Independence

The inspectors (WHO staff members and selected regulatory and technical experts) shall be impartial and free from influences that could affect their objectivity.

Inspection objectives and scope

The objectives and scope of the inspection of the manufacturing site shall be defined in a general inspection plan provided to the manufacturer and agreed upon with the manufacturer before the inspection. Modification of the plan may occur to accommodate the manufacturing site's processes and to follow audit trails depending on the observations made at the time of the inspection..

Roles and responsibilities

Roles and responsibilities of all personnel involved in the assessment shall be clearly defined so that expectations can be met and accountability maintained.

Resources

Resources shall be adequate in terms of competent inspectors, expertise as deemed necessary, time allocation, and access to external technical and other information. The resources used shall ensure that the inspection results are highly reliable.

Competence of the inspection team

The inspection team shall consist of WHO staff and external experts appointed by WHO (inspectors) with inspection skills and with the education and experience in regulatory requirements and device technologies appropriate for their tasks during the inspection. Representatives of the national regulatory authorities, procurement agencies of WHO Member States, representatives of other United Nations agencies, and other WHO staff members may accompany the inspection team to the manufacturing site(s) as observers or for training purposes.

Consistency of procedures

The inspection procedure shall be performed according to defined guidelines and with a lead inspector to enable consistency during the inspection. The WHO staff member responsible for inspections will oversee consistency between inspections of the same type and scope.

Adequacy of inspection documentation

Documentation associated with each inspection, such as inspection reports, shall provide adequate information related to the prequalification assessment of the product and to the post-prequalification phase, for continuity between successive inspections and to provide opportunities for quality improvement to the manufacturer.

Confidentiality and standard of conduct

The inspectors shall maintain confidentiality with regard to confidential information and documentation related to the inspection, and shall comply with the applicable WHO standards of conduct and WHO conflict of interest rules. Within these considerations, the inspection process is to be transparent to all participants.

Inspection results and conclusions

The results and conclusions of the inspection shall be consistent and accurate subject to the normal limitations of an inspection, noting that the objective evidence collected during the inspection is generally a sample. The grading of nonconformities is the responsibility of WHO, including the final release of all reports.

Quality system

WHO inspections are conducted in compliance with the prescribed WHO prequalification quality management system.

A WHO inspection team generally consists of:

• at least one WHO staff inspector, who serves as the lead inspector;
• one co-inspector from from a stringent national regulatory authority (NRA) inspectorate, Pharmaceutical Inspection Co-operation Scheme (PIC/S) country or a recognized individual (eg. ex-rotational inspectors or ex-WHO staff members inspector)
• an expert (for most in vitro diagnostic (IVD) and vaccine inspections only)
• a qualified interpreter, if the language used at the inspection site other than English, and whose role is to facilitate communication between the inspection team and the manufacturer' personnel, to support open and effective communication throughout the inspection.
• an observer, if an observer is available/nominated to attend, for instance from an inspection agency or an inspection trainee; not considered to an inspector but who must nevertheless comply with the same standards of conduct as the inspectors).

Inspection roles and responsibilities

The lead inspector will coordinate and lead the inspection team and should be familiar with the type of inspection to be performed, and the products and processes that will be inspected, except under circumstances of training by the co-inspector.

The lead inspector is responsible for all phases of the inspection. S/he has the authority to make final decisions regarding conduct of the inspection and observations made during the inspection. The lead inspector will normally be a WHO staff member. However, WHO may delegate this role to an external consultant when deemed appropriate.

Co-inspectors are external co-inspectors or experts. For collaborative or joint inspections, the co-inspector shall be nominated, whenever possible by the collaborating NRA. When the lead inspector is not a WHO staff member, some of these responsibilities will be delegated to a member of the inspection team who is a WHO employee.

In exceptional circumstances, and with the approval of the inspections team lead, an inspection may be conducted by only one WHO lead inspector on his or her own, or by an external inspector who is a WHO ex-staff member.

For IVD inspections, the IVD assessment team will nominate an external technical expert, who is familiar with the dossier of the product(s) to be inspected, to be part of the WHO inspection team. 

For vaccine inspections, the vaccine assessment team will nominate an internal assessor, who is familiar with the dossier of the product to be inspected, to be part of the WHO inspection team.

For medicines and vector control products, a technical expert is generally only part of the inspection team under unusual circumstances (for example, the inspection of a clinical study that is not focused on bioequivalence may require the participation of a clinician).

The manufacturer will be informed of the identity of each inspector and observers before the inspectionand receive the curriculum vitae of each to ensure that there are no conflicts of interest. The manufacturer has the opportunity to express possible concerns regarding any of the inspectors to WHO before the manufacturing site inspection. If such concerns cannot be resolved in consultation with WHO, the manufacturer may object to a team member's participation in the manufacturing site visit. Such an objection must be made in writing by the manufacturer to WHO within 10 days of receipt of the proposed team composition. In the event of such an objection, WHO reserves the right to cancel all or part of its agreement with, and the activities planned to be undertaken by that inspector.

The lead inspector:

• plans and prepares the inspection
• communicates with the manufacturer about the inspection
• assists with the selection of the inspection team members
• defines the scope of the inspection
• prepares and/or reviews (if prepared by a co-inspector) the inspection plan, working documents, and briefing documents
• supervises the inspectors' travel arrangements
• represents the inspection team with the manufacturer/CRO/QCL
• supervises inspectors during the inspection
• communicates regarding any obstacles regarding the inspection to the manufacturer/CRO/QCL and to WHO before or during the inspection
• prepares and presents the general inspection outcome, after consultation with the other inspectors, to the manufacturer/CRO/QCL at the closing meeting
• compiles the final inspection report, after consultation with the other inspectors, for review and approval by the WHO officer with overall responsibility for inspections
• sends the report to the manufacturer/CRO/QCL
• follows up on the corrective and preventive actions (CAPAs) proposed and taken by those inspected regarding any observations made during the inspection
• when applicable, verifies that corrective actions have been taken within agreed timelines and have been shown to be effective.

The co-inspector:

• uses established inspection methods to ensure consistency in the inspection process
• plans and carry out assigned responsibilities objectively, effectively and efficiently within the inspection scope
• safeguards confidentiality of documents and information during and subsequent to the inspection
• complies with WHO standard of conduct
• performs the inspection to achieve the objectives in a polite and enquiring manner, and is never discourteous or intimidating
• complies with WHO prequalification requirements for inspections
• collects, analyses and documents objective evidence to establish the extent of compliance with the quality system and the effectiveness of its implementation
• establishes the extent to which the procedures, documents and other available information are understood and used by the manufacturer's/CRO/QCL personnel
• brings to the attention of the lead inspector in a timely manner, any indications or observations that could influence the inspection results, require more in-depth inspection or are an obstacle to the proper performance of the inspection
• minimizes disruption to the manufacturer's/CRO/QCL personnel and processes during the inspection and complies with any health and safety or other requirements of the manufacturer
• assists the lead inspector in preparing the report of the inspection
• assists the manufacturer/CRO/QCL to understand WHO prequalification requirements
• when and where applicable provides input to verify that corrective actions that have been taken and have been or will be taken are likely to be effective.

Inspectors who are not WHO staff:

The responsibilities of those inspectors, including, if applicable, the lead inspector, who are not WHO staff members are to:

• use established inspection methods to achieve consistency in the inspection process
• plan and carry out assigned responsibilities objectively, effectively and efficiently within the scope of the inspection of the manufacturing site
• safeguard confidentiality of confidential documents and information in association with the inspection
• comply with the WHO standard of conduct and conflict of interest rules
• comply with the WHO requirements for inspections, including information in this document
• collect, analyse and document objective evidence to establish the extent of compliance with the quality system and the effectiveness of its implementation
• establish the extent to which the procedures, documents and other available information is understood and used by the manufacturer's personnel
• cooperate with and support the lead inspector and maintain a means of obtaining prompt guidance during the inspection, if required
• bring to the attention of the lead inspector and/or WHO inspector(s), in a timely manner, any indications or observations that could influence the results of the inspection results, require more in-depth inspection or are an obstacle to the proper performance of the inspection
• when applicable, verify corrective actions have been taken and have been effective
• minimize disruption to the manufacturer's personnel and processes during the inspection and comply with any health and safety or other requirements of the manufacturer
• perform the inspection to achieve the objectives in a polite and enquiring manner without discourteous or intimidating conduct
• assist the lead inspector and/or WHO inspector(s) in preparing the inspection report.

Inspection duration

Inspectors may fulfil multiple roles. If more than one product or production line is to be inspected, an additional inspector may be added to the inspection team, to ensure that the time spent on site does not exceed four days.

Standard of conduct

All members of the inspection team, and all observers and interpreters, must be made aware of and agree to meet the high standard of conduct expected during the entire inspection process (including pre- and post-inspection activities), maintain confidentiality and ensure absence of conflict of interest. The conduct required is in keeping with the requirements of the WHO and International Civil Service Commission Standards of Conduct for the International Civil Service.

Inspection documentation

All notes and other documented evidence gathered in connection with the inspection will be considered confidential and part of the WHO records of the inspection

• In vitro diagnostics WHOPIRs
• Medicines WHOPIRs
• Vaccines WHOPIRs
• Vector control products WHOPIRs

A notice of concern (NOC) is a letter that is issued by WHO to a manufacturer to remind the manufacturer of its obligation to maintain quality assurance procedures and practices, as well as to inform suppliers and procurement agencies of any potential risks associated with a given product or manufacturer.

A Notice of Suspension (NOS) is a letter issued by WHO after serious concerns have arisen about the conduct of a manufacturer, or in relation to data and/or information about a prequalified active pharmaceutical ingredient (API) or finished pharmaceutical product (FPP).

When is an NOC issued?

An NOC may be issued by WHO to a manufacturer, CRO or QCL by WHO if:

• observations were made during an inspection that indicate poor compliance or failure to comply with specified standards
• the response to the observations noted in an inspection report, detailing the corrective actions taken or proposed to be taken, is considered insuffiently robust and unlikely to deal with the underlying root cause of a critical or major observation; this may include not providing suitable objective evidence of corrective actions
• the requested response to the observations noted in an inspection report, detailing the corrective actions taken or proposed to be taken, was not received by WHO on or before the due date (i.e. 30 days from the inspection date)
• if a manufacturer refuses inspection of a manufacturing site.

An NOC is not necessarily a cause for public concern. But if immediate public health concerns were identified during the inspection, or if the inspection observations relate to misrepresentation of data, falsification or manipulation of data with the intent to deceive, the NOC will be posted immediately on WHO’s website. WHO has a zero tolerance policy in relation to such activities since they indicate a serious quality system failure that should be urgently addressed by the senior management of the manufacturer. The NOC will remain on WHO's website until adequate and appropriate corrective actions have been implemented effectively by the manufacturer concerned and verified by WHO.

If WHO does identify a public health risk linked to a given product or manufacturer it will take appropriate additional steps, including provision of advice to the public, which may include:

• suspension of products included on the relevant WHO list of prequalified products
• issuing of a compulsory variation to temporarily or permanently suspend the use of a manufacturing site
• if applicable, recall of batches of products on the relevant WHO list of prequalified products that have been supplied by a manufacturer
• rejection of applications for prequalification assessment submitted by the manufacturer or QCL.

What does an NOC contain?

An NOC states observations made during an inspection that are considered to be:

• "critical" or "major" non-compliances with WHO norms, requirements and standards, that are of concern in relation to quality management or quality assurance, or
• “critical” or “major” non-compliances with WHO norms, requirements and standards, that were not satisfactorily addressed in manufacturer's response to findings of the inspection.

For example, deficiencies relating to Good Manufacturing Practice are as follows:

• critical deficiency – an observation of a deficiency that has resulted in or that presents a significant risk of producing a product that is harmful to the user
• major deficiency – a non-critical deficiency which either:
  • resulted in production or may result in production of product that does not comply with WHO prequalification requirements and/or
  • indicates a major deviation from the GMP guide and/or
  • indicates a failure to carry out satisfactory procedures for release of batches and/or
  • indicates a failure of the person responsible for quality assurance/quality control to fulfil his/her duties and/or
  • consists of several other deficiencies, none of which in itself is major, but which, combined, may represent a major deficiency and should be explained and reported as such.

Is there a right of appeal?

Yes. An NOC contains the factual observations made during an inspection; these will have been discussed during the inspection and listed in the inspection report. Generally, the facts that form the basis of the observation(s) are not in dispute. However, the manufacturer or CRO or QCL may disagree that a risk exists or with the level of risk identified by WHO, and that has resulted in the issuing of the NOC.

If the manufacturer, CRO or QCL disagrees with any aspect of the inspection report and subsequent NOC, it should email WHO (prequalinspection@who.int, indicating "Team Lead" in the subject line), outlining the basis of its disagreement. The matter will then be investigated and a response provided within 15 days. Should the manufacturer not be satisfied with the response, the manufacturer should email: Director, Regulation and Prequalification (RPQ) (RPQinfo@who.int), indicating "Attention: Director, RPQ" in the subject line.

All feedback will be treated in confidence and without prejudice.

How long is an NOC in effect?

An NOC will remain on this website until WHO is satisfied that adequate and appropriate corrective actions have been implemented effectively by the manufacturer, CRO or QCL concerned.

When is an NOC lifted?

During the period that an NOC is in place, WHO will perform additional and more frequent inspections if the NOC relates to a manufacturing site that is continuing to supplying prequalified product(s). If the manufacturing site has been suspended the next inspection will be performed after the manufacturer has advised that it considers that it has adequately dealt with the observations that led to the issuing of the NOC. Following such follow-up inspection(s), and if satisfied that sufficient improvements have been made, WHO will lift the NOC and recommend that the site inspected be named/continue to be named in the relevant dossiers under prequalification or already prequalified. The NOC will be removed from this website and archived, and a notice to this effect posted on this website.

Advice to procurers

In all cases where a number of critical and/or a significant number of major observations have been made, and particularly where an NOC was issued and subsequently lifted, WHO reminds the relevant manufacturer, CRO or QCL that the improvements made and the level of compliance with the relevant WHO guidelines must be sustained and continue to be improved. Therefore, in accordance with WHO's risk-based approach to planning inspections, the next full inspection ― in the case of a manufacturing site or QCL ― will be performed at an earlier date than usual, and subsequent inspections performed more frequently until evidence has been provided that the improvements implemented are permanent.

Procurement organizations should monitor their suppliers, including monitoring their compliance with international standards. WHO therefore expects that they will take appropriate action when an NOC is issued, and after lifting of an NOC apply an enhanced level of due diligence, as part of their supply chain audit and assurance systems, when dealing with suppliers that have failed to comply adequately with international standards.

Organizations supplying products and/or services from a manufacturing site or QCL for which an NOC has been lifted may expect greater scrutiny from their customers, and should plan to support this in the foreseeable future.

Why is an NOS issued?

An NOS is issued not only to:

• remind the manufacturer concerned of its obligations to procurers and patients

• but also to:

• inform suppliers and procurement agencies of potential risks associated with a product, if these have been identified
• motivate manufacturers to take appropriate corrective and/or preventive actions in a timely manner, and to address observations and non-compliances
• help maintain transparency about WHO prequalification activities and decisions.

An NOS will not disclose commercially-sensitive information.

In situations of immediate public health concern an NOS may lead to the:

• suspension of products included on the relevant WHO list of prequalified products
• issuing of a compulsory variation to temporarily or permanently suspend the use of a manufacturing site
• if applicable, recall of batches of products on the relevant WHO list of prequalified products that have been supplied by a manufacturer
• rejection of applications for prequalification assessment submitted by the manufacturer.

How long will the suspension remain in force?

An NOS will remain on this website until the necessary corrective actions have been implemented by the manufacturer and approved by WHO.

Advice to procurers

Procurement organizations should monitor their suppliers, including monitoring their compliance with international standards. WHO Therefore expects that they will take appropriate action when an NOS is issued, and after lifting of an NOS apply an enhanced level of due diligence, as part of their supply chain audit and assurance systems, when dealing with suppliers that have failed to comply adequately with international standards.

WHO advises organizations supplying products from a manufacturing site for which an NOC has been lifted should reasonably expect an enhanced level of supervision by their customers, and should plan to support this in the foreseeable future.