostic and risk analysis SOPs “SOP XXX”, “SOP XXXX” intended use will not be adversely affected by medical devices – Information held by QM Department transport and storage conditions (for example,
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THE Manufacturing Company – SIMU™ self-test for HIV 12O Product Codes Y1234-B & Y1234-O A/NA = Applicable/Not Applicable No. Essential Principles A/ Method(s) and references used to Reference -to supporting controlled documents NA demonstrate conformity of Manufacturer fluctuations of temperature and humidity) taking supplied by the manufacturer Risk analysis output documents “SIMU™ self- account of the instructions and information (labelling) – Parts 1 and 4 test for HIV 12O -risk-design”, “SIMU™ self-test provided by the manufacturer ISO 14971:2007 Medical devices – for HIV 12O risk - processes”, “SIMU™ self-test Application of risk management to for HIV 12O risk-users” medical devices “SIMU™ self-test for HIV 12O Risk Management ISO 23640:2011 In vitro diagnostic and Control Report” held by QA medical devices - Evaluation of SIMU™ self-test for HIV 12O Instructions for stability of in vitro diagnostic reagents Use CLSI EP25A:2009 Evaluation of Stability of In Vitro Diagnostic Reagents; Approved Guideline A6 All known and foreseeable risks, and any GHTF/SG5/N6:2012 Clinical Evidence Risk analysis output documents “SIMU™ self- undesirable effects, should be minimised and be for IVD medical devices – Key test for HIV 12O -risk-design”, “SIMU™ self-test acceptable when weighed against the benefits of Definitions and Concepts for HIV 12O risk - processes”, “SIMU™ self-test the intended performance of medical devices GHTF/SG5/N8:2012 Clinical Evidence for HIV 12O risk-users” during normal conditions of use for IVD Medical Devices - Clinical “SIMU™ self-test for HIV 12O Risk Management Performance Studies for In Vitro and Control Report” held by QA Diagnostic Medical Devices ISO 14971:2007 Medical devices – Application of risk management to medical devices
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THE Manufacturing Company – SIMU™ self-test for HIV 12O Product Codes Y1234-B & Y1234-O A/NA = Applicable/Not Applicable No. Essential Principles A/ Method(s) and references used to Reference -to supporting controlled documents NA demonstrate conformity of Manufacturer C DESIGN AND MANUFACTURING PRINCIPLES C1 Chemical, physical and biological properties C1.1 The IVD medical devices should be designed and A Application of recognised standards All verification -studies (refer Section 7 of this manufactured in such a way as to ensure the Verification and Validation -Studies dossier) characteristics and performance referred to in Section 7 ISO 13485:2003 Medical Risk analysis output documents “SIMU™ self- Section A. -Particular attention should be paid to Devices - Quality Management test for HIV 12O-risk-design”, “SIMU™ self-test the possibility of impairment of analytical Systems-Requirements for Regulatory for HIV 12O risk - processes”, “SIMU™ self-test performance due to incompatibility between the Purposes for HIV 12O risk-users” materials used and the specimens and/or analyte “SIMU™ SELF-TEST FOR HIV 12O Risk (measurand) to be detected (such as biological ISO 14971:2007 Medical devices – Management and Control Report” held by QA tissues, cells, body fluids and micro-organisms), Application of risk management to taking account of its intended purpose. medical devices SIMU™ self-test for HIV 12O Instructions for ISO 18113:2009 In vitro diagnostic Use (“Warnings for Users”, ”Specimen medical devices – Information Collection, Preparation and Storage”) supplied by the manufacturer (labelling) – Parts 1 and 4 C1.2 The IVD medical devices should be designed, A Application of recognised standards Risk analysis output documents “SIMU™ self- manufactured and packaged in such a way as to ISO 14971:2007 Medical devices – test for HIV 12O-risk-design”, “SIMU™ self-test minimise the risk posed by contaminants and Application of risk management to for HIV 12O risk - processes”, “SIMU™ self-test residues to the persons involved in the transport, medical devices for HIV 12O risk-users” storage and use of the devices and to patients, ASTM D4169 − 14 “SIMU™ SELF-TEST FOR HIV 12O Risk taking account of the intended purpose of the Management and Control Report” held by QA device. Packing and Shipping SOP XXX SIMU™ self-test for HIV 12O -Robustness Studies (held on site)
Working document 21 December 2015 Page 110 of 165 Annex I: Essential principles checklist | WHO Sample product dossier
THE Manufacturing Company – SIMU™ self-test for HIV 12O Product Codes Y1234-B & Y1234-O A/NA = Applicable/Not Applicable No. Essential Principles A/ Method(s) and references used to Reference -to supporting controlled documents NA demonstrate conformity of Manufacturer Package Robustness Studies (held on site) C1.3 The IVD medical devices should be designed and A Application of recognised standards Risk analysis output documents “SIMU™ self- manufactured in such a way as to reduce as far as ISO 14971:2007 Medical devices – test for HIV 12O-risk-design”, “SIMU™ self-test reasonably practicable and appropriate the risks Application of risk management to for HIV 12O risk - processes”, “SIMU™ self-test posed by substances that may leach or leak from medical devices for HIV 12O risk-users” the IVD medical device. -Special attention should “SIMU™ self-test for HIV 12O Risk Management be given to substances which are carcinogenic, and Control Report” held by QA mutagenic or toxic to reproduction. SIMU™ self-test for HIV 12O Robustness Studies (held on site) C1.4 IVD medical devices should be designed and A Application of recognised standards Risk analysis output documents “SIMU™ self- manufactured in such a way as to reduce as far as Verification and Validation -Studies - test for HIV 12O-risk-design”, “SIMU™ self-test reasonably practicable and appropriate risks posed for HIV 12O risk - processes”, “SIMU™ self-test ISO 14971:2007 Medical devices – by the unintentional ingress or egress of for HIV 12O risk-users” Application of risk management to substances into or from the IVD medical device medical devices “SIMU™ self-test for HIV 12O Risk Management taking into account the device and the nature of and Control Report” held by QA the environment in which it is intended to be used. SIMU™ self-test for HIV 12O Cartridge Robustness Studies (held on site) C2 Infection and microbial contamination C2.1 The IVD medical devices and manufacturing A Application of recognised standards All verification studies (refer Section 7 of the processes should be designed in such a way as to Verification and Validation Studies dossier). - eliminate or to reduce as far as reasonably Section 7 ISO 13485:2003 Medical Risk analysis output documents “SIMU™ self- practicable and appropriate the risk of infection to Devices - Quality Management test for HIV 12O-risk-design”, “SIMU™ self-test user, professional or lay, or, where applicable, - Systems-Requirements for Regulatory for HIV 12O risk - processes”, “SIMU™ self-test other person . -The design should: Purposes for HIV 12O risk-users” allow easy and safe handling ; and, where ISO 14971:2007 Medical devices – “SIMU™ self-test for HIV 12O Risk Management Working document 21 December 2015 Page 111 of 165 Annex I: Essential principles checklist | WHO Sample product dossier
THE Manufacturing Company – SIMU™ self-test for HIV 12O Product Codes Y1234-B & Y1234-O A/NA = Applicable/Not Applicable No. Essential Principles A/ Method(s) and references used to Reference -to supporting controlled documents NA demonstrate conformity of Manufacturer necessary: Application of risk management to and Control Report” held by QA reduce as far as reasonably practicable and medical devices Materials management requirements and policy appropriate any microbial leakage from the IVD EN 13641:2002 Elimination or kept in R&D (Control materials contain medical device and/or microbial exposure during reduction of risk of infection related to potentially infectious components. Policy reflects use; and in vitro diagnostic medical devices requirements to source materials that pose the prevent microbial contamination of the IVD least possible risk of transmission of infection) medical device or specimen where applicable, by the user, professional or lay, or other person C2.2 IVD medical devices labelled either as sterile or as NA Not provided in a sterile state having a special microbiological state should be designed, manufactured and packaged to ensure they remain so when placed on the market and remain so 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 Not provided in a sterile state. 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 NA Not provided in a sterile state. should be manufactured in appropriately controlled (e.g. environmental) conditions. C2.5 Packaging systems for non-sterile IVD medical A Application of recognised standards Robustness studies (results available in R&D devices should maintain the integrity and Sections 6&7 ISO 13485:2003 Medical Department). - cleanliness of the device Devices - Quality Management Control Specimen Antimicrobial Effectiveness
Working document 21 December 2015 Page 112 of 165 Annex I: Essential principles checklist | WHO Sample product dossier
THE Manufacturing Company – SIMU™ self-test for HIV 12O Product Codes Y1234-B & Y1234-O A/NA = Applicable/Not Applicable No. Essential Principles A/ Method(s) and references used to Reference -to supporting controlled documents NA demonstrate conformity of Manufacturer Systems -Requirements for Regulatory study (results available in R&D Department). - Purposes Environmental Control SOP XXX ISO 14001 Environmental management systems - Requirements with guidance for use C3 IVD medical devices incorporating materials of biological origin C3.1 Where IVD medical devices include tissues, cells A Application of recognised standards No TSE transmissible agents in the device but and substances originating from animals, the Verification and Validation Studies “Management and Control Report” held by QA processing, preservation, testing and handling of ISO 14971:2007 Medical devices – Materials management requirements and policy tissues, cells and substances of animal origin Application of risk management to kept in R&D: should be carried out so as to provide optimal medical devices Policy reflects requirements to source materials safety for user, professional or lay, or other person EN 13641:2002 Elimination or that pose the least possible risk of transmission In particular, safety with regard to viruses and reduction of risk of infection related to of infection other transmissible agents should be addressed by in vitro diagnostic medical devices Document control policy requires on-going implementation of validated methods of review of risk posed by scientific methods used elimination or inactivation in the course of the Section 4.2.4 ISO 13485:2003 Medical to reduce or eliminate potential infectious manufacturing process. -This may not apply to Devices - Quality Management agents in components for Systems already on certain IVD medical devices if the activity of the Systems -Requirements for Regulatory the market virus and other transmissible agent are integral to Purposes the intended purpose of the IVD medical device or Material specification sheets 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
Working document 21 December 2015 Page 113 of 165 Annex I: Essential principles checklist | WHO Sample product dossier
THE Manufacturing Company – SIMU™ self-test for HIV 12O Product Codes Y1234-B & Y1234-O A/NA = Applicable/Not Applicable No. Essential Principles A/ Method(s) and references used to Reference -to supporting controlled documents NA demonstrate conformity of Manufacturer retain information on the geographical origin of the animals. C3.2 Where IVD medical devices include human tissues, A Application of recognised standards No such materials in the device but - see C3.1 for cells and substances, the selection of sources, Verification and Validation -Studies THE Manufacturing Company’s policy on such donors and/or substances of human origin, the materials ISO 14971:2007 Medical devices – processing, preservation, testing and handling of Application of risk management to tissues, cells and substances of such origin should medical devices be carried out so as to provide optimal safety for user, professional or lay, or other person EN 13641:2002 Elimination or reduction of risk of infection related to In particular, safety with regard to viruses and in vitro diagnostic medical devices other transmissible agents should be addressed by implementation of validated methods of Section 4.2.4 ISO 13485:2003 Medical elimination or inactivation in the course of the Devices - Quality Management manufacturing process. -This may not apply to Systems -Requirements for Regulatory certain IVD medical devices if the activity of the Purposes 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 C3.3 Where IVD medical devices include cells and Application of recognised standards Applicable to monoclonal antibodies (mouse cell substances of microbial origin, the processing, Verification and Validation Studies origin) and to recombinant antigens (bacterial preservation, testing and handling of cells and cell origin) in the SIMU™ self-test for HIV 12O ISO 14971:2007 Medical devices – substances should be carried out so as to provide Application of risk management to Risk analysis output documents “SIMU™ self- optimal safety for user, professional or lay, or medical devices test for HIV 12O-risk-design”, “SIMU™ self-test other person. - for HIV 12O risk - processes”, “SIMU™ self-test EN 13641:2002 Elimination or In particular, safety with regard to viruses and Working document 21 December 2015 Page 114 of 165 Annex I: Essential principles checklist | WHO Sample product dossier
THE Manufacturing Company – SIMU™ self-test for HIV 12O Product Codes Y1234-B & Y1234-O A/NA = Applicable/Not Applicable No. Essential Principles A/ Method(s) and references used to Reference -to supporting controlled documents NA demonstrate conformity of Manufacturer other transmissible agents should be addressed by reduction of risk of infection related to for HIV 12O risk-users” implementation of validated methods of in vitro diagnostic medical devices “SIMU™ self-test for HIV 12O Risk Management elimination or inactivation in the course of the Section 4.2.4 ISO 13485:2003 Medical and Control Report” held by QA manufacturing process. -This may not apply to Devices - Quality Management See also C 3.1 above for policy certain IVD medical devices if the activity of the Systems -Requirements for Regulatory virus and other transmissible agent are integral to Purposes. the intended purpose of the IVD medical device or when such elimination or inactivation process would compromise the performance of the IVD medical device. C4 Environmental properties C4.1 If the IVD medical device is intended for use in NA No unsupplied items needed combination with other devices or equipment, the whole combination, including the connection system 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 instructions for use C4.2 IVD medical devices should be designed and manufactured in such a way as to remove or reduce as far as reasonably practicable and appropriate: C4.2.1 the risk of injury to user, professional or lay, or A Application of recognised standards Risk analysis output documents, mostly related other person in connection with their physical and Validation -Studies to lancets: ergonomic features; Section 7 ISO 13485:2003 Medical “SIMU™ self-test for HIV 12O-risk-design”, Working document 21 December 2015 Page 115 of 165 Annex I: Essential principles checklist | WHO Sample product dossier
THE Manufacturing Company – SIMU™ self-test for HIV 12O Product Codes Y1234-B & Y1234-O A/NA = Applicable/Not Applicable No. Essential Principles A/ Method(s) and references used to Reference -to supporting controlled documents NA demonstrate conformity of Manufacturer Devices - Quality Management “SIMU™ self-test for HIV 12O risk - processes”, Systems-Requirements for Regulatory “SIMU™ self-test for HIV 12O risk-users” Purposes “SIMU™ self-test for HIV 12O Risk Management ISO14971:2097 Medical devices– and Control Report” held by QA Application of risk management to Design specifications (held on site) medical devices All validation data (refer Section 7.4 of this dossier) C4.2.2 the risk of use error due to the ergonomic A Application of recognised standards Risk analysis output documents “SIMU™ self- features, human factors and the environment in Validation -Studies test for HIV 12O-risk-design”, “SIMU™ self-test which the IVD medical device is intended to be for HIV 12O risk - processes”, “SIMU™ self-test Section 7 ISO 13485:2003 Medical used; for HIV 12O risk-users” Devices - Quality Management Systems-Requirements for Regulatory “SIMU™ self-test for HIV 12O Risk Management Purposes and Control Report” held by QA ISO14971:2097Medicaldevices– Design specifications (held on site) Application of risk management to SIMU™ self-test for HIV 12O Instructions for medical devices use, ISO 18113:2009 In vitro diagnostic SIMU™ self-test for HIV 12O Job aid medical devices – Information All validation data (refer to Section 7.4 of this supplied by the manufacturer dossier). (labelling) – Part 4 C4.2.3 risks connected with reasonably foreseeable A Application of recognised standards Copy of subcontractor’s Declaration of external influences or environmental conditions, Validation and Stability -Studies Conformity (Annex IV) to DIRECTIVE such as magnetic fields, external electrical and Section 7.4 ISO 13485:2003 Medical All validation data (refer Section 7.4 of this electromagnetic effects, electrostatic discharge, Devices - Quality Management dossier) pressure, humidity, temperature or variations Systems-Requirements for Regulatory Stability studies (refer Section 7.2 of this dossier)
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THE Manufacturing Company – SIMU™ self-test for HIV 12O Product Codes Y1234-B & Y1234-O A/NA = Applicable/Not Applicable No. Essential Principles A/ Method(s) and references used to Reference -to supporting controlled documents NA demonstrate conformity of Manufacturer thereof; Purposes 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 C4.2.4 the risks associated with the use of the IVD A Application of recognised standards Risk analysis output documents “SIMU™ self- medical device when it comes into contact with Validation Studies test for HIV 12O-risk-design”, “SIMU™ self-test materials, liquids, and gases to which it is exposed for HIV 12O risk - processes”, “SIMU™ self-test Section 7 ISO 13485:2003 Medical during normal conditions of use; for HIV 12O risk-users” Devices - Quality Management Systems-Requirements for Regulatory “SIMU™ self-test for HIV 12O Risk Management Purposes and Control Report” held by QA ISO 14971:2007 Medical devices – Design specifications (held on site) Application of risk management to All validation data (refer Section 7.4 of this medical devices dossier) C4.2.5 the risk associated with the possible negative NA interaction between software and the environment within which it operates and interacts; C4.2.6 the risks of accidental penetration of substances A Application of recognised standards Risk analysis output documents “SIMU™ self- into the IVD medical device; Validation Studies test for HIV 12O-risk-design”, “SIMU™ self-test
Working document 21 December 2015 Page 117 of 165 Annex I: Essential principles checklist | WHO Sample product dossier
THE Manufacturing Company – SIMU™ self-test for HIV 12O Product Codes Y1234-B & Y1234-O A/NA = Applicable/Not Applicable No. Essential Principles A/ Method(s) and references used to Reference -to supporting controlled documents NA demonstrate conformity of Manufacturer Section 7 ISO 13485:2003 Medical for HIV 12O risk - processes”, “SIMU™ self-test Devices - Quality Management for HIV 12O risk-users” Systems-Requirements for Regulatory “SIMU™ self-test for HIV 12O Risk Management Purposes and Control Report” held by QA ISO 14971:2007 Medical devices – Design specifications (held on site) Application of risk management to All validation data (refer to Section 7.4 of this medical devices dossier) C4.2.7 the risk of incorrect identification of A Application of recognised standards Single use, home use, no likely chance of mix up, specimens/samples; Validation Studies for clinical use, ISO 22870 applies Risk analysis output documents “SIMU™ self-test for HIV Section 7 ISO 13485:2003 Medical 12O-risk-design”, “SIMU™ self-test for HIV 12O Devices - Quality Management risk - processes”, “SIMU™ self-test for HIV 12O Systems-Requirements for Regulatory risk-users” Purposes “SIMU™ self-test for HIV 12O Risk Management ISO 14971:2007 Medical devices – and Control Report” held by QA Application of risk management to medical devices Design specifications (held on site) ISO 22870:2006 Point-of-care testing All validation data (refer Section 7.4 of this (POCT) — Requirements for quality dossier) and competence SIMU™ self-test for HIV 12O Instructions for use, SIMU™ self-test for HIV 12O Job aid C4.2.8 the risks of reasonably foreseeable interference NA Single use device only. No chance of with other devices such as carry over between IVD carry over medical devices. C4.3 IVD medical devices should be designed and A Application of recognised standards manufactured in such a way as to minimise the No risks
Working document 21 December 2015 Page 118 of 165 Annex I: Essential principles checklist | WHO Sample product dossier
THE Manufacturing Company – SIMU™ self-test for HIV 12O Product Codes Y1234-B & Y1234-O A/NA = Applicable/Not Applicable No. Essential Principles A/ Method(s) and references used to Reference -to supporting controlled documents NA demonstrate conformity of Manufacturer risks of fire or explosion during normal use and in Section 7.4 ISO 13485:2003 Medical single fault condition. -Particular attention should Devices - Quality Management be paid to IVD medical devices whose intended Systems-Requirements for Regulatory use includes exposure to or use in association with Purposes flammable substances or substances which could cause combustion. C4.4 IVD medical devices should be designed and NA No such aspects 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 A Application of recognised standards Risk analysis output documents “SIMU™ self- manufactured in such a way as to facilitate the ISO 14001:2004 Environmental test for HIV 12O-risk-design”, “SIMU™ self-test safe disposal of any waste substances management systems. Requirements for HIV 12O risk - processes”, “SIMU™ self-test with guidance for use for HIV 12O risk-users” ISO 14971:2007 Medical devices – “SIMU™ self-test for HIV 12O Risk Management Application of risk management to and Control Report” held by QA medical devices Design specifications (held on site) SIMU™ self-test for HIV 12O Instructions for use, SIMU™ self-test for HIV 12O Job aid C5 Performance characteristics C5.1 IVD medical devices should be designed and A Application of recognised standards Design specifications (held on site) manufactured in such a way that the performance Performance Studies and Stability All validation and verification studies, and characteristics support the intended use, based on Studies stability studies (refer to all of Section 7 of this appropriate scientific and technical methods. -In Section 7 ISO 13485:2003 Medical dossier)
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THE Manufacturing Company – SIMU™ self-test for HIV 12O Product Codes Y1234-B & Y1234-O A/NA = Applicable/Not Applicable No. Essential Principles A/ Method(s) and references used to Reference -to supporting controlled documents NA demonstrate conformity of Manufacturer particular, where appropriate, the design should Devices - Quality Management Lot release procedures “SOP QC xxx”. address sensitivity, specificity, accuracy which is Systems-Requirements for Regulatory trueness and precision (repeatability and Purposes reproducibility), control of known relevant ISO 23640:2011 In vitro diagnostic interference and limits of detection medical devices - Evaluation of These performance characteristics need to be stability of in vitro diagnostic reagents maintained during the lifetime of the IVD medical CLSI EP25A:2009 Evaluation of Stability device as indicated by the manufacturer. 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 CLSI ILA 30-A Immunoassay Interference by Endogenous Antibodies; Approved Guideline FDA Guidance for Industry - - Bioanalytical Method Validation EN 13975:2003 Sampling procedures used for acceptance testing of in vitro diagnostic medical devices - Statistical
Working document 21 December 2015 Page 120 of 165 Annex I: Essential principles checklist | WHO Sample product dossier
THE Manufacturing Company – SIMU™ self-test for HIV 12O Product Codes Y1234-B & Y1234-O A/NA = Applicable/Not Applicable No. Essential Principles A/ Method(s) and references used to Reference -to supporting controlled documents NA demonstrate conformity of Manufacturer aspects C5.2 Where the performance of devices depends on the NA 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. C5.3 Wherever possible values expressed numerically NA should be in commonly accepted, standardised units, and understood by the users of the device. C6 Protection against radiation NA C6.1 IVD medical devices should be designed, NA No radiation utilized in the design of manufactured and packaged in such a way that the SIMU™ self-test for HIV 12O. 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. C6.2 When IVD medical devices are intended to emit NA potentially hazardous, visible and/or invisible radiation, they should as far as reasonably practicable and appropriate be: designed and manufactured in such a way as to ensure that the characteristics and the quantity of radiation emitted can be controlled and/or
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THE Manufacturing Company – SIMU™ self-test for HIV 12O Product Codes Y1234-B & Y1234-O A/NA = Applicable/Not Applicable No. Essential Principles A/ Method(s) and references used to Reference -to supporting controlled documents NA demonstrate conformity of Manufacturer 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 NA software 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. C8 IVD medical devices connected to, or equipped NA with, an energy source C8.1 IVD medical devices where the safety of the NA 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. C8.2 IVD medical devices should be designed and NA 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.
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THE Manufacturing Company – SIMU™ self-test for HIV 12O Product Codes Y1234-B & Y1234-O A/NA = Applicable/Not Applicable No. Essential Principles A/ Method(s) and references used to Reference -to supporting controlled documents NA demonstrate conformity of Manufacturer C8.3 IVD medical devices should be designed and NA manufactured in such a way as to provide an adequate level of intrinsic immunity to electromagnetic disturbance to enable them to operate as intended. C8.4 IVD medical devices should be designed and NA 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 SIMU™ self-test for HIV 12O contains User and patient Risk assessment found no manufactured in such a way as to protect the user, only a user operated sliding issues professional or lay, or other person against mechanism mechanical risks connected with, for example, resistance to movement, instability and moving parts C9.2 Where there are risks due to the presence of A Refer to C9.1, C3.2 and C3.3 moving parts, risks due to break-up or detachment, or leakage of substances, then appropriate protection means must be incorporated
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THE Manufacturing Company – SIMU™ self-test for HIV 12O Product Codes Y1234-B & Y1234-O A/NA = Applicable/Not Applicable No. Essential Principles A/ Method(s) and references used to Reference -to supporting controlled documents NA demonstrate conformity of Manufacturer C9.3 IVD medical devices should be designed and NA 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. C9.4 IVD medical devices should be designed and NA SIMU™ self-test for HIV 12O does not manufactured in such a way as to reduce to the generate noise 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 C9.5 Terminals and connectors to the electricity, gas or NA 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 minimise all possible risks. C9.6 IVD medical devices should be designed and NA 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. C9.7 Accessible parts of the IVD medical devices NA SIMU™ self-test for HIV 12O does not (excluding the parts or areas intended to supply generate heat
Working document 21 December 2015 Page 124 of 165 Annex I: Essential principles checklist | WHO Sample product dossier
THE Manufacturing Company – SIMU™ self-test for HIV 12O Product Codes Y1234-B & Y1234-O A/NA = Applicable/Not Applicable No. Essential Principles A/ Method(s) and references used to Reference -to supporting controlled documents NA demonstrate conformity of Manufacturer heat or reach given temperatures) and their surroundings should not attain potentially dangerous temperatures under normal use C10 Protection against the risks posed by IVD medical A Applicable standards: Risk analysis output documents “SIMU™ self- devices for self-testing ISO 18113-4:2009 In vitro diagnostic test for HIV 12O-risk - design”, “SIMU™ self-test medical devices - Information supplied for HIV 12O risk - processes”, “SIMU™ self-test by the manufacturer (labelling) for HIV 12O risk - users” ISO 22870:2006 Point-of-care testing “SIMU™ self-test for HIV 12O Risk Management (POCT) — Requirements for quality and Control Report” held by QA and competence GHTF/SG1/N43:2005 Labelling for Medical Devices A broad range of user skills have been considered in the design C11 Labels and Instructions for Use C11.1 Users should be provided with the information A Application of recognised standards Risk analysis output documents “SIMU™ self- needed to identify the manufacturer, to use the ISO14971:2007Medicaldevices– test for HIV 12O-risk - design”, “SIMU™ self-test device safely and to ensure the intended Application of risk management to for HIV 12O risk - processes”, “SIMU™ self-test performance, taking account of their training and medical devices for HIV 12O risk - users” knowledge. -This information should be easily ISO 18113-4:2009 In vitro diagnostic “SIMU™ self-test for HIV 12O Risk Management understood medical devices - Information supplied and Control Report” held by QA by the manufacturer (labelling) SIMU™ self-test for HIV 12O Instructions for Use, SIMU™ self-test for HIV 12O Job aid
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THE Manufacturing Company – SIMU™ self-test for HIV 12O Product Codes Y1234-B & Y1234-O A/NA = Applicable/Not Applicable No. Essential Principles A/ Method(s) and references used to Reference -to supporting controlled documents NA demonstrate conformity of Manufacturer C12 Performance evaluation including analytical performance and, where appropriate, clinical performance C12.1 For an IVD medical device a performance A Application of GHTF Guidance Performance Evaluation Summary (refer Section evaluation should be conducted in accordance GHTF/SG5/N6:2012 Clinical Evidence 7 of this dossier). with GHTF guidance. -The performance evaluation for IVD medical devices – Key should review analytical performance data and, Definitions and Concepts where appropriate, clinical performance data in GHTF/SG5/N7:2012 Clinical Evidence the form of any: for IVD medical devices – Scientific literature, Validity Determination and performance study reports; and Performance Evaluation experience gained by routine diagnostic testing GHTF/SG5/N8:2012 Clinical Evidence to establish that the IVD medical device achieves for IVD Medical Devices - Clinical its intended performance during normal Performance Studies for In Vitro conditions of use and that the known, and Diagnostic Medical Devices. foreseeable risks, and any undesirable effects, are minimised and acceptable when weighed against the benefits of the intended performance. C12.2 Clinical performance studies using specimens from A Ethics committee approval of all Documentation of all ethics committee approval human subjects should be carried out in prospective clinical performance (held on site). accordance with the spirit of the Declaration of studies. 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
Working document 21 December 2015 Page 126 of 165 Annex I: Essential principles checklist | WHO Sample product dossier
THE Manufacturing Company – SIMU™ self-test for HIV 12O Product Codes Y1234-B & Y1234-O A/NA = Applicable/Not Applicable No. Essential Principles A/ Method(s) and references used to Reference -to supporting controlled documents NA demonstrate conformity of Manufacturer informed consent.
Working document 21 December 2015 Page 127 of 165 Annex II: Risk management policy | WHO Sample product dossier
2190 Annex II: Risk management policy
2191 THE Manufacturing Company DOC XXX 2192 NOTE 1: The following DOC XXX Risk Management Policy has been prepared for the 2193 purposes of this sample dossier, and is not a complete document. It is to provide an 2194 example of some aspects to be considered in such a document and must reflect the 2195 internal policies of the company. 2196 NOTE 2: all documents submitted to WHO must be signed and dated.
2197 Risk Management Policy Document version # 02 Document date: 2011 09 15 Written by: Approved by: signatures date Head of QA signature date Head of manufacturing signature date Changes from earlier versions: Item Modification Version modified 01 2011 01 01 N/A Document created according to SOP x3w Reference to the proposed European in vitro diagnostic 02 2011 09 15 Para. 6 c) regulation added 03 … …
2198 Introduction 2199 1. The company is committed to the effective management of risk at every level: 2200 1.1. Reducing as far as possible any risks associated with any product developed or manufactured 2201 by the company, at every stage of the product lifecycle from design to in-use surveillance. 2202 1.2. Ensuring a safe environment for its employees and customers. 2203 1.3. Training to enable its employees to undertake their work effectively, efficiently and safely. 2204 1.4. Enhancing and protecting the local environment. 2205 2. The company will achieve these objectives 2206 2.1. By ensuring company management fully accepts the need for risk control, which cannot be 2207 balanced against financial profit. 2208 a) The Head of Quality Assurance will be responsible for risk management and control 2209 throughout the company, subject to this.
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2210 b) The Head of Research & Development will be responsible for risk management and 2211 control in the design of product and process. 2212 c) The Head of Manufacturing will be responsible for risk management and control 2213 related to supply of product, safety in the facility, and respect for the environment. 2214 d) These responsibilities cannot be passed to subordinates. 2215 2.2. By following the guidelines of the GHTF/SG3/N15R8 and 98/79/EC in a hierarchy of control 2216 methods: 2217 a) Inherent safety by design of any items we develop or manufacture, and their 2218 manufacturing processes, including risks related to security of supply. 2219 b) Protective measures for the user and patient in the device, and for our employees in 2220 the manufacturing processes. 2221 c) Information for safety, such as warnings, as a last resort for risks that cannot be 2222 removed by design of the products or the processes. 2223 2.3. By ensuring that risk management is integrated into the quality management system of the 2224 company, to include risk management planning and plans for all aspects of our work and 2225 product development. 2226 2.4. By training of all employees in the importance of safe practices in all aspects of their work. 2227 2.5. By training specific employees in the regulations and methods of risk analysis and control. 2228 a) ISO 13485 Medical devices -- Quality management systems -- Requirements for 2229 regulatory purposes EN ISO 14971:2012, Medical Devices. Application of risk 2230 management to medical devices documentation, GHTF and IMDRF guidelines, FDA 2231 and ICH Q9 and Q10 guidance, 2232 b) Standard methods for the tools of risk analysis, including Failure Mode and Effects 2233 Analysis (FMEA),Fault Tree Analysis, Preliminary Risk Analysis, Risk Ranking and 2234 Filtering and Hazard and Operability Studies. 2235 3. The company will ensure consistent application of risk control methods through a set of standard 2236 operating procedures (SOP) directed by this policy. The SOPs will include, but are not limited to: 2237 a) SOP and template for FMEA – who, how, when 2238 b) SOP for training in the use of risk management tools 2239 c) SOP for estimation of degrees of hazard and control measures
2240 This is not intended to be a complete policy document.
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2241 Annex III: Residual risk statement
2242 SIMU™ self-test for HIV 12O
2243 THE Manufacturing Company 2244 Following optimisation of the design and performance characteristics by comprehensive testing in- 2245 house and in the hands of intended users, as verified when testing populations representative of the 2246 intended patient population, THE Manufacturing Company considers the remaining risks to users and 2247 patients are minimal and acceptable for the SIMU™ self-test for HIV 12O. The testing is used for 2248 monitoring the status of a user in resource limited settings or in the home. Positive results will result in 2249 the user visiting a professional laboratory for further testing. Any unlikely, unexpected test result will be 2250 balanced by the major clinical value for patients who would otherwise have limited or no access to 2251 monitoring. 2252 The remaining risks to manufacture, continuity of supply, and to manufacturing staff are also minimal 2253 and acceptable in view of the training and safety measures in place for our staff and the supplier 2254 management and material testing specified for this product. 2255 Documented evidence to support these statements is filed on site in the Risk Management and Control 2256 Report of the Risk Management File for this product. This report contains the assessment of all 2257 remaining risks after implementation of risk control measures. This report is subject to continuous 2258 review, based on experience with the device, to ensure the positive status of the benefit versus risk 2259 profile remains unchanged.
2260 Signed: Date: 2261 Head of QA, THE Manufacturing Company: responsible for risk management and control
2262 Signed: Date: 2263 Head of R&D, THE Manufacturing Company: responsible for design and process risk control
2264 Signed Date: 2265 Head of Manufacturing, THE Manufacturing Company: responsible for risk management and control 2266 related to supply of product, safety in the facility, respect for the environment
2267 Submitted documents must be signed and dated
2268
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2269 Annex IV: Design inputs FMEA Design inputs FMEA: SIMU™ self-test for HIV 12O Product codes: Y1234-B and Y1234-O FMEA Version: 4 Date: 2013 02 26 THE Manufacturing Company design input FMEA template version 2 Controlling SOP: Design input risk analysis SOP 00967 version 3 Version Revision date Changes Control 1.0 2010 09 03 Initial, following finalisation of customer requirements documentation Added a requirement that timing be in-built Added a requirement that the package be light and discrete 2.0 2011 01 08 Added hazards Y –Z following R&D project review and further literature searches 3.0 2011 11 28 Product codes defined and added to this and other documents Life of product extended from the minimally required 2 years to 4.0 2013 02 26 3 years
Approval of this version: Head of department or project leader (SOP 00967)
Department Name Signature Date Marketing Anne Smith 2013 02 29 Manufacturing Bill Jones 2013 02 26 QA Pete Brown 2013 02 27 R&D Joe White 2013 02 26
Present at FMEA meetings at least two representatives from each department (SOP 00967)
Department Name Signature Date Marketing Anne Smith 2013 02 24 Manufacturing Tom Jackson 2013 02 24 QA Jean Roberts 2013 02 24 R&D Dave White 2013 02 24 Marketing Simon Richard 2013 02 24 Manufacturing John Jensens 2013 02 24 QA Sylvie Martin 2013 02 24 R&D Sam Dupont 2013 02 24
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Design inputs FMEA: SIMU™ self-test for HIV 12O Product codes: Y1234-B and Y1234-O
Prepared by: Simon Richard. Blogs, Marketing
Hazard No (from
inputs) Known or suspected problem Potential effects Recommended action Comments
Severity Occurrence indexRisk Antibody excess prozone on 3rd False negative or weaker than A medium risk, should be 1.1.1 4 2 8 Ig capture in the device generation assays expected signals eliminated by design Low antibody content in oral Use Ig capture, see Parry, J. 1993 1.2.1 False negative 4 4 16 High risk must be eliminated mucosal transudate in the text Rare to obtain false negatives Use of augmented colour Visual reading is highly variable 1.2.2 False reactions 4 2 8 (Occ = 2) but still medium nanoparticles, clearer than gold between untrained persons risk, design to eliminate or selenium Dry atmosphere can interrupt flow Design the assay so that Membrane across the top of the 4.1.1, across the result window, or cause False negatives, invalid results 3 3 8 humidity high or low does not result window, good absorption 5.3.1, 5.8.2 back-flow and invalidity of assays affect the result in the waste reservoir … Users might be illiterate and will The IFU must be pictorial and 3.3.2 not speak European languages Invalid use, unsafe with lancets, 3 4 12 absolutely clear anyway … Sexual active males may have anti- False positives in populations Occ. for homosexual males. Evaluate in STD clinics to validate 5.4.3 E. coli – problem with recombinant 3 4 12 expected to be positive Eliminate by design. non-occurrence antigens … And so on, working through each section (user, regulatory, management, and manufacturing) of the customer input documents (Annex VI) thinking carefully about all possible hazards. This gives R&D a solid basis to work with and usually results in innovation suited to customer requirements. Outputs from this FMEA lead to a product requirement document. Update this FMEA if there are any design changes
This process led to the need for device-contained wash fluid, functional control line beyond measuring flow, protection against infection round the input port, in- built timing, no pipetting of specimens 2270 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 2271 FMEA below). Justification for using this approach, in place of the more common quantitation approach, can be found in Shebl NA, Franklin BD, Barber N, 2272 “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?” 2273 BMC Health Services Research 12 (2012) 150-160. However it is performed, the actions involved in generating FMEA early in the life of a device are 2274 invaluable and give evidence of original thought about the work. Working document 21 December 2015 Page 132 of 165 Annex IV: Design inputs FMEA | WHO Sample product dossier
2275 The following SOP XXX “Preparation of design input FMEA” has been prepared for the 2276 purposes of this sample dossier, and is not a complete document. It is to provide an example 2277 of some aspects to be considered in such a document and must reflect the internal policies of 2278 the company. 2279 NOTE: all documents submitted to WHO must be signed and dated.
2280 Extracts from SOP XXX Preparation of design input FMEA
2281 1. Health, Safety and the Environment: 2282 There are no health and safety implications as this is a documentation SOP.
2283 2. Training Requirements 2284 Complete the sheet in appendix 1 to indicate the trainee has read and understood this procedure. 2285 Signatures by trainee and trainer required
2286 3. Responsibilities 2287 The R&D project leader must:
2288 establish who will participate in the FMEA. This must include at least representation from the 2289 R&D project team, marketing, QA and manufacturing groups; 2290 ensure that an FMEA is started at the time the first draft of the input documentation is being 2291 written; 2292 ensure the FMEA is updated as required until product launch. 2293 ensure that each version is approved as below. 2294 after launch FMEA for design changes are addressed in SOP x/yy: the project is no longer an R&D 2295 responsibility. 2296 The heads of department or departmental project leaders must all: 2297 review the content and approve each version of the FMEA
2298 4. Procedure for a design input FMEA 2299 Ensure that the customer input responses are available: 2300 Customers include: users, patients, distributors, funders, regulators, manufacturing, 2301 management, finance. 2302 Complete the general information relating to the FMEA requested at the top of the form. 2303 Complete each major section and subsection in the FMEA form. 2304 Work through the input requirements point by point and document any potential hazard, using 2305 previous experience, literature information, general knowledge. 2306 Record for each hazard the effect(s) that could be caused: 2307 there may be more than one effect for each hazard. 2308 assess the severity of each effect. 2309 score the severity using the definitions in the Severity Table in Appendix 3 and record it the 2310 severity column. 2311 Complete the effect severity supporting information in appendix 4 (see below) 2312 …and so on.
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2313 Table Annex IV–1: Hazard categorisation: Appendix 3 to SOP XXX Vernacular term Description Category Catastrophic Results in patient death 4 Critical Results in life threatening injury or permanent disability 4 Serious Results in injury or disability requiring qualified medical intervention 3 Results in temporary injury or disability not requiring qualified 2 Minor medical intervention Negligible Inconvenience or temporary discomfort 1
2314 Table Annex IV–2: Severity supporting information: Appendix 4 to SOP XXX Hazard # Rationale / Support for assigned category of hazard 1.1.1 1.1.2
2315 ISO 14971 and ISO/TR 24971 for general risk severity groupings 2316 Approval of severity to be by a qualified medical professional as specified by ISO 14971 annex H 2.5.2
2317 Table Annex IV–3: Occurrence categorisation: Appendix 5 to SOP XXX Vernacular Description Rate of non-conformance Category term Probable Very high: non-conformance is almost 4 >1:3 certain: Probable High: similar functions or activities have 4 >1:20 frequent non-conformance Occasional Moderate: non-conformances with similar 3 >1:2 000 functions or activities occur occasionally Rare Low: non-conformances with similar 2 >1:15 000 functions or activities occur rarely Improbable Very low: non-conformances with nearly 1 >1:150 000 identical functions or activities occur rarely Improbable Remote: Non-conformance unlikely >1:1 500 000 1
2318 ISO 14971 and ISO/TR 24971for general risk occurrence probability groupings. This table is modified from one 2319 published by the Automotive Industry Action Group: actual values were specified and agreed at Head of QA level and 2320 are company specific.
2321 Table Annex IV–4: Occurrence supporting information: Appendix 6 to SOP XXX Hazard # Rationale / Support for assigned category of occurrence 1.1.1 1.1.2
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2322 Figure Annex IV–5: Risk Grid: Appendix 7 to SOP XXX
Severity of Effect
4 3 2 1
Critical Serious Minor Negligible
4 Probable High High Med Low
3 Occasional High Med Low Low
2 Rare Med Low Low Low
1 Improbable Low Low Low Low
Probabilityof Occurrence 2323
2324 Figure Annex IV–6: All items must be addressed: High Redesign or improve Redesign and/or improve, or add a control method to reduce the Med categorisation to Low Low Review with QA and marketing and/or improve if possible
2325 This risk grid applies to both design input FMEA and user and patient FMEA. It is modified to require that if a 2326 medium risk is found during manufacturing process FMEA that process must be redesigned.
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2327 Annex V: User and patient FMEA User and patient FMEA: SIMU™ self-test for HIV 12O Product codes: Y1234-B and Y1234-O FMEA Version: 4 Date: 2013 02 26 THE Manufacturing Company design input FMEA template version 2 Controlling SOP: Design input risk analysis SOP 00967 version 3 Version Revision date Changes Control Initial, following finalisation of customer requirements documentation 1.0 2010 09 05 including FMEA Hazards related to in-built timing added 2.0 2011 01 10 Hazards related to transport and storage following from the package be light and discrete 3.0 2011 11 28 Product codes defined and added to this and other documents 4.0 2013 02 26 Life of product extended from the minimally required 2 years to 3 years
Approval of this version: Departmental Project leader (SOP 00967)
Department Name Signature Date Marketing Anne Smith 2013 02 27 Manufacturing Bill Jones 2013 02 27 QA Pete Brown 2013 02 27 R&D Joe White 2013 02 27
Present at FMEA meetings at least two representatives from each department (SOP 00967)
Department Name Signature Date Marketing Anne Smith 2013 02 24 Manufacturing Steve White 2013 02 24 QA Jean Roberts 2013 02 24 R&D Dave White 2013 02 24 Marketing Simon Richard 2013 02 24 Manufacturing Tom Weber 2013 02 24 QA Adrian Becker 2013 02 24 R&D Sharon Dupont 2013 02 24
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2328 User and patient FMEA: SIMU™ self-test for HIV 12O 2329
Product codes: Y1234-B, Y1234-O & Y1234-A
Prepared by David Brown R&D
Status at initial FMEA Status after risk minimization activity Hazard # Activity Function Potential Potential Severity Potential Causes Current Controls Occur. Risk Recommended Action Action Action taken (ref to Severity After Risk Notes and comments failure Effects of of Fai9lure Index owner change documentation before control Index Modes Failure Mode or notebook occur- rence
User 1 Blood taking Obtain Blood By-standers 4 Poor lancets, ppor Training, 2 Med Modify lancets, design to R&D Device designed to 4 1 Low See later, hazard # GGC specimen for splashing, infected pipettes, poor statements in IFU eliminate pipetting and measure volume, to lancet supplier needed to analysis con- entry port spillage close after use, designed be changed tamination entry port and auto volume
User 2 Pipetting Wash solution Insufficient False result User untrained to None 4 High Design to eliminate this R&D On-board wash solution 3 1 Low Acceptable: required new into device or too much handle dropper or step in the device, no instrument in factory but volume pipette pipetting cost outweighed by performance
User 3 Timing Develop result Too long or Incorrect 3 No timers Training, 3 Med Design so as timing is not R&D Flow monitor by dye 3 1 Low Required nanoparticles too short result available statements in IFU required system, very stable not gold, dye flow and result reading window
User 4 Reading IFU Accuracy of Unable to Incorrect 3 Illiterate or wrong Diagrams and text 3 Med Diagrams should stand by Market Obtained graphic design 3 1 Low method use the result or language in IFU themselves – no text ing support device invalid assay
User 5 Taking saliva Obtain None False 4 Poor IFU, poor Diagrams and text 4 High Obtain better sponge R&D Design of device and 4 1 Low Occurrence rate proven specimen for collected, negative collection device, in IFU device, design entry port, validation during verification and analysis saliva not failure to extract require small assay volume, validation crevicular from device add lg capture to improve fluid sensitivity
User 6 User activity Use as green Window AIDS 4 Incorrect IFU 3 High Clear instruction Market Obtained psychological 4 1 Low Could still be improved, light for risky period of utilization of ing layout support needs further thought activities sero- device conversion
2330 This is an extract of a larger spreadsheet, attached as document 3, (Annex III user & patient risk FMEA_01.xlsx). 2331 The appendixes of Annex IV Design inputs FMEA are applicable to patient and user FMEA. User and patient FMEA is controlled by SOP YYY which is similar to 2332 SOP XXX except that the FMEA is started when R&D work is begun and the form of the device and its use take shape. This FMEA is re-evaluated with each 2333 project group meeting and with each major milestone in development. It ceases to be an R&D responsibility with product launch and its maintenance is taken 2334 by marketing using SOP x/yy as noted in SOP XXX.
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2335 Annex VI: Input requirements self-testing device 2336 Customer Requirements 2337 This document follows from the Input Requirements produced according to SOP-DDD of THE 2338 Manufacturing Company following market research with users, regulators, purchasers, 2339 funders.
2340 The notes in black are from the template in SOP-DDD and those in blue are added to the template 2341 according to each specific project. Those added in green are compiled from customer 2342 responses and will form the basis of the numeric, measurable product requirements.
2343 1. Functional requirements
2344 This section unchanged by user inputs – it is the highest managerial level description of the 2345 device.
2346 1.1 What is the kit supposed to do? 2347 1.1.1 HIV 1, 2, O, M antibody detection for self-testing (home use) in Western 2348 countries and resource restricted settings, giving identical results to those from 2349 3rd generation clinical/screening assays for adults. To be approved for self- 2350 testing. 2351 1.2 What inputs and what outputs? 2352 1.2.1 Inputs: whole blood (fingerstick, not venous), oral mucosal transudate (gingival 2353 crevicular fluid,). 2354 1.2.2 Outputs: visual reading only; no instrumentation for users. 2355 2. Management requirements
2356 This section is unchanged – management has already made inputs according to SOP-DDD prior to 2357 release of the design to other “customers”.
2358 2.1 Financial including staff allocation 2359 2.1.1 Staffing in R+D to be kept within budget constraints, no new staff to be taken on 2360 except as replacements. 2361 2.1.2 Total costs to be less than $100,000 per staff member per year. 2362 2.2 Administration and control structure 2363 2.1.3 The usual R+D, QA and manufacturing control systems, administered by the HIV 2364 team. 2365 2.3 Reporting methods and intervals 2366 2.1.4 By the normal project management group, with reporting to senior 2367 management through the design control committee at a minimum of 2 monthly 2368 intervals.
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2369 3. Format 2370 3.1 Interfaces to other systems (measurement system – fluorescence, OD; result recording) 2371 3.1.1 No interfaces – visual reading only 2372 a) Ensure common visual defects (colour blindness, tropical optical 2373 afflictions) will not interfere. 2374 b) Reading in low light conditions must be possible. 2375 c) Ensure that test and control lines are very clear, even to those who do 2376 not know English and perhaps cannot read. 2377 d) Locations of test and control lines clearly identified and clear 2378 instructions of what to do if lines are not correctly located. 2379 e) Maximise line intensity to help users with poor vision. 2380 3.2 Methodology – RDT, EIA, or NAT 2381 3.2.1 Lateral flow only, visual readout, in-house colour development reagents for test 2382 and control lines as per other RDT lines 2383 a) Ensure common problems of lateral flow are avoided – red-cell 2384 interference, split test and control lines, artefacts from skewed flow. 2385 b) Ensure the invalid rate is minimal to prevent user confusion and waste 2386 of money. 2387 3.3 Presentation of the product 2388 3.3.1 Single device per package, everything required to be in the package. 2389 a) Lancets and oral mucosal transudate collection system must be 2390 provided. 2391 b) Package must be easily opened in an obvious and correct fashion and 2392 easily, safely disposable. 2393 c) Package must completely protect the product against the environment 2394 expected in users’ homes. 2395 d) No parts of value for anything other than this test. 2396 e) The pack for the user must be light, small and discrete to avoid 2397 embarrassment. 2398 3.3.2 Labelling in accord with ISO 18113-5 and aligned with Jacobs et al., Malaria 2399 Journal 13 (2014) 505-514. 2400 a) Ensure absolute clarity for non-English speaking, non-readers – 2401 implications for IFU. 2402 4. Operating requirements 2403 4.1 Expected physical environment – temperature, power availability, equipment, materials 2404 available (distilled water, pipette tips), transport capability, physical stability … )
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2405 4.1.1 Private environment in resource restricted areas. No power, no equipment, no 2406 water: no external requirements allowable. Transport: limited capabilities. 2407 a) The expected environment can be particularly harsh dusty, not 2408 microbiologically clean. 2409 b) High altitudes and extremes of temperature, humidity and pressure can 2410 be expected. 2411 c) Children must not be able to play unsafely with used devices, see safety 2412 critical below. 2413 d) Transport to end-users and storage by users can be very haphazard and 2414 likely not under controlled conditions. 2415 e) Storage by distributors cannot be guaranteed. 2416 f) Timing might be impossible – no timers, watches, phones. 2417 4.2 Expected technological environment (nature of the working area) 2418 4.2.1 None whatever – private environment by untrained individuals unfamiliar with 2419 testing device. 2420 a) This will have major consequences for documenting instructions their 2421 interpretation and subsequent actions by users. 2422 b) Fail safe design – no confusion over specimen and diluent ports (if 2423 different). 2424 c) Counting is difficult for some, need to count drops must be avoided. 2425 d) Fingerstick might be difficult to perform by some users. 2426 5. Performance requirements 2427 5.1 Safety critical 2428 5.1.1 Specimen collection, use and disposal to be safe in completely untrained hands. 2429 a) Blood might well be contaminated with infections other than HIV so a 2430 negative test result does not mean a used device is safe. 2431 b) Lancets, collection devices must be safe to handle during and after use. 2432 c) Disposal facilities might be subject to scavenging, the used device must 2433 be secure. 2434 d) It must be impossible to attempt to use a device and accessories, 2435 especially following a negative result, on a second occasion. 2436 e) Oral specimen collection device must be inert, and unable to cause 2437 adverse effects to untrained users. 2438 5.2 Specimen types 2439 5.2.1 Oral mucosal transudate and whole fingerstick blood.
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2440 a) Instructions for use of lancets must be clear as must the collection of 2441 sufficient specimen volume for blood and oral mucosal transudate. 2442 b) Clear instructions as to what to do if blood does not flow after using the 2443 lancet. 2444 c) Consider edentate patients, and patients with oral disease, not 2445 uncommon. 2446 5.3 Operating temperatures for the device 2447 5.3.1 From 12 – 45°C. 2448 a) Humidity is also an issue: both high and low must be accommodated. 2449 5.4 Sensitivity, specificity, precision at the cut-off, degree of confidence in these values, 2450 definition of populations. 2451 5.4.1 To meet performance characteristics. 2452 a) Ideally to match blood screening tests, not just diagnostic tests. 2453 5.4.2 Precision to be excellent between different readers of the device. 2454 a) Readers must detect the same difficult / borderline specimens at least 2455 90% of the time. 2456 5.4.3 Population: general public, country and city dwellers in developed and resource 2457 restricted countries. Adults of sexually active ages, not infants. 2458 5.5 Precision, trueness and accuracy: if quantitative 2459 5.5.1 Not quantitative. 2460 5.6 Interfering factors 2461 5.6.1 To meet CLSI expectations and risk evaluated potential infections in HIV 2462 prevalent populations. 2463 a) Malaria, sleeping sickness, leishmaniasis (oral ulcers), Chagas’ disease, 2464 are all important. 2465 b) Consider periodontal diseases and micro-organism from that source. 2466 c) Consider users who chew different stimulants – coca leaves, betel nut, 2467 tobacco – and other material potentially in the mouth – alcohol, 2468 cigarette residue, tooth cleaning agents. 2469 5.7 Internal QA requirement (“run controls”) 2470 5.7.1 A control line that establishes stability of all the reagents, not just showing flow 2471 or stability of the label system. 2472 a) The control line must prove the functionality of the test line and the 2473 labelling material in addition to flow. 2474 b) Must show specimen added in sufficient volume to operate normally. 2475 5.8 Stability of device
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2476 5.8.1 Transport stability: to meet ANSI packaging expectations and to survive 2477 shipment and storage in resource limited areas. 2478 a) Temperatures in transport can reach 55°C in some lorries and on 2479 airports. 2480 b) Transport and storage can reach freezing temperature at high altitude 2481 and high latitude. 2482 5.8.2 Shelf-life after manufacture under stated conditions: at least 1 year following 2483 transport to the end-user with subsequent storage at up to 45°C. 2484 a) Note that transport temperatures can be extreme for long periods and 2485 variable. 2486 b) Consider humidity and pressure, too. 2487 5.8.3 Stability after first use: Not applicable, single use, self-contained. 2488 5.8.4 Stability on-board: Not applicable. 2489 5.8.5 Stability once opened if kept in sachets: at least 2 hours. 2490 a) See section 4.1.1 there may be no timers available. 2491 5.8.6 Stability of result after assay – time allowed prior to reading: resource restricted, 2492 timing might be an issue, long period of stability. 2493 a) See section 4.1.1 there may be no timers available, stability of the test 2494 result is important; the result might be shown to others over long time 2495 periods; might be taken to a paramedic for interpretation and aid. 2496 5.9 Stability of specimens 2497 5.9.1 Time at ambient or cold: not relevant for blood, needs market involvement for 2498 oral mucosal transudate but at least an hour. 2499 5.9.2 Time frozen: Not applicable. 2500 5.10 Robustness or fault tolerance, “ruggedness”, “guard band studies”. 2501 5.10.1 Insensitive to temperature, time, volume, light within wide limits, insensitive to 2502 orientation of the device during running period, readable by untrained 2503 individuals. 2504 a) See various previous comments, the users are totally untrained with no 2505 facilities and no experience of diagnostic devices. 2506 5.11 Speed to result and batching of assays 2507 5.11.1 Rapid (less than 30 minutes), no batching. 2508 a) Need to give some idea of how long to wait prior to reading. 2509 5.11.2 Capacity – assays per technician or instrument per hour or per day. 2510 a) Not applicable.
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2511 6. Manufacturing requirements
2512 This section will be company-specific; guidance cannot be given beyond a suggestion of 2513 things to be considered. Sections 6.7 – 6.10 will be exemplified in other sections of the 2514 dossier.
2515 6.1 Where to be made 2516 6.1.1 In-house, entirely, THE Manufacturing Company, except for moulded parts, 2517 possibly oral mucosal transudate and blood sampling, and routine supplies. 2518 6.2 Equipment, staff, space available or to be obtained 2519 6.2.1 Qualification of work-space, instruments, services. 2520 6.3 Cost of production 2521 6.3.1 No more than XXX. 2522 6.4 Cost of materials 2523 6.4.1 No more than YYY % of total cost of production. 2524 6.5 Constraints on materials to be used – safety, storage, environmental. 2525 6.5.1 As usual in THE Manufacturing Company, but with attention to safe disposal 2526 and minimal waste in-use. 2527 6.6 Sourcing of raw materials 2528 6.6.1 Supplier qualification and monitoring processes as usual, SOP-AAA, biologicals 2529 to be developed and qualified in-house. 2530 6.7 Storage, in-process stability of intermediates, product 2531 6.7.1 To meet SOP-BBB THE Manufacturing Company. 2532 6.8 Packaging 2533 6.8.1 Labelling to meet international expectations, IFU to be particularly clear. 2534 6.9 QA factors – “manufacturing capability” in the statistical sense 2535 6.9.1 Based on known factory capability analysis for other flow device made by THE 2536 Manufacturing Company. 2537 6.10 In-process and release QA values 2538 6.10.1 To meet SOP-CCC. 2539 7. Maintainability and support requirements 2540 7.1 Maintenance requirements 2541 7.1.1 Irrelevant: applies specifically to instrumented assays in this context. 2542 7.2 Supportability requirements 2543 7.2.1 Will require considerable user feedback in the days after commercial launch to 2544 ensure that validation of the product was accurate and that the device can be 2545 used and interpreted in the expected environments.
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2546 a) User feedback will be nearly impossible to obtain; distributor feedback 2547 not reliable except perhaps from Médecins Sans Frontières (MSF) and 2548 research units. 2549 7.3 Installation requirements 2550 7.3.1 Nil. 2551 8. Cultural and political requirements 2552 8.1 Cultural requirements – bovine, porcine materials. 2553 8.2 Political requirements. 2554 9. Regulatory requirements 2555 9.1 Compliance requirements – ISO, CE in vitro regulation, WHO, FDA. 2556 9.1.1 Environmental ISO 14001, safety, performance, registration 2557 a) National use and export regulations not covered by international 2558 regulation. 2559 9.1.2 Risk management ISO 14971. 2560 9.1.3 Material safety data sheets. 2561 9.2 Standards requirements – if quantitative: ISO 17511 2562 a) See WHO standards and reference listings in TGS 1. 2563 9.3 Clinical trials requirements ISO 14155: 2009 (not IVD but relevant) 2564 9.3.1 Helsinki Declaration. 2565 10. Usability and “human factors” requirements 2566 10.1 Ease of use 2567 10.1.1 Critical for home use. 2568 10.2 Ease of learning – training – staff technical ability 2569 10.2.1 MUST be self-explanatory. 2570 10.3 Accessibility requirements – colour blindness 2571 10.3.1 Minimal manipulation – untrained users. 2572
2573
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2574 Annex VII: THE Manufacturing Company Quality Manual 2575
2576 THE Manufacturing Company 2577 Quality Manual 2578 THE Manufacturing Company, 2579 987 Somewhere Street, 2580 Somewhere in Europe, EU-1234, 2581 Europe 2582 2583 (29 pages) 2584 Version 5: (08/2015) 2585
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Document QM 001 Number Document Title THE Manufacturing Company Quality Manual
NAME TITLE SIGNATURE DATE Author
Reviewer
Authoriser
2586
Effective Date: 2587 2588 Document Version Updates Prepared by Version Summary of changes Date Version 1 First release
Version 2
Version 3 Change of organisation
Version 4 Addition of manufacture of SIMU™ Self –test HIV 01.01.2014 12O Version 5 Update to reflect inclusion of WHO PMS 06.08.2015 requirements 2589 2590
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2591 1. Scope
2592 1.1. THE Manufacturing Company Quality System covers the Design, Manufacturing and 2593 Supply of in vitro diagnostic reagents and related systems in all areas and locations.
2594 1.2. Company Background
2595 THE Manufacturing Company is a venture capitalist supported ISO 9001-, ISO 13485- certified 2596 manufacturing company founded in 2001 and based in Europe.
2597 2. Quality System Requirements
2598 THE Manufacturing Company Quality System meets the requirements of ISO 9001:2000, ISO 2599 13485:2003. The scope of the current valid ISO 13485:2003 Certificate obtained by THE 2600 Manufacturing Company is as follows: 2601 “Thedevelopment, production, distribution of in-vitro diagnostics and supporting products for infection 2602 diseases” 2603 Additional THE Manufacturing Company Quality System meets the quality system requirements of the 2604 In-vitro Diagnostics Medical Devices Directive 98/79/EC (The IVD Medical Devices Regulations 2002 2605 - UK Statutory Instrument No. 618),the Korea FDA and the China FDA, and the Indonesia National 2606 Agency of Food and Drug Control.
2607 3. Definitions and Abbreviations
2608 BPIC Inventory Control System
2609 DHF Design History File
2610 DMR Device Master Record
2611 IVDD In-vitro Diagnostics Medical Devices Directive 98/79/EC
2612 OEM Original Equipment Manufacturer
2613 QA Quality Assurance
2614 SOP Standard Operating Procedure
2615 4. Quality Management System
2616 4.1. General Requirements
2617 The Quality Manual and SOPs describe the processes for the quality 2618 4.2. Documentation Requirements
2619 General
2620 Insert a company structure chart here.
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2621 The Quality Management System Documentation includes the documents shown below:-Policy 2622 Documents are generated by individual Departments to give more detailed guidance of activities carried 2623 out by or managed by the particular Department. 2624 SOPs are written for systems and processes which may affect product quality or the quality of service. 2625 SOPs are controlled by the central Documentation Group and circulation is usually across departments. 2626 SOPs are technical or administrative instructions intended to provide standard methods and/or 2627 procedures for conducting scientific tests, processes, manipulations or administrative procedures. The 2628 writing and departmental control of SOPs is described in SOP XXX & SOP XXX and the authorisation, 2629 approval and change control of SOPs is described in SOP Production Documents are controlled by the 2630 central Documentation Group. 2631 Work Instructions/Local Procedures are written for tasks which are only used within a single working 2632 group. The control of Work Instructions and Local Procedures is detailed in SOP XXX. 2633 Technical Specifications are written for raw materials and packaging items which are manufactured 2634 specifically by a supplier for THE Manufacturing Company and/or where specific additional testing is 2635 required by either THE Manufacturing Company or the supplier, and also, if the item is manufactured 2636 from materials of human or animal origin, to ensure compliance with the Essential Principles. 2637 Technical Specifications are agreed with and authorised by the supplier together with representatives of 2638 THE Manufacturing Company . Writing, authorisation and Control of Technical Specifications is 2639 defined in SOP XXX. 2640 Product Structure & Routing Specifications are a document set for a reagent or finished pack which 2641 includes the bill of materials for a manufacturing operation and the associated department instructions. 2642 Product Structure & Routing Specifications are used in nitrocellulose striping, coating, drying, , 2643 labelling and final packing of product. The relevant SOPs describing writing, authorisation and control 2644 of these documents are SOP XXX. 2645 Quality Assurance Product Release Specifications detail the testing that is carried out by Product 2646 Quality Assurance team to ensure that the claims for the product detailed in the Instruction for Use (IFU) 2647 are met. Writing and authorisation of these documents is detailed in SOP XXX. 2648 Device Master Records (DMRs) reference the location of all documents containing the design 2649 specifications, manufacturing procedures, quality assurance requirements and labelling of THE 2650 Manufacturing Company manufactured and marketed products. The preparation, authorisation and 2651 maintenance of DMRs is described in SOP XXX. Manufacturing activities are conducted in accordance 2652 with these documents. 2653 Quality Policies, Procedures and Processes define Quality System requirements. 2654 Technical Documentation/Technical File/Design Dossiers form the total documentary evidence that a 2655 product conforms with the appropriate requirements of the various regulatory bodies as well as the 2656 Essential Principles. Technical Files and Design Dossiers provide a summary of the Technical 2657 Documentation. Preparation and maintenance of Technical Files and Design Dossiers is described in 2658 SOP XXX. 2659 4.2.1. Quality Manual
2660 The Quality Manual is maintained according to SOP XXX.
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2661 5. Control of Documents
2662 A List of Documents held under the QMS should be appended here.
2663 Controlled documents are authorised and issued following the appropriate SOPs. The distribution and 2664 revision of most controlled documents is controlled by the central Documentation Group. The Planning 2665 Department is responsible for the control and maintenance of Product Structure and Routing 2666 Specifications. 2667 Changes are proposed, processed, authorised and implemented using the procedure known as the THE 2668 Manufacturing Company Change Management System. This includes changes to a production process, 2669 production documentation, technical documentation, QA specification, Instruction for Use, other printed 2670 material, labels, or other documentation which may affect either the performance claim of the product, 2671 the manufacturing process or product presentation. The change procedure is defined in SOP XXX. 2672 Changes to quality documents (e.g. correction of content-related errors) may be made according to SOP 2673 XXX. 2674 Certain changes to THE Manufacturing Company products and THE Manufacturing Company Quality 2675 System must be notified to the various Competent Authorities or their recognized assessment body (for 2676 example, the Notified Body under the provisions of the IVD Directive (98/79/EC) for CE marked 2677 products).Theprocessfordeterminingandnotifyingof‘significantchanges’isoutlinedinSOPXXX. 2678 In addition, copies of applicable national or international standards/regulations are controlled by 2679 Regulatory Affairs. 2680 5.1. Control of Records
2681 Records are maintained to provide evidence of conformity to requirements and of the effective 2682 operation of the quality management system. Records are completed according to SOP XXX, and must 2683 be legible and readily identified. 2684 The major record types and retention times are defined in SOP XXX. 2685 Quality records are maintained in such a way that they are readily retrievable and unlikely to deteriorate.
2686 6. Management Responsibility
2687 6.1. Management Commitment
2688 The senior managers demonstrates its commitment to the development and implementation of the 2689 quality management system requirements by 2690 Establishing and maintaining a quality system
2691 Defining the quality policy and quality objectives (quality plan) and communicating these 2692 throughout the organization
2693 Ensuring the availability of resources
2694 Conducting management reviews (SOP )
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2695 6.2. Customer Focus
2696 The senior managers ensure that customer requirements are defined throughout all stages of product 2697 realisation. Performance against these is reviewed to improve customer satisfaction via the Complaint 2698 Handling process (SOP), Customer Requirements (SOP), Design Reviews, Post Market Surveillance 2699 (SOP) and CAPA Oversight / Management Review (SOP). In addition THE Manufacturing Company 2700 Marketing Executive communicates within the company and with customers to provide further 2701 definition of customer needs.
2702 7. Quality Policy and objectives 2703 The Quality Policy of THE Manufacturing Company Biotech Limited (THE Manufacturing Company ) 2704 is to improve health care by providing high quality, safe and effective diagnostic products. 2705 This is achieved 2706 a) Through the processes of design, development, manufacture and distribution carried out by 2707 competent and empowered staff.
2708 b) by striving for continuing quality improvement.
2709 c) by recognising that the involvement and commitment of all THE Manufacturing Company 2710 personnel is essential.
2711 d) by providing appropriate training and an organisational structure which promotes 2712 empowerment.
2713 e) by assessment of and effective communication with OEM suppliers
2714 f) by ensuring appropriate investment in technology and systems
2715 Effectiveness is measured by 2716 g) customer feedback through the enquiry and complaint system.
2717 h) product availability.
2718 i) quality metrics
2719 j) employee feedback.
2720 The Quality Policy is communicated to all employees via the Annual Quality System Training, the 2721 policy is reviewed at management Review Meetings (SOP XXX). 2722 7.1. Planning
2723 7.1.1. Quality Objectives
2724 The requirements for quality are defined within the relevant Quality System Procedures, including POIs, 2725 Technical Specifications, POIs and QA Product Release Specifications and the Design & Development 2726 Plan for new products. The activities include identification and acquisition of resources and skills to 2727 achieve the required quality.
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2728 Senior managers establish Quality objectives as part of the Quality Plan for each year. Each employee 2729 has a job description which includes the quality accountabilities of the position. In addition an 2730 employee may have specific quality goals. 2731 7.1.2. Quality Management System Planning
2732 Senior managers review data relating to the Quality System requirements and objectives at the six- 2733 monthly Management Review and at the monthly meetings of the CAPA Oversight Review Board and 2734 Europe Site Management Team. This includes identification and acquisition of resources and skill to 2735 achieve the Quality Policy. Key metrics of the Quality System are reviewed at these meetings. SOP 2736 XXX details the aspects of the quality system that are reviewed. 2737 7.2. Responsibility, Authority and Communication
2738 7.2.1. Senior managers are responsible for ensuring that responsibilities and authorities are defined 2739 and communicated. 2740 7.2.2. Senior managers and their responsibilities are defined following:
2741 Site Director
2742 This position has overall responsibility for the site 2743 Functional Managers in R&D, QA and Finance
2744 These positions report into their respective directorates within the company but also report to the Site 2745 Director on a day to day operational basis. 2746 The position holder has overall responsibility for THE Manufacturing Company Quality Policy and for 2747 the quality of all products produced by THE Manufacturing Company , and is chairman of the CAPA 2748 Oversight Review Board and Management Review Board. 2749 Operations Manager
2750 The prime accountability of the Operations Manager is to ensure that the manufacturing laboratories 2751 meet their cost, quality and service level goals and that the facilities and HS&E functions are effectively 2752 managed. This is achieved through delegated responsibilities to line reports. 2753 Financial Controller
2754 The principal responsibilities of this position are to provide the executive and line management of THE 2755 Manufacturing Company and other Companies managed from the site with accurate and timely 2756 financial information on which informed business decisions can be made. The position holder is also 2757 responsible for safeguarding the Companies' assets through the maintenance of a system of internal 2758 accounting controls and ensuring that the Companies are at all times compliant with all statutory 2759 financial requirements. 2760 The Financial Controller is responsible to the Site Director for the operation and development of 2761 electronic information systems. This includes the purchase and maintenance of hardware; systems 2762 security; data security; software licensing; and software development. Basic user training is provided in 2763 the use of systems. The position holder is also responsible for the development of improved business 2764 processes, in collaboration with other managers. 2765 Quality Assurance (QA) Manager
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2766 The position holder is responsible for ensuring that THE Manufacturing Company Quality System is in 2767 compliance with regulations and is operating to assure quality in all products and services. 2768 It is the responsibility of this position holder to ensure that THE Manufacturing Company Quality 2769 Systems requirements are communicated to all THE Manufacturing Company managers and employees 2770 and that the actions required to maintain compliance with ISO 9001: 2000, ISO 13485:2003 and the 2771 requirements of the IVDD and other relevant regulations are highlighted to appropriate personnel. 2772 The QA Manager is responsible for ensuring that the performance of THE Manufacturing Company 2773 Quality System is reviewed in order to improve its effectiveness. 2774 Other responsibilities include the Internal Audit System, training personnel on the Quality Policy and 2775 Quality System, defining criteria for release of products, assessment and release of incoming raw 2776 materials and packaging items, issuing Quality Holds and Recalls due to internal failure and/or 2777 customer complaints: and authorisation of the IVDD Declaration of Conformity. 2778 The QA Manager reports to the ADD Director, Immunoassay and Clinical Chemistry Quality 2779 Assurance. 2780 Regulatory Affairs Manager
2781 The Regulatory Affairs Manager is responsible to the QA Manager for ensuring that site management is 2782 aware of legal and regulatory requirements, which affect the company and its products. 2783 The Regulatory Affairs Manager has defined regulatory responsibilities for labelling and product safety 2784 including defining the products already on the market to which the IVDD applies, and the classification 2785 of these products according to the various regulations in country of export. The position holder has sign 2786 off authority for non-conformances and all changes to THE Manufacturing Company products. 2787 The position holder facilitates any changes in processes and procedures, which are needed in order to 2788 meet new regulatory requirements. 2789 It is the responsibility of the Regulatory Affairs Manager to ensure the knowledge of national and 2790 international regulatory requirements affecting THE Manufacturing Company ’sproductsismaintained 2791 up-to-date within the Regulatory Affairs Department. This includes ensuring the requirements are met 2792 for both existing and new products. Where appropriate, new requirements are incorporated into THE 2793 Manufacturing Company quality system documentation. 2794 The Regulatory Affairs Manager is responsible for Product Support and has vigilance 2795 responsibilities under the various regulations. 2796 Services QA Manager
2797 The Services QA Manager reports to the QA Manager. This position holder is responsible for the 2798 management of the documentation systems and administration of systems such as change management. 2799 The position holder is also responsible for the environmental quality through the use of effective 2800 sampling and monitoring, and the assessment and release of incoming goods using appropriate sampling 2801 and test methods. These responsibilities are met through the management of accountable teams. 2802 Product QA Manager
2803 The Product QA Manager reports to the Quality Assurance Manager and is responsible for the 2804 management of the trend analysis process which ensures that production departments carry out effective 2805 trend reviews and that appropriate action is taken. Other responsibilities include ensuring that Test
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2806 Method Validation is completed according to plans and approving all product related validation plans 2807 and reports. 2808 Human Resources Manager
2809 Reporting to the Site Director, the Human Resources Manager has responsibility for manpower 2810 resourcing, training, development and education, employee relations and reward. 2811 Manufacturing Services Manager
2812 Reporting to the Site Director, the Manufacturing Services Manager is responsible for all manufacturing 2813 operation 2814 Supply Chain Manager
2815 Reporting to the Site Director, the Supply Chain Manager is responsible for ensuring that all the 2816 Manufacturing areas know what to manufacture; for planning orders on OEM suppliers and for the 2817 availability of purchased materials and other items to support the forecasted demands. 2818 The Supply Chain Manager is supported by a team of Planners and Purchasing staff. Responsibility for 2819 the different aspects of planning and procurement are allocated to these staff. These responsibilities 2820 extend to include the control and design of Packaging Materials. Plans include both quantities and due 2821 dates, and consist of both short- and mid-term requirements. Short-term requirements include specific 2822 lots with priorities and expediting requirements. Longer-term requirements are aimed at ensuring overall 2823 capacity requirements for both labour and plant are communicated in a timely manner to the 2824 manufacturing area Managers and OEM suppliers. Procurement activities aim to optimise quality and 2825 costs whilst maintaining high service level performance. 2826 Health, Safety and Environmental Manager
2827 Reporting to the Operations Manager, the Health, Safety& Environmental Manager is responsible for 2828 providing a comprehensive health and safety service to all functions of the company. The job holder is 2829 responsible for ensuring that the demands of relevant national and international legislation are met, 2830 taking into consideration what is reasonably practicable in relation to the level of risk. 2831 In addition to the above responsibilities the job holder advises on environmental issues which affect the 2832 company's operation. 2833 The position holder is also the Dangerous Goods Safety Advisor for the company and advises on the 2834 shipping of items which are classified as dangerous under the various mandatory codes and regulations. 2835 Research & Development Department Manager
2836 The Research and Development Manager is responsible or all aspects of assay projects within Research 2837 and Development including: 2838 a) the development of new products. 2839 b) the introduction and approval of new and improved materials and processes to 2840 be used for the manufacture of existing products. 2841 c) approval of changes to manufacturing processes. 2842 d) the authorisation of production documentation relating to these projects. 2843 e) the content of the instructions for use.
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2844 f) Validation of new instruments and generation of validation protocols for 2845 running THE Manufacturing Company products. 2846 g) Management of THE Manufacturing Company Marketing Executive who is 2847 the company’s principle customer contact for developing customer 2848 requirements and Marketing Plans. 2849 h) In addition the position holder has responsibility to the Site Director for the 2850 resolution of technical problems related to the performance of products 2851 already on the market. 2852 Facilities Manager
2853 Reporting to the Operations Manager, the Facilities Manager is responsible for installation, service, 2854 maintenance and repair of all manufacturing machinery, building services, utilities, environmental 2855 control equipment and qualification of equipment, utilities and facilities. 2856 The position holder is also responsible for the calibration policy of quality critical devices and for 2857 providing traceable primary reference devices. The Facilities Manager is responsible for ensuring that 2858 the Company complies with all legal and statutory requirements in respect of electrical, mechanical and 2859 building services. 2860 7.2.3. Internal Communication
2861 The senior managers are responsible for communicating customer, statutory and regulatory 2862 requirements to all members of the company. This is achieved by means of All-Employee Meetings, 2863 Team Briefs, Communication Meetings and annual Quality System training. 2864 7.3. Management Review
2865 7.3.1. General
2866 Monitoring and review of the THE Manufacturing Company Quality System is performed by the 2867 Management Review Board (SOP XXX), which includes the Site Director and senior managers from 2868 Operations, R&D and Quality. 2869 At least twice per calendar year the Management Review Board reviews the adequacy and effectiveness 2870 of the THE Manufacturing Company Quality System, and reviews opportunities for improvement and 2871 the need for changes to the quality management system, including the Quality Policy and Quality 2872 objectives. 2873 7.3.2. Review Input
2874 Inputs to Management Review includes review of Internal Audits, Complaint Issues, review of process 2875 and product conformance, Post Market Surveillance Reviews, issues from Corrective and Preventive 2876 Action, Supplier issues, review of training and Regulatory issues and other changes that could Affect 2877 the Quality System. 2878 7.3.3. Review Output
2879 Outputs of the Management Review Board are documented including summaries of data evaluation, 2880 analyses and recommendations and actions relating to the effectiveness of the Quality System and its 2881 processes
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2882 8. Resource Management 2883 8.1. Provision of Resource
2884 THE Manufacturing Company identifies resources required through the budgeting process, and inputs 2885 from the senior managers to maintain the Quality System and ensure Customer and Regulatory 2886 requirements are met. 2887 8.2. Human Resource
2888 8.2.1. General
2889 All staff have a Job Description, describing the primary objective of the position, major accountabilities, 2890 supervisory responsibilities, education and background experience required for the job and an outline 2891 training plan (SOP). 2892 8.2.2. Competence, Awareness and Training
2893 All staff will receive the necessary training to enable them to perform their job effectively and safely 2894 SOP. It is a THE Manufacturing Company policy that all personnel take responsibility for the quality of 2895 their work. This training will be both formal and informal and will be provided by the Human 2896 Resources Department, external trainers or local area supervisors as appropriate. 2897 It is the responsibility of individual managers to assess whether their staff require re-training following 2898 changes to procedures. 2899 Direct job related training will be supplemented by educational and developmental opportunities in line 2900 with the business needs. 2901 Job related, functional training of all critical operating tasks will be provided by a formal system in 2902 accordance with SOP 20/4. This system also covers other non-critical operating tasks, which are of a 2903 functional nature. 2904 Training on the processes and procedures is completed by reading SOPs and signing off on the 2905 Electronic Training Management System (ETMS). If competency assessment is required this is 2906 documented by means of a Training Assessment Form as described in SOP 5/265. 2907 All Departments identify individual training needs on an annual basis via the performance appraisal 2908 process and these are consolidated by the Human Resources Department into a company training plan. 2909 Annual Quality System training is given to all employees and includes consideration of how they can 2910 contribute to the achievement of the quality objectives. 2911 8.3. Infrastructure and Work Environment
2912 Systems have been established to provide an infrastructure to ensure conformity to product requirements. 2913 Where special arrangements are required e.g. Category III working these are defined in specific SOPs 2914 and training is given. 2915 Equipment is qualified and is maintained to ensure continuing process capability. Monitoring the 2916 requirement for maintenance is carried out either locally according to the SOP for the equipment 2917 concerned or by the Engineering Department 2918 Environmental monitoring is carried out, according to SOP 3/59, to ensure that product performance is 2919 not impacted by the environment.
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2920 Facility cleaning is defined by the Cleaning Contract specification for Contract Cleaners, and cleaning 2921 of work surfaces by SOP XXX. The monitoring of Facility cleaning is described in SOP XXX. 2922 Clothing procedures for staff working in manufacturing areas are detailed in SOP XXX.
2923 9. Product Realisation 2924 9.1. Planning of Product Realisation
2925 Stock and work in progress is considered before determining the net requirements. Firm orders for 2926 finished goods are raised on the system and become the driver for the manufacture of lower local 2927 components, bulks and the purchase of raw materials. Purchase orders are also placed for OEM products. 2928 The Design Control Procedures and responsibilities of personnel within the system are described in SOP 2929 XXX. Projects are approved and design goals set within the budgeting process. Products are then 2930 developed according to a procedure which ensures that the product has been designed to meet, the 2931 design inputs. A Design History File (DHF) is compiled during the development of a product, and is 2932 updated throughout the life cycle of the product. The methods of how product is manufactured and 2933 released for sale are detailed in SOPs and POIs for the processes used. 2934 9.2. Customer-related processes
2935 9.2.1. Determination of requirements related to the product
2936 Customer Requirements Document (CRD) and Product Requirement Document (PRD) are written for 2937 new or redeveloped products (SOP XXX). The CRD defines the physical and performance requirements 2938 of a device based on input from internal and external customers. The PRD translates customer 2939 requirements into a technical product description that is measurable and verifiable. These include 2940 statutory and regulatory requirements. 2941 9.2.2. Determination of requirements related to the product
2942 The ongoing review of requirements to ensure customer needs and customer satisfaction are meet is 2943 through the Product Co-Ordination Group, chased by THE Manufacturing Company Marketing 2944 Executive and through annual Post Market Surveillance Reviews (SOP XXX). 2945 At each Design Review, and for changes made during the product life cycle, the appropriate 2946 requirements of the IVDD will be considered. Risk Analysis (User, Patient) is carried out according to 2947 SOP XXX. 2948 9.2.3. Customer communication
2949 Customers are provided with information relating to the products through THE Manufacturing 2950 Company Marketing Executive and the ADD organisation. Information on products is also 2951 communicated to customers through Product Information Letters, follow up of complaint investigations, 2952 Technical Bulletins and communication to the customer where product requirements are not met. 2953 9.3. Design and Development
2954 9.3.1. Design and Development Planning
2955 The design and development activities fall into the key project stages listed below. These are defined in 2956 the Design and Development Plan (SOP X/XXX). At each stage there may be several organisational 2957 functions involved.
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2958 During the course of the project there will be regular reviews of the development activities against 2959 Design Input requirements. 2960 The Design and Development Template is developed into the project plan by the Project Manager and is 2961 circulated to Project Group Members. As the project progresses, the plan is updated/revised as 2962 necessary and re-issued. Progress with the relevant parts of the Design and Development Plan are noted 2963 as the project progresses. 2964 During the initial planning stage, appropriate and adequate resource is assigned to each activity 2965 and this also is reviewed during the course of the project. 2966 Having received the approval to develop a product, the Project Group is the controlling body for a 2967 project. Regular meetings (normally monthly) are held, chaired and minuted by a Project Manager; 2968 copies of these minutes are distributed to Project Group members and appropriate members of the Site 2969 Management Team. Review of progress against the plan is made by this group. 2970 Detailed issues are addressed outside the Project Group at R&D Technical meetings and Operations 2971 meetings. Technical Meetings run by R&D are normally held monthly and include members from 2972 Operations. 2973 Minutes of these meetings form part of the DHF and are circulated appropriately. The functional leader 2974 for a specific area will report back to the next Project on resulting issues. 2975 9.3.2. Design and Group meeting Development Inputs
2976 The Design Inputs are defined according to SOP. The product requirements (SOP) are documented and 2977 agreed by Marketing and R&D. The needs of the user and patient are considered during this process. 2978 A summary of the regulatory requirements relevant to the product in the countries into which it will be 2979 sold is prepared according to SOP XXX. 2980 The conformity assessment route to be followed will be determined according to the risk class that the 2981 product falls into (Refer GHTF GHTF/SG1/N045:2008 Principles of In Vitro Diagnostic (IVD) Medical 2982 Devices Classification). Where a product may, according to the risk classification rules, fall into several 2983 classes, the conformity assessment route must be determined by the highest risk class that may apply. 2984 Products are then designed and developed to meet the specification, with regular reviews of the product 2985 against the Design Inputs. 2986 Current statutory safety requirements are addressed by performing COSHH assessments, providing 2987 Material Safety Data Sheets and in the "Warnings & Precautions" section in the package inserts. Each of 2988 these activities are covered by the Design and Development Plan or project minutes. 2989 9.3.3. Design and Development Outputs
2990 The design output is routinely monitored through Design Review and Technical and Project Group 2991 meetings to ensure that it meets the requirement of the Design Inputs. 2992 Design output in the form of documentation and data such as POIs, QA Specifications, SOPs and 2993 stability reports is reviewed before release. 2994 9.3.4. Design and Development Review
2995 An independent review of the design output against the Design Input Requirements takes place at 2996 various stages during product development including design input, design verification, design validation.
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2997 Prior to release for sale the product is reviewed by Division and appropriate Site Management (SOP 2998 XXX). 2999 For products which will be CE marked under the IVD Directive, Product QA cannot release the first 3000 batch for sale until the Declaration of Conformity is signed. 3001 9.3.5. Design and Development Verification
3002 During the development process R&D undertake evaluations using materials of clinical origin and if 3003 available appropriate external standards to ensure that the product meets the Product Specification (SOP 3004 XXX). A Design Verification review is performed according to SOP XXX. 3005 9.3.6. Design and Development Validation
3006 Design validation is carried out by performing Performance Evaluation Trials under the direction of the 3007 Project Manager. The new product is evaluated against the CRD using clinical samples (SOP XXX). 3008 Results are analysed and assessed by R&D Scientist. Details of how the evaluation is planned and 3009 carried out can be found in SOP XXX. 3010 For products classified by the IVDD as Annex II List A, the requirements of the Common Technical 3011 Specifications are met as part of the Design Validation. 3012 9.3.7. Control of Design and Development changes
3013 During the development phase of a new product any changes which are proposed are reviewed, agreed 3014 by all signatories and incorporated into the Product Specification. 3015 The Design Change Control Procedure is defined in SOP XXX. 3016 Once Design Validation has been undertaken changes are managed through a controlled procedure for 3017 the review, approval and implementation of change which is detailed in SOP XXX. 3018 The correct transfer of product design into POIs is checked by R&D and Manufacturing personnel 3019 during the Pre-Production Phase (SOP XXX). 3020 Process validation is a key part of design and development in order to ensure quality critical processes 3021 are sufficiently well defined and controlled. 3022 The DHF (SOP XXX) is completed throughout the Design Phase. It is a compilation of records which 3023 describe the design history of the finished device and includes the Design and Development Plan, the 3024 Product Specification and the dossier from each review meeting. 3025 9.4. Purchasing
3026 9.4.1. Purchasing Process
3027 Materials which form part of the manufacturing process for THE Manufacturing Company products are 3028 identified by means of an item coding system. Ad hoc purchases for R&D purposes, facilities 3029 maintenance and administration are dealt with separately. Where possible THE Manufacturing 3030 Company item codes are linked to supplier catalogue codes and both are stated on purchase orders. 3031 Where this combination is not possible, technical specifications are agreed with suppliers and 3032 referenced to THE Manufacturing Company item code. These specifications define the dimensional 3033 and quality requirements together with any other parameters critical to the performance and 3034 acceptability of the item being purchased.
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3035 Where a finished product is purchased from an OEM supplier, the process for evaluation and approval 3036 of the product is defined in SOP XXX. 3037 Suppliers are selected on the basis of ability to supply the required items or services at the right quality 3038 in the most timely and economic manner. 3039 Suppliers are the subject of a rating/approval scheme (SOP XXX) which assesses either the suitability 3040 to supply (for a new supplier) or the effectiveness of supply (for existing suppliers). Ratings are 3041 regularly reviewed and updated and the results of the review process determine the priority of the 3042 requirement to audit. 3043 Suppliers are approved following assessment of their Quality System (SOP). A list of Approved 3044 Suppliers is maintained. 3045 9.4.2. Purchasing Information
3046 Requirements are communicated to suppliers by means of authorised Purchase Orders. Purchasing 3047 documents are controlled by Standard Operating Procedures. 3048 Purchase Orders will contain references, as appropriate, to THE Manufacturing Company Item Codes, 3049 Supplier Catalogue Codes, agreed Technical or Purchasing Specifications or legal agreements between 3050 THE Manufacturing Company and the Supplier. If necessary, copies of specifications, drawings etc. 3051 will be referenced in the Purchase Order document and that document will be annotated accordingly. 3052 Review and authorisation of Purchase Orders is carried out as described in SOP XXX. Purchase orders 3053 are quality records and are retained for traceability purposes. 3054 9.4.3. Verification of Purchased Product
3055 Inspection and verification of incoming goods, including raw materials, packaging components and 3056 instrumentation is carried out according to documented procedures. 3057 Testing is only performed at THE Manufacturing Company when quality critical material is involved 3058 and it is not possible to be sure that adequate controls are exercised at source. If components are 3059 required urgently for production, there are systems to allow production to progress before testing has 3060 been completed, but the final product cannot be released before the testing has been completed 3061 satisfactorily. 3062 9.5. Production and Service Provision
3063 9.5.1. Control of Production and Service Provision
3064 Manufacturing processes are controlled in accordance with Process Operating Instructions (POIs) or 3065 Production Specifications. Some processes, such as filling, are monitored and controlled using statistical 3066 process control techniques throughout the operation. 3067 Product structure and routing information to support the production of products is defined by Product 3068 Structure & Routing Specifications which are controlled by the Planning Section. 3069 Products are manufactured using software, facilities, utilities, equipment, materials and processes that 3070 have undergone appropriate validation (SOP XXX). 3071 Transfer of manufacture of antibodies and recombinant proteins between ADD sites is detailed in SOP 3072 XXX.
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3073 All materials from Incoming Goods through intermediate manufacturing stages to final product are 3074 handled in accordance with written, approved specifications and Standard Operating Procedures. 3075 The intention of THE Manufacturing Company is that premises are as far as possible suited to their 3076 intended use, being secure, of adequate size and design to allow product security by minimising the risk 3077 of mix-up occurring. Safety, ease of cleaning and adequate pest control receives high priority. 3078 Procedures are followed to maintain labelling integrity and to prevent labelling errors. 3079 The packing process, including the information printed by THE Manufacturing Company on the labels 3080 and packaging, is controlled by Product Structure & Routing specifications. 3081 Final product can only be picked for distribution if it has been approved for issue by Product QA. 3082 Product packaging and shipping containers are designed to protect the products from damage during 3083 normal conditions of storage, handling and distribution. 3084 Records relating to the identification and quantity of product shipped and the identity of the consignee 3085 are retained. 3086 Installation and Servicing Activities are not undertaken by THE Manufacturing Company . 3087 9.5.2. Validation of Processes for Production and Service Provision.
3088 The approach to validation is defined in SOP XXX. 3089 Equipment qualification is performed to ensure that equipment used in the manufacture of quality 3090 critical processes has been designed to meet the needs of that function and will operate consistently to 3091 meet the needs of the intended process (SOP XXX). 3092 Process validation is performed to establish a high level of confidence that quality critical processes are 3093 sufficiently well controlled so as to ensure a consistently high level of quality in terms of efficacy and 3094 product stability (SOP XXX). 3095 Test Method Validation is performed to establish that the performance characteristics of the method 3096 meet the requirements of the intended use of the test (SOP XXX). 3097 Software validation is completed according to SOP XXX. 3098 9.5.3. Identification and Traceability
3099 Materials used as part of the manufacturing process for products are identified by a part code and the 3100 manufacturer's lot number or the THE Manufacturing Company allocated batch number. All 3101 intermediate products and bulks are identified by unique THE Manufacturing Company lot numbers 3102 assigned by Manufacturing. 3103 Final components and kits are labelled with the component or kit product code together with individual 3104 batch numbers. The Batch Histories which are maintained by the Quality Assurance Department can be 3105 used to trace the history of the product or component batch to the Production Records kept by 3106 Manufacturing. 3107 Material/component/product status is computer driven and under the control of Purchasing Quality 3108 Services/Product QA. Product release for sale is the responsibility of the respective Product QA 3109 Manager, but may be delegated to appropriate authorised personnel from within Quality Assurance.
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3110 Inspection and testing activities which verify that the specified requirements for that product are met are 3111 defined in the relevant Quality System Procedure. 3112 In-Process inspection and testing of THE Manufacturing Company products is carried out by 3113 manufacturing personnel following procedures described in Production Specifications. Quality 3114 Assurance personnel also perform in-process inspection and testing following QA Specifications. 3115 Depending on the results of the inspection and testing, products may be passed, referred or rejected. 3116 Final inspection, and testing where appropriate, of THE Manufacturing Company products is carried 3117 out by Quality Assurance personnel following QA Specifications. 3118 For CE marked products classified as Annex II List A products, the Product QA Manager is responsible 3119 for ensuring that the verification of manufactured product by the Notified Body is received before the 3120 batch is released for sale (SOP XXX). 3121 Production records containing the results of inspection and testing by Manufacturing personnel are held 3122 within the Manufacturing area before archiving. 3123 Batch Histories (Secondary Manufacturing records and Quality Assurance testing of each product batch) 3124 are held accessible as original hard copy for up to 3 months beyond the expiry of the product. Beyond 3125 that point QA records are archived in the form of microfiche. The personnel responsible for the release 3126 of product are defined in appropriate SOPs and indicated on the Batch Histories. 3127 9.5.4. Preservation of Product
3128 Storage areas preclude adverse environmental effects on stored materials and allow orderly stock 3129 control by providing effective separation of different materials and materials of different status. 3130 Appropriate facilities are available for the storage and handling of materials that are potentially 3131 infectious. 3132 9.6. Control of Monitoring and Measuring Devices
3133 All quality influencing equipment is subject to regular calibration and is traceable to national standards. 3134 The management of routine calibration work will, for the most part, be the responsibility of the 3135 Facilities Manager. This responsibility will be shared by responsible personnel in each area who ensure 3136 that only properly calibrated equipment is in routine use. 3137 The frequency with which equipment is calibrated and the tolerances that are allowed before 3138 adjustments are made will be as recommended in manufacturer's user guides and/or service manuals. In 3139 deciding on the optimum retest cycle and adjustment limits the Engineering Department will take 3140 account of the reliability and criticality of the relevant equipment. 3141 Calibration records will be kept adjacent to the relevant equipment in the various operating areas and/or 3142 centrally by the Engineering Department as appropriate. 3143 Implementation of this policy is controlled in SOP XXX. 3144 Where products contain calibrators or quantified controls, traceability to an independent standard where 3145 available is ensured through Design Input and the QA Release Specifications.
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3146 10. Measurement, Analysis and Improvement 3147 10.1. General
3148 Procedures have been designed / developed and implemented to monitor 3149 if customers requirements for products and service delivery have been met, 3150 the effectiveness of the Quality Management System, 3151 and the ongoing improvement of the Quality Management System. 3152 10.2. Monitoring and Measurement
3153 10.2.1. Customer Satisfaction
3154 Procedures have been developed and implemented, which define the process for the determination of 3155 product and service quality levels. 3156 End-user satisfaction is monitored by the country organisations. The country organisations provide 3157 feedback through the complaint management system. A review is held annually for each product (SOP 3158 XXX) as part of Post Market Surveillance. 3159 10.2.2. Internal Audit
3160 Internal audits are co-ordinated by the Audit Co-ordinator within QA and are performed by trained 3161 internal auditors from a range of Departments. Audits are performed by personnel independent of the 3162 process or area being audited. 3163 Audits are performed of specified activities (e.g. Hold/Corrective Action, Control of Change, 3164 Calibration) and of specific areas, to cover all relevant aspects of IS0 9001, ISO 13485 and the IVDD. 3165 The procedure followed is described in SOP XXX. 3166 The progress with corrective actions arising from internal audits involves visits to the appropriate area. 3167 Failure to meet agreed dates is highlighted to the CAPA Oversight Review Board. 3168 10.2.3. Monitoring and Measurement of Processes and Product
3169 Processes have been designed and implemented to ensure that the data on records relating to the Quality 3170 Management System, and product quality are gathered, evaluated and analysed for trends. This trend 3171 data is then used to implement corrective and/or preventive actions. 3172 In-process materials are sampled, inspected and tested by trained personnel in accordance to 3173 documented standardised and validated test procedures. Requirements are stated in the applicable 3174 testing procedures and sampling plans. 3175 Material conformance is based on test and/or inspection results and work order review. Disposition is 3176 assigned by trained personnel. Materials are held until all tests and inspections have been completed and 3177 approved. Any non-conforming in-process materials are controlled, segregated, where practicable, and 3178 the non-conformity documented. 3179 Final sampling, testing, inspection and disposition of product are done by trained quality personnel in 3180 accordance to documented standardised and validated test procedures. Requirements are stated in the 3181 applicable testing procedures and referenced sampling plans.
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3182 Final product test records, certifying that all required tests have been satisfactorily completed, are 3183 required prior to disposition by authorised personnel. 3184 Appropriate statistical techniques are used for packaging materials inspection, and in-process inspection 3185 and testing during manufacture. These are defined in the relevant SOPs. 3186 Where appropriate, sampling methods are reviewed in the light of non-conformances in product or 3187 processes or other appropriate information. 3188 Assessment of product performance for Design Verification is performed using techniques which are 3189 the accepted norm in the IVD industry. 3190 Product trend are reviewed according to SOP XXX. 3191 Product is released to distribution upon final approval or, in cases where regulatory requirements have 3192 to be met upon regulatory approval or consent (e.g. in case of notifications). The stability of products is 3193 monitored after release for sale (SOP XXX). 3194 10.3. Post-market surveillance and measurement
3195 A post market surveillance and reporting system (SOP XXX and Recall SOP XX) is followed which 3196 aligned with the responsibilities outlined in the WHO document Post-Market Surveillance of in vitro 3197 diagnostics. 3198 The aim of the system is to ensure that nonconformities, changes and complaints are identified and 3199 examined including a risk analysis (as per figure 2 pg 14 of PMS guidance), and that necessary action is 3200 taken. 3201 Any customer complaints are to be documents by the team member in charge of complaints reporting as 3202 per SOP XX. 3203 It is the responsibility of the safety officer to perform a risk analysis. The responsibilities of all staff 3204 involved in post market surveillance is outlined in SOP XXX. 3205 QM manager that an analysis of risks and causes and initiation of a CAPA is undertaken as per SOP 3206 XXX. The timeframe for the investigation depends on the severity of the adverse event as defined by 3207 Table 4 pg 25 of PMS guidance. 3208 10.3.1. Recalls
3209 Recalls are measures to avert the risks to customers due to products that have deviated from the 3210 intended product specifications. Product recalls involve the following actions 3211 Notification of customers and users 3212 Returns 3213 Destruction 3214 Revision of IFUs 3215 The recalls procedure is described in SOP XXX. THE Manufacturing Company follow: 3216 MEDDEV 2 12-1 rev. 8 Vigilance, European Commission guidelines on a 3217 medical devices vigilance system 3218 GHTF/SG2/N54R8:2006 Medical Devices Post Market Surveillance: Global 3219 Guidance for Adverse Event Reporting for Medical Devices,
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3220 GHTF/SG2/N008R4:1999 Guidance on How to Handle Information 3221 Concerning Vigilance Reporting Related to Medical Devices, 3222 GHTF/SG2/N57R8:2006 Medical Devices Post Market Surveillance: Content 3223 of Field Safety Notices
3224 10.4. Control of Nonconforming Product
3225 The control of non-conforming raw material or components and non-conforming final product is the 3226 responsibility of appropriate Quality Assurance personnel. The procedures followed are described in 3227 SOP XXX. The procedure for quarantining non-conforming material is detailed in SOP XXX. 3228 Appropriate corrective action following a product failure after release is initiated and co-ordinated by 3229 the Quality Assurance Manager. The procedures followed are described in SOP XXX. 3230 The review and disposition of non-conforming product is carried out according to SOP XXX. 3231 If product is reworked, the specific requirements of SOP are followed. It is the responsibility of the 3232 Regulatory Affairs Manager or agreed deputy to ensure regulatory requirements are met before 3233 authorising a non-conformance report. The procedure for the complete rejection of product and 3234 subsequent disposal is described in SOP XXX. 3235 10.5. Analysis of Data
3236 Procedures have been implemented to collect and analyse appropriate data. Data is evaluated for the 3237 reviews by Site Management. 3238 10.6. Improvement
3239 Post Market Surveillance and related activities to meet the requirements of the IVDD 3240 (Annex III (5), Annex IV (3.1) or Annex VII (3.1)) is carried out according to SOP 3241 XXX for ALL products, regardless of the regulatory version. 3242 10.6.1. Continual Improvement
3243 Data on trends in non-conformances related to the Quality Management System, suppliers, product and 3244 processes are input to the Management Review Meeting to determine that appropriate corrective / 3245 preventive action is taken. 3246 10.6.2. Corrective Action
3247 Customer complaints are received, investigated, reported, and replied to by the Product Support Group. 3248 SOP XXX describe the procedures followed and include the requirements for Vigilance reporting under 3249 the various regulations. 3250 The investigation of the cause of non-conforming product following customer complaints is detailed in 3251 SOP XXX if action is required for products with customers. 3252 The procedure for investigations and defining of Corrective Action following a non-conformance or a 3253 Customer Complaint is detailed in SOP XXX. Subsequent to implementation of that Corrective Action 3254 Plan, the effectiveness of the action is reviewed. 3255 The following SOPs outline the activities associated with corrective action and preventative actions. 3256 Control of non-conforming products
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3257 Control of non-conforming incoming goods 3258 Control of key suppliers 3259 Customer complaints 3260 Internal audits 3261 Risk management policy 3262 10.6.3. Preventive Action
3263 A variety of sources of information are reviewed in order to detect, analyse and eliminate potential 3264 causes of non-conformities. The information reviewed includes Non-Conformance reports, 3265 Investigations and Corrective Actions, reports of internal and external audits, Change Notes, trend 3266 analysis and complaints. 3267 Preventive action is progressed or monitored by the Management Review Board (SOP XXX).
3268 10.6.4. Control of key suppliers
3269 Suppliers are subject to an approval evaluation before being included in the approved list of suppliers. 3270 The suppliers of quality related products and key components (as identified by the risk analysis) are 3271 subject to yearly evaluation (SOP XXX and rating scale SOP XXX). The evaluation is organized by the 3272 purchasing team and overseen by the quality management department. Yearly evaluation is conducted 3273 on a risk based analysis and frequency may be decreased by as on SOP XXX. The suppliers are 3274 evaluated on a number of different indicators: 3275 Quality management 3276 Commercial aspects and pricing 3277 Service 3278 Ability to meet deadlines and quantity requirements 3279 Internal feedback is also used for continual yearly evaluations. 3280 3281 ------END OF DOCUMENT------3282
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