International Organization for Standardization 

ISO 13485:2016 Medical devices ‒ Quality management systems ‒ Requirements for regulatory purposes

ISO 19011:2018 Guidelines for auditing management systems

ISO 14971:2019 Medical devices ‒ Application of risk management to medical devices
Note: EN ISO 14971:2012 applies only to manufacturers placing devices on the market in Europe; for the rest of the world, ISO 14971:2007 remains the applicable standard.

ISO 9000:2015 Quality management systems – Fundamentals and vocabulary

ISO 9001:2015 Quality Management Systems ‒ Requirements

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

ISO 15223-1:2016 Symbols to be used with medical device labels, labelling and information supplied ‒ Part 1 General requirements

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

Global Harmonization Task Force (GHTF), available on the IMDRF site

GHTF/SG1/N071:2012 Definition of the terms 'Medical device' and 'In vitro diagnostic (IVD) medical Device

GHTF/SG1/N70:2011 Label and instructions for use for medical devices

GHTF/SG3/N19:2012 Quality management system – medical devices – nonconformity grading system for regulatory purposes and information exchange

GHTF/SG3/N18:2010 Quality management system – medical devices – guidance on corrective action and preventive action and related QMS processes

GHTF/SG3/N17:2008 Quality management system – medical devices – guidance on the control of products and services obtained from suppliers

GHTF/SG3/N15R8 Implementation of risk management principles and activities within a quality management system

GHTF/SG3/N99-10:2004 (Edition 2) Quality management systems – process validation guidance

GHTF/SG4/N84:2010 Guidelines for regulatory auditing of quality management systems of medical device manufacturers – Part 5: Audits of manufacturer control of suppliers

WHO

Overview of WHO prequalification of in vitro diagnostics assessment (version 8, 1 August 2018)

Abridged prequalification assessment: prequalification of in vitro diagnostics (PQDx_173 v3, 12 September 2017)

Information for manufacturers on the inspection of manufacturing sites (Assessment of the quality management system) (PQDx_014 V4, 8 September 2017)

Prequalification assessment and change assessment target deadlines (PQDx_300 v1, 21 July 2017)

Reportable changes to a WHO prequalified in vitro diagnostic (PQDx_121 v2, December 2016)

WHO and CLSI

Evaluation of stability of in vitro diagnostic reagents: approved guideline (CLSI EP25A Vol.29 No. 20)

IMDRF MDSAP (Medical Device Single Audit Program)

MDSAP_AU_P0019.004: Medical Device Regulatory Audit Reports Policy

Other Reference Documents (European Commission)

The standards listed at the following website are harmonized standards and thus conformity with the relevant essential requirements is assumed:
http://ec.europa.eu/enterprise/policies/european-standards/documents/harmonised-standards-legislation/list-references/iv-diagnostic-medical-devices/index_en.htm

Common Technical Specifications on IVD are published under: "Other amending and implementing legislation" at http://ec.europa.eu/health/medical-devices/documents/index_en.htm

The responsibilities of the manufacturer will be communicated to the manufacturer before the inspection. It is expected that the manufacturer will be responsible for:

• agreeing upon the objectives and the scope of the inspection with the WHO prequalification team
• inform the WHO prequalification inspection team of any issues that may affect an effective and efficient inspection process
• cooperating with the inspectors to ensure that the objectives of the inspection are achieved
• appointing an employee to be responsible for coordinating and facilitating the inspection process on behalf of the manufacturer
• informing relevant employees and personnel about the objectives and scope of the inspection
• determining which members of staff will accompany members of the inspection team
• ensuring that the inspectors are aware of health, safety and other applicable requirements
• providing on-site resources, such as a meeting room, for the inspection team, in order to ensure an effective and efficient inspection process
• providing full access to the manufacturing facilities, documents and records and other evidence as requested by the inspectors, in a timely manner, to ensure an effective and efficient inspection process and so that the inspection timetable can be adhered to.

If nonconformities are identified during inspection of the manufacturing site, information about these will be provided to the manufacturer at the closing meeting. The manufacturer will subsequently receive an inspection report that will include the nonconformities. Upon receipt of the inspection report the manufacturer will be required to:

• determining the root cause of all nonconformities identified
• determining the corrective actions to be implemented, including those aimed at preventing recurrence of the nonconformities
• submitting a corrective action plan to WHO within 30 days of receipt of the final inspection report
• implementing and verifying the effectiveness of the corrective actions in a timely manner
• informing WHO of completion of these corrective actions, as required
• informing WHO of any subsequent significant change to the quality system or the product
• informing all those personnel who may be impacted by the results of the inspection.

An on-site inspection will seek to confirm the adequacy and effectiveness of the manufacturer’s documented quality management system (QMS), with emphasis on the control of the production processes and compliance with state-of-the-art practices, including WHO technical guidelines.

Documents and records from all levels of the quality system will be reviewed. Post-market surveillance data, as well as marketing and training material, may be included in the review.

Informal interview of personnel at all levels and discussions with persons selected by an inspector will form part of the inspection process.

Evidence will be collected on-site, as follows:

• by examination of documents, including standard operating procedures and records
• by visual observation of activities
• by visual observation of environmental conditions
• by confirmation of statement of fact that is acquired through interviews and may include
  • random sampling of product for laboratory quality control testing
  • photographs.

Nonconformities identified during the document review or interviews will be notified to the accompanying representative of the manufacturer and may be verified by acquiring additional information where possible. The manufacturer will be given an immediate opportunity to comment on the evidence of nonconformities. Based on this evidence, a nonconformity, even if corrected immediately, will be noted and form part of the final inspection report.

QMS inspection overview

The QMS inspection will be conducted in a format that follows the production process. Note that ISO13485 is used as a basis for the inspection and that other product and system-related standards and references may be used by the manufacturer to ensure good practice in the manufacture of the IVDs.

The QMS inspection process includes, but is not limited to the following processes:

• management: to ensure that an adequate and effective QMS is in place, including management review
• product documentation, including design and development: to ensure that the manufacturer has established sufficient documented systems and adequate communication of the systems (including change control) to all personnel, to ensure a quality product outcome
• production and process controls: to ensure that the manufacturer has established sufficient systems such as testing, infrastructure, facilities, equipment and personnel to ensure a quality outcome; demonstrated independence between the production and quality unit and that the quality unit controls release of product batches
• corrective and preventive actions, internal audits: inspection of this section is to confirm that the manufacturer collects and analyses actual and potential quality problems through investigation and appropriate action
• purchasing controls: especially important when significant components are outsourced – the manufacturer must ensure that raw material, intermediates, components and services provided by suppliers are of an appropriate standard
• documentation and records: to ensure that relevant documents and records are defined, established and controlled, for example, by being updated and properly authorized; and to ensure procedure and process documents are readily available and in routine use by staff as needed
• customer-related processes: in this context, customers include purchasers and users of the product and relevant regulatory bodies
• training of personnel and training records: to ensure that qualifications and training of personnel are appropriate to the tasks required of them
• infrastructure and work environment: to ensure the adequacy of facilities, manufacturing, equipment, monitoring and quality control equipment; calibration and maintenance.

Verification of data supporting IVD product dossier submission

During the inspection, an inspector will sample the quality records and reports that support the data submitted with the product dossier for WHO prequalification. This may include, but is not limited to, data recorded for the batches submitted for WHO performance evaluation or testing, data collected in performance studies (internal and independent external), quality control data and batch manufacturing records. The manufacturer must ensure that the entire product dossier submitted to WHO is available on-site during the time of the inspection.

MCD technical/production inspection overview

The technical inspection will be conducted in a format that follows the production process. The numbers in brackets indicate the area of ISO 13485: Medical devices – Quality management systems – Requirements for regulatory purposes that are relevant to this process.

• Planning of product realization (7.1)
• Customer-related processes (7.2)
• Design and development (7.3)
• Purchasing (7.4)
• Production and service provision (7.5)
• Control of monitoring and measuring devices (7.6).

Organization of an inspection of an IVD manufacturing site is similar to organization of an inspection of an MCD manufacturing site. Where the two differ, this is indicated by the prefixes: "For an IVD inspection", "For an MCD inspection".

The dates and time allocated for the inspection are to be agreed upon by all participants under the guidance of the WHO Lead inspector and will be documented in an inspection plan. The inspection should be scheduled for a time when:

• the production line of the product undergoing prequalification assessment is active (if several products are inspected during the same inspection, the production line for at least one must be active)
• quality control activities are being performed
• the key personnel for the quality management system (QMS), quality control and production line will be present.

Usually the inspection plan will be provided one to two weeks prior to the inspection and will include details of the type of inspection to be conducted and the sites and products to be inspected, using information about the product and QMS that has already been submitted, and including the quality manual. The plan is a guide only and will be flexible to permit changes in emphasis based on information gathered during the inspection.

The inspection plan will include the following information:

• the scope and purpose of the inspection of the manufacturing site
• identification of inspection team members and of the contact person representing the manufacturer for the inspection
• date and place of the inspection
• expected time and duration of each inspection activity, including meetings to be held with the manufacturer's management team.

The time allocated to the inspection will be calculated according to the complexity of the scope of the inspection, the number of manufacturing technologies, and the number and type of IVDs undergoing assessment for prequalification. The WHO Lead Inspector will allocate responsibilities to the inspection team members according to their expertise and inspection requirements.

Documentation regarding subcontractors, outsourced processes and significant suppliers (critical suppliers)

For an IVD and MCD manufacturing site: The manufacturer must have the necessary documentation available to demonstrate that the processes to control product supply are effective and meet the relevant quality expectations. This includes, but is not limited to, documentation relating to providers of critical raw material, interim components, packaging or other services used to produce the IVD. The manufacturer shall be responsible for the sufficient control of any critical supplier, including outsourced processes. If this requirement is not sufficiently met, a nonconformity against the respective ISO 13485 requirement will be issued and an inspection of subcontractor sites may be necessary.

The report for an inspection of an IVD manufacturing site is similar to that for an inspection of an MCD manufacturing site. Where the two differ, this is indicated by the prefixes: "For an IVD inspection", "For an MCD inspection".

Overview

The purpose of the inspection report is to provide:

• the manufacturer with information on nonconformities identified during the inspection: identified examples of nonconformity must be investigated to determine what corrective actions to take to prevent recurrence of the nonconformity and then those corrective actions must be implemented
• the manufacturer with information upon which to base improvements to the quality of the manufacturing system
• a permanent record of the findings of the inspection
• recommendations to the WHO team on actions to be taken following the inspection.

A more detailed description of the purpose of the inspection report can be found in guidance such as IMDRF/MDSAP WG/N24 FINAL: 2015 – Medical device regulatory audit reports and ISO 19011:2011 Guidelines for auditing management systems.

The WHO Lead inspector will prepare the inspection report and is responsible for its accuracy and content.

For an IVD and MCD inspection: A final inspection report will be issued by WHO to the manufacturer generally within 30 days of the inspection, although this time may extend during periods of high workload. If a final inspection report cannot be issued within a 30-day timeframe, the manufacturer will be notified accordingly. The manufacturer understands and agrees that WHO will have absolute, exclusive control over the manner in which the inspection is carried out, including publication of the results of the inspection, irrespective of the outcome. The manufacturer also understands and agrees that WHO reserves the right to share the manufacturer's prequalification application and related information, as well as the results of the inspection and the full inspection reports, including any drafts thereof and including (subject to appropriate obligations of confidentiality) any confidential information to which WHO may gain access in the course of the prequalification process and/or inspection, with the relevant authorities of any interested Member State of the Organization, with interested national regulatory authorities (NRAs), and with relevant inter-governmental organizations. As used here, "Confidential information" means:

• confidential intellectual property, know-how and trade secrets (including, e.g. formulas, processes or information contained or embodied in a product, unpublished aspects of trade mark, patents, etc.);
• commercial confidences (e.g. structures and development plans of a company).

Contents of an inspection report

An inspection report generally includes:

• the purpose, scope and objectives of the inspection, including the manufacturing site(s), processes and the product(s)
• details of the inspection team
• details of the areas covered in the inspection
• limitation of the inspection or product
• details of nonconformities (and their relative severity) and date for submission of any corrective actions required
• comment and conclusions about the effectiveness of the manufacturer's quality system in meeting quality objectives
• summary of conclusions
• authorized signature and date of the report.

The report will include the following comment: "This report contains the collective views of the inspection team performing this inspection and does not necessarily represent the decisions or the stated policy of the World Health Organization."

Nonconformities

During the on-site inspection, nonconformities may have been identified with respect to:

• quality management system (QMS) inspection criteria
• verification of data supporting the product dossier claims.

Both types of nonconformities, as well as the objective evidence contributing to the nonconformity, including the inspection criterion that was not met, will be individually stated and described in the manufacturing site inspection report.

The severity of nonconformities will be classified according to the Global Harmonization Task Force SG3 N19:2012 document: with level 1 being the lowest level on nonconformity and level 5 the highest. The QMS shall be considered critically deficient, if the following occur:

• 1 or more level 5 nonconformity(s) or
• 7 or more level 4 nonconformities.

Additional findings to the same requirement may contribute to the severity grading of a nonconformity, thus raising its level. If any nonconformities are included in the final inspection report, a corrective action plan (CAP) shall be submitted to WHO by the manufacturer within 30 days after receipt of the final inspection report. For each identified nonconformity, the CAP shall include:

• a root-cause analysis
• the corrections required for the identified nonconformities
• the corrective actions required to remove the cause and to prevent recurrence
• a timeline for implementation of corrections and corrective actions
• indication of those responsible for implementation
• evaluation of the effective implementation of the corrective action(s).

The manufacturer must provide the CAP to WHO in an editable format, such as a Word document or Excel spreadsheet. This will facilitate communication regarding the approval or rejection of the CAP, or a request for additional information and documents. 

WHO review of corrective action plan

The WHO lead inspector will request, and the inspection team will review submissions from the manufacturer relating to correction of the nonconformities. Thereafter, if:

• the CAP submissions are acceptable to WHO, the WHO lead inspector will notify the manufacturer by letter that the inspection and follow-up are complete
• the manufacturer’s CAP submissions are not acceptable to WHO, the WHO inspector will request an improved CAP and may ask the manufacturer for further evidence of their effectiveness/implementation. In such cases, both the improved CAP and the additional evidence must be presented by the manufacturer to WHO within 30 days of receipt of the first CAP review report received from WHO
• if the effective implementation of corrective actions cannot be evaluated by document review, a follow-up inspection will be required before the nonconformities may be closed out.

Before finalizing the manufacturing site inspection, all nonconformities identified in the inspection report must have been satisfactorily corrected (as determined by WHO) by the manufacturer. However, sometimes a satisfactory outcome is not reached if, for example:

• the manufacturer does not submit (whether within the specified timeline, or at all) a CAP to WHO
• the manufacturer is unable to implement all agreed corrections and corrective actions during the agreed time period
• more than six months have elapsed after the initial inspection and the manufacturer has still not provided WHO with satisfactory responses to the identified nonconformities.

In any of the above cases, the manufacturer’s application for WHO prequalification of the product(s) concerned will be terminated by WHO and a new application will be required and an evaluation for prequalification of the product is to be initiated once more.

Any subsequent application for WHO prequalification will not be accepted unless and until the manufacturer submits sufficient evidence demonstrating that the nonconformities have been corrected. If the manufacturer's QMS was found to be critically deficient, a re-inspection and review of any available additional data must take place before the inspection component can be completed.

Retention of inspection reports

WHO and the manufacturer shall retain inspection reports and associated documentation for the period of 3 consecutive inspections and for 5 years following the last inspection.

Review of corrective action plans to remedy nonconformities

The WHO inspector will be responsible for requesting, reviewing and reporting on the manufacturer's responses to nonconformities observed during the inspection.

For an IVD and MCD inspection: The manufacturer will have a maximum of two opportunities to supply WHO with the necessary information to correct nonconformities and implement corrective actions to prevent recurrence in a timely manner, usually within one month of the request.

The manufacturer will supply such information and correct the nonconformities identified during the inspection within 30 days of the request for information, unless WHO agrees in writing (given the nature of the nonconformities) to grant the manufacturer an extended time period in which to supply the requested information.

Inspections for prequalification: In certain cases, WHO may agree, at its sole discretion, to permit the manufacturer to correct specific nonconformities after prequalification, provided that the manufacturer commits in writing to correct them by an agreed deadline. Such a "commitment to prequalification" will be monitored by the WHO Lead Inspector and verified during the re-inspection. Failure to comply with prequalification commitments within agreed deadlines will result in the delisting of the product from the relevant WHO list of prequalified products. If the manufacturer fails to respond adequately to requests for submissions relating to nonconformities in the requested timeframe, the process will be terminated and the manufacturer will have the option to reapply for prequalification in 12 months from the date of termination.

Completion of the inspection of a manufacturing site(s) and re-inspection

When the identified nonconformities have been corrected, corrective actions to prevent recurrence have been implemented by the manufacturer as requested by WHO, and the results accepted by WHO, the manufacturer will receive a letter advising it of the completion of the inspection process.

The re-inspection period will be determined by WHO using a risk management approach that takes into account all of the information from the product dossier review, performance evaluation and inspection.

Criteria for not recommending prequalification 

Based on the consensus view of the inspectors, and following review by WHO, it may be recommended that the product not be included in WHO's List of Prequalified In Vitro Diagnostics Products. Criteria/reasons used for not recommending a product's inclusion may include:

• failure to maintain an adequate quality system (deficient quality system)
• falsification of data or submitted evidence or deliberate misrepresentation of facts regarding the manufacturing and quality system (level 5 nonconformity)
• excessive number of nonconformities level 4 identified (see above)
• failure to implement appropriate action when post market data has identified a pattern of defects
• failure of the product to meet the manufacturer's own specifications
• failure of the manufacturer to respond adequately to requests for submissions relating to nonconformities.