This section provides information on Inspection activities
in the Prequalification Programme. The following
topics are covered:
General information on
The WHO prequalification team plans and
coordinates the performance of inspections (announced or
unannounced) of the site(s) of
manufacture of selected Active Pharmaceutical Ingredients
API(s), the Finished Pharmaceutical Product (FPP), and of
selected clinical testing units or Contract Research
The inspections of the manufacturing
site(s) are conducted to assess compliance with Good
Manufacturing Practices (GMP) for
Finished Pharmaceutical Products (FPPs)
and GMP for
Active Pharmaceutical Ingredients (APIs)
as recommended by WHO. A
Site Master File (SMF)
submitted by the applicant will be reviewed before an
inspection is performed. (Please note that a SMF should be
submitted on a CD or DVD at the same time a product dossier
is submitted for assessment. See Q&A). Data and information
submitted in dossiers and SMFs will be verified during
The inspections of
clinical testing units or organizations
are carried out to assess compliance with
GLP, and to perform data verification.
(Please note that a
Contract Research Organization Master
File (CROMF) should be submitted on a CD or DVD
upon request. See Q&A)
The inspections are performed by a team
of inspectors consisting of experts appointed by WHO
(preferably from drug regulatory authorities inspectorates,
who act as temporary advisers to WHO) and WHO staff members.
The inspectors have relevant qualifications and experience
to perform such inspections, and are competent in areas such
as production and quality control of pharmaceuticals, have
appropriate experience in GMP and GCP or GLP. A
representative of the drug regulatory authority of the
country of manufacture would normally be expected to
accompany the team to the manufacturing and testing
facilities to assess the compliance with GMP and GCP or GLP.
The inspectors must comply with the
confidentiality and conflict of interest rules of WHO. Each
inspection team will perform the inspection and report on
its findings to in accordance with SOPs established by WHO
for that purpose so as to ensure a standard harmonized
An inspection report listing all the
observations and findings is prepared after the inspection
and provided to the manufacturer or CRO as relevant. The
manufacturer and or CRO has to take appropriate corrective
and preventive action and submit a response to the
inspection report for assessment by the inspectors.
Follow-up inspections to verify the implementation of
corrective and preventive actions can be done by WHO.
Norms and Standards
Manufacturers and CROs
will be assessed though inspections (announced or
unannounced), for compliance with WHO
norms and standards including Good Manufacturing Practices
(GMP), and Good Clinical Practices (GCP) and Good Laboratory
Practices (GLP) as appropriate.
Manufacturing Practices (GMP)
Good Clinical Practices (GCP):
Quality Control Laboratories (QCL):
Other WHO norms and standards may be applicable. For more
details and related guidelines, please see the additional material on the
following web links:
Transfer of Technology in Pharmaceutical
A CD-ROM is available containing training modules on basic
good manufacturing practices as well as supplementary
training material covering validation, water systems etc.
The contents are also available on the link below:
Training modules on quality control:
Presentations made at recent training
manufacturers of FPPs meeting GMP requirements included in
the list of prequalified products. Prior to listing, all the
critical, major and other observations listed in the
inspection report must be addressed and brought to a
satisfactory level of compliance by the manufacturers.
In accordance with World Health Assembly
Resolution WHA57.14 of 22 May 2004, WHO will – subject to
the protection of any commercially sensitive confidential
information – publish WHO Public Inspection Reports
(WHOPIR(s)) on the manufacturers and CROs that were found to
be in compliance with WHO-recommended guidelines and
WHO Public Inspection Report
A WHOPIR reflects the inspection performed and gives a
summary of the observations and findings made during the
inspection, but excludes confidential proprietary
information as well as all the individual observations that
were communicated in the full inspection report. It also
indicates the date and duration of the inspection as well
as the scope of the inspection. WHOPIRs are listed below in
After a period of three years, WHOPIRs are moved to the
section marked "Archived WHOPIRs". If a site is inspected
and found to be non-compliant with GMP after a WHOPIR was
a previous inspection, that WHOPIR will be removed
from the web site (as the site is then no longer considered
compliant with GMP).
Notices of Concern (NOC)
In accordance with World Health Assembly
Resolution WHA57.14 of 22 May 2004 – subject to the
protection of any commercially sensitive confidential
information – WHO is entitled to publish negative evaluation
"3. (4) to ensure that the prequalification review
process and the results of inspection and assessment reports
of the listed products, aside from proprietary and
confidential information, are made publicly available;"
What is an NOC?
An NOC is a letter that is issued to a
manufacturer, contract research organization or quality
control laboratory, by the WHO Prequalification of Medicines
When is an NOC issued?
An NOC is issued after an inspection was
performed at a site where observations were made that result
in concern regarding compliance of the site with specified
standards such as Good Manufacturing Practices (GMP) or Good
Clinical Practices (GCP) or Good Laboratory Practices (GLP).
An NOC may also be issued if the
requested response to the observations noted in an
inspection report, detailing the corrective actions taken or
proposed to be taken, is not received by WHO on or before
the due date (i.e. 30 days from the inspection date).
In addition, an NOC may be issued if a
manufacturer refuses inspection of their manufacturing site.
What does an NOC contain?
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 in the GMP context:
observation that has produced, or may result in a
significant risk of producing a product which is
harmful to the user.
non-critical deficiency which either:
has produced or may produce a product which does not
comply with its prequalification application (including
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 QA/QC to fulfill his/her duties; and/or
consists of several other
deficiencies, none of which on its own may be major, but
which may together represent a major deficiency and
should be explained and reported as such.
What is the purpose of an NOC?
An NOC is issued to remind a manufacturer, research
organization or a laboratory of their obligations to quality assurance and
to inform suppliers and procurement agencies of potential
risks associated with a given product, manufacturer,
organization or laboratory.
It is not necessarily cause for public concern.
If WHO identifies a public health risk, appropriate
additional steps will be taken to advise the public.
These steps may include:
suspension of products on the "List of prequalified
products"; (See Notice of Suspension)
recall of batches of products on the "List of
prequalified products" that had been supplied by a
rejection of applications submitted for assessment to
the Prequalification Programme.
When will an NOC be published?
If there are immediate public health concerns or if the
inspection observations relate to misrepresentation of data,
falsification or manipulation of data with the intent to
deceive, the NOC will be immediately published on the
Prequalification of Medicines Programme web site.
Note: The WHO Prequalification of Medicines
Programme has a zero tolerance policy in relation to such
activities. it is usually an indicator of a serious
quality system failure that needs to be addressed and it is
regarded as a top management responsibility to ensure that
it does not occur.
In other cases the NOC will be published after the
corrective actions described in the response to the
observations noted in the NOC have been reviewed and the
review determines that the corrective actions are
unsatisfactory (which may include not providing suitable
objective evidence of corrective actions, if applicable).
It may also be published if a response to the observations
noted in the NOC is not received within 30 days from the
date of the NOC, as requested.
How long is an NOC in effect?
will remain active on the WHO Prequalification of Medicines
Programme web site until WHO is satisfied that the
corrective actions taken are appropriate and have been
Notices of Concern
with NMRAs in inspection activities
Questions and Answers (Q&A)