A Notice of Concern (NOC) is a letter that is issued to a manufacturer, contract research organization (CRO) or medicines quality control laboratory (QCL), by WHO, to remind a manufacturer, CRO or QCL of its obligation to maintain quality assurance procedures and practices, and to inform suppliers and procurement agencies of any potential risks associated with a given product, manufacturer, CRO or QCL.
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).
Why is an NOC issued?
An NOC is issued not only to remind a manufacturer, CRO or QCL of its obligation to maintain quality assurance procedures and practices, but also and to inform suppliers and procurement agencies of any potential risks associated with a given product, manufacturer, CRO or QCL.
An NOC is not necessarily cause for public concern. However, if WHO does identify a public health risk linked to a given product, manufacturer, CRO or QCL, it will take appropriate additional steps, including provision of advice to the public. These may include:
- suspension of products or a QCL included on the WHO List of Prequalified Medicinal Products, or WHO List of Prequalified Active Pharmaceutical Ingredients or WHO List of Prequalified Quality Control Laboratories)
- issuing of a compulsory variation to temporarily or permanently suspend the use of a manufacturing site
- recall of batches of products on the WHO List of Prequalified Medicinal Products that have been supplied by a manufacturer
- rejection of applications for prequalification assessment submitted by the manufacturer or QCL.
When is an NOC issued?
A notice of concern (NOC) may be issued 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 (be these WHO Good Manufacturing Practices (GMP), WHO Good Practices for Trials on Pharmaceutical Products, WHO Guidance for Organizations Performing In Vivo Bioequivalence Studies, WHO Good Practices for Quality Control Laboratories, or WHO Good Practices for Pharmaceutical Microbiology Laboratories)
- 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.
If immediate public health concerns have been identified, 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 this website. (WHO has a zero tolerance policy in relation to such activities since they indicate a serious quality system failure that needs to be urgently addressed by senior management responsibility.)
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 and standards, that are of concern in relation to quality management or quality assurance
- or "critical" or "major" non-compliances with WHO norms and standards that were not satisfactorily addressed in the response from the company to an inspection.
For example, deficiencies relating to GMP 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 company, CRO or QCL disagrees with any aspect of the inspection report and subsequent NOC, it should send information to WHO that gives the basis for its disagreement, by email (firstname.lastname@example.org, indicating Coordinator, WHO in the subject line). The matter will then be investigated and a response provided within 15 working days. Should the site not be satisfied with the response, the site is advised to email the Head, Regulation of Health products and Technologies (RHT) at RHTinfo@who.int, indicating Attention: Head, RHT 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:
- withdrawal of product(s) from the WHO List of Prequalified Medicinal Products and/or WHO List of Prequalified Active Pharmaceutical Ingredients
- recall of batches of products on the WHO List of Prequalified Medicinal Products that have been supplied by the manufacturer concerned
- rejection of FPP or API applications submitted to WHO for assessment.
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.