WHO prequalification programme

1. WHO PREQUALIFICATION PROGRAMME
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CREATED BY: SHWETA MORE
GUIDED BY: DR INDIRA PARAB
Department of Quality Assurance
C.U.Shah College Of Pharmacy
Date : 24/02/2015

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WHO Prequalification aims to ensure that
diagnostics, medicines, vaccines and
immunization related equipment and devices for
high burden diseases meet global standards of
quality, safety and efficacy, in order to optimize
use of health resources and improve health
outcomes.
The prequalification of a transparent,
scientifically sound assessment, which includes
dossier review, consistency testing or
performance evaluation and site visits to
manufacturers.

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VISION: Good quality medicines for
everyone
MISSION: To make quality priority
medicines available for the benefits of those
in need.
This is achieved through its evaluation and
inspection activities, and by building
National capacity for sustainable
manufacturing and monitoring of quality
medicines.

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STRATEGY: Applied unified standards of
acceptable quality, safety and efficacy.
Comprehensively evaluate the quality,
safety, and efficacy of medicinal products,
based on information submitted by the
manufacturers, and inspection of the
corresponding manufacturing, and clinical
sites.
Prequalify sources of active
Pharmaceutical ingredients by
comprehensively evaluating the quality of
the API’s based on information of the
corresponding manufacturing sites.
Prequalify Quality Control laboratories of
pharmaceuticals.

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The Programme was launched
in 2001, in partnership with
UNAIDS, UNICEF and the UN
Population Fund, with support
from the World Bank. Its focus
was tackling the quality
problems commonly associated
with medicines for treating
HIV/AIDS, malaria and
tuberculosis (TB)

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DISEASE PROBLEMS
HIV/AIDS For the people living with HIV/AIDS,
antiretroviral products offer hope for
prolonged survival- yet they are not available in
sufficient quality or quantity where they are
needed most.
MALARIA Data from a recent WHO survey in six African
countries showed that 10-65% of sampled anti-
malarial Chloroquin tablets contained too little
active ingredients. The poor quality of first-line
treatment is contributing to drug resistance
and treatment failure.
TB Many generic anti-TB medicines have serious
quality defects, due to their poor
manufacturing quality. Also, bioequivalence
have often not been proved.
QUALITY PROBLEMS WITH MEDICINES FOR
TREATING HIV/AIDS, MALARIAL, TB

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In 2006, this was extended to cover medicines and
products for reproductive health. Expanding the
list of prequalified medicines, together with
capacity building in developing countries,
remained the principal objectives in 2006. Forty-
four products were added to the list, representing
an increase of 38% over 2005, when 32 products
were prequalified. Thirty-one of the 44 products
were generic products.
As in 2005,more generic than brand-name
medicines were prequalified, illustrating the
continued success of the Programme in capacity
building in the generic sector .In 2008, to cover
prequalification of zinc, for managing acute
diarrhea in children. At the end of 2012, the WHO
List of Prequalified Medicinal Products contained
316 medicines for priority diseases.

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KEY STEPS INVOLVED IN WHO PREQUALIFICATION PROGRAMME
Expression of interest
PREQUALIFICATION MAINTENANCE AND MONITORING

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INVITATION FOR EXPRESSION OF
INTEREST
Medicines not
assessed by SRA
Dossier and SMF
submitted for assessment
WHO assessment and
inspection organized
COMPLIANCE
Medicines
assessed by SRA
Valid for innovators and
Generic
SRA registration
(assessment and
compliance check)
ACCEPTANCE
PREQUALIFICATION

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KEY STEP OF WHO PREQUALIFICATION PROGRAMME
STEP1: PUBLICATION OF EXPRESSION OF
INTEREST
1. Published widely
2. Open and transparent
3. Specifies products required
4. Identifies where to find WHO guidelines for
compiling a product dossier
STEP2: SUBMISSION OF DOOSIER
I. INNOVATOR PRODUCTS
1. WHO type Certificate of Pharmaceutical
Product (CPP)
2. Assessment report by the National Regulatory
Authority (NRA)
3. Batch certificate
4. Other documentation
II. MULTI-SOURCE PRODUCT
1) Dossier with required as in WHO manual,
marketing authorization of pharmaceutical
products with special Reference to multisource
(generic) products

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III. DOSSIER REQUIREMENTS
1 Details of the product
2 Regulatory Status in other countries
3 Active Pharmaceutical Ingredients (API)
a) Properties of API
b) Sites of manufacture
c) Route(s) of synthesis
d) Specification: API described in pharmacopeia
API not described in pharmacopeia
e) Container closure system
f) Stability testing

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IV. FINISHED PRODUCT
1) Formulation
2) Sites of manufacture
3) Manufacturing procedure
4) Specification of excipients
5) Specification of finished product
6) Container/ closure system and other
packaging requirements
7) Stability testing
8) Container labeling
9) Product information
10)Patient information and package inserts
11)Justification for any differences to the
product in the Country issuing the
submitted WHO type certificate
12)Interchangeability (bioequivalence studies)
13)Summary of Pharmacology, toxicology and
efficacy of the product

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STEP 3: INITIAL SCREENING OF
DOOSIERS
a. Screen for completeness
b. Inform supplier
c. Listed for a possible site inspection
STEP 4: ASSESSMENT OF DOOSIERS
a. Team of experts (Pharmaceutical
development, bioequivalence, etc) from
NRA
b. Standards: WHO manual and
guidelines marketing authorization of
pharmaceutical products with special
reference to multisource (generic)
product
c. Outcome of the evaluation
communicated to supplier.

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STEP 5: SITE INSPECTION
1) According to WHO current Good Manufacturing
Practices (CGMP)
2) Inspection team
3) Appointed inspector: technically qualified, preferably
from NRA
4) Local or National inspectorate
5) WHO representative
STEP 6: REPORT ON FINDINGS AND
RECOMMENDATIONS
1) Reports on dossier evaluation and site inspection
2) Communicated to supplier and manufacturer
3) If not complaint additional information to be
submitted is identified
STEP 7: PUBLICATION OF EVALUATION RESULTS
1) Meet standards: added to prequalified suppliers list
2) Outcome communicated to manufacturers and NRA
3) WHO public assessment report published on WHO
website
4) WHO public inspection report published on WHO
website.

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STEP 8: SAMPLING AND TESTING
1. Samples submitted with product dossier
2. Random sample of products supplied after
Prequalification and inspection batch verification
3. Failure: investigation and communication to
manufacturer.
STEP 9: RE-EVALUATION AND RE-INSPECTION
1. At regular intervals(minimum every 3 years), unless
changes are made to product by supplier and/or
manufacturer
2. Other instances: misconduct, suspension of supply,
complaints
3. Complaints investigated
4. Written report and action to be taken identified
5. NRA involvement
STEP 10: DE-LISTING

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The WHO prequalification of medicines
programme (PQP) facilitates access to qualify
medicines through assessment of products
and inspection of manufacturing sites. Since
good quality Active Pharmaceutical
Ingredient’s (APIs) are vital to the production
of good quality medicines, PQP has started a
pilot project to prequalify APIs.
WHO list of prequalified Active Ingredient’s
provides United Nation agencies, National
Medicines Regulatory Authorities (NMRAs)
and others with information on APIs that have
been found to meet WHO-recommended
quality standards. It is believed that
identification of sources of good-quality APIs
will facilitate the manufacture of good-quality
finished Pharmaceutical product (FPP) that
are needed for procurement by UN agencies
and disease treatment programs.

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WHAT IS API PREQUALIFICATION?
API prequalification provides an assurance
that the API concerned is of good quality
and manufactured in accordance with
WHO Good Manufacturing Practice (GMP).
API prequalification consists of a
comprehensive evaluation procedure that
has two components-
1 Assessment of API Master File (APIMF)
to verify compliance with WHO norms
2 Standards and assessment of the sites of
API manufacture to verify compliance with
WHO GMP requirements.

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STEPS IN THE PROCESS OF PREQUALIFICATION
INFORMATION
REQUEST
APPLICANT

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APPLICATION ACCEPTED FOR ASSESSMENT
APIMF GMP
REVIEW OF GMP
CERTIFICATION, INSPECTION
REPORTS, SITE MASTER FILES
(SMF)
ACCEPTED
FINAL DECISION ON PREQUALIFICATION
LISTING ON WHO WEBSITE
VARIATIONS
COMPLAINTS
RANDOM
SAMPLING

22. THE WHO PREQUALIFICATION PROCEDURE FOR MEDICINES AND
ACTIVE INGEDIENTS
1) Initially, an applicant is screened to determine
whether it is covered by the relevant Expression Of
Interest (EOI).
2) It is also screened for completeness; in particular,
the formatting of the submitted APIMFs is
reviewed.
3) Once the application has been accepted a WHO
reference number is assigned to it.
4) A team of assessor then reviews the submitted
APIMF, primarily at bimonthly meetings in
Copenhagen.
5) Invariably, assessors raise questions during
assessment of the APIMF that requires revision of
the information submitted and/or provision of
additional information, and / or replacement of
certain sections within the APIMF 22

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6) Applicants are contacted to resolve any issues
raised by the assessors.
7) It is important that any prequalified API can be
unambiguously identified with a specific
APIMF.
8) Therefore, once any and all issues regarding
its production have been resolved, the
applicant will be asked to submit an updated
APIMF that incorporates any changes made
during assessment.
9) The version number of the revised and up-to-
date APIMF will be included on the WHO list of
prequalified active-pharmaceutical ingredients,
to serve as a reference regarding the
production and quality control of that API.
10) For APIMF that have already been accepted in
conjunction with the prequalification of an FPP,
full assessment is generally not required.

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11)Such APIMFs are reviewed only for key
information and conformity with administrative
requirements.
12)Nonetheless, a request for further information
may be made, to ensure that the APIMF meets
all current norms and standard; PQP reserves
the right to do so.
13)An assessment is also undertaken of WHO
GMP compliance at the intended site(s) of API
manufacture.
14)Depending on the evidence of GMP supplied
by the applicant, this may necessitate on site
inspection by WHO.
15)If a WHO inspection is conducted and the site
is found to be WHO GMP-compliant, the API
will be recommended for prequalification.

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16)Additionally, a WHO Public Inspection Report
(WHOPIR) will be published on the PQP
website.
17)When the APIMF and the standard of GMP at
the intended manufacturing site (s) have each
been found to be satisfactory, the API is
prequalified and listed on the WHO list of
prequalified Active Pharmaceutical Ingredients.
18)The successful applicant will also be issued a
WHO confirmation of API prequalification
document.
19)This document contains the accepted active
ingredients specification and copies of the
assay and related substances test
methodology.
20)This document may be provided by the API
manufacturer.

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The World Health Organization (WHO) provides
United Nations agencies to meet WHO
recommended quality standards for such
laboratories, i.e. Good practices for pharmaceutical
quality control laboratories (GPCL) and the
relevant parts of good manufacturing practices
(GMP). This is done through a standardized quality
assessment procedure. The purpose of the quality
assessment procedure is to evaluate whether the
quality control laboratories to be used for the
quality control of pharmaceutical products meet the
requirements recommended by WHO for such
laboratories.

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The quality assessment procedure established by
WHO is based on the following principles:
— commitment of the laboratory to providing services
of testing of pharmaceutical products to United
Nations agencies;
— a general understanding of the quality assurance
management and quality control testing activities of
the laboratory;
— evaluation of information submitted by the
laboratory;
— assessment of compliance with WHO
recommended quality standards for quality control
laboratories, i.e. GPCL and the relevant parts of GMP.
monitoring of performance of prequalified
laboratories.

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WHO invites the national medicines regulatory
authority (NMRA) having regulatory oversight over a
laboratory participating in the prequalification
procedure, to join as an observer in the inspection of
the laboratory compliance with WHO recommended
standards for quality control laboratories.
 WHO recommends that laboratories expressing an
interest in participating in the prequalification
procedure, inform the regulatory authority of the
country in which they are established as well as
relevant networks (e.g. the Official Medicines Control
Laboratories (OMCL network) of their submission for
prequalification.
This procedure is to be followed for prequalification
of quality control laboratories for use by the United
Nations agencies.

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1. PUBLICATION OF INVITATION FOR
EXPRESSION OF INTEREST
2. SUBMISSION OF EXPRESSIONS OF
INTEREST AND LABORATORY
INFORMATION
3. SCREENING OF SUBMITTED
LABORATORY INFORMATION
4. EVALUATION OF LABORATORY
INFORMATION
5. SITE INSPECTION
6. REPORT AND OUTCOME OF INSPECTION
7. RESULTS OF ASSESSMENT
8. MONITORING OF PREQUALIFIED Q.C
LABORATORIES
9. MONITORING OF COMPLIANTS
10. COST RECOVERY
11. CONFIDENTIALITY UNDERTAKING
12.CONFLICT OF INTEREST

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0
10
20
30
40
50
60
70
2007 2008 2009 2010 2011 2012 2013
NTD
Diarrhea
Influenza
RH
Malaria
TB
HIV
PRODUCTS PREQUALIFIED 2007- 2013

33. DIFFERENCE BETWEEN PQP AND
NATIONAL APPROVAL PROCEDURES
1. Only certain categories of products are
accepted
2. Voluntary - no direct legal implications
3. Free of charge (yet)
4. Assessment and inspections done by
multinational teams
5. Assessment and inspection outcomes are
publically available, no negative conclusions
and findings published (yet)
6. Issues of IP fully in responsibility of applicant /
manufacturer
7. Definitive negative conclusions exceptional
8. Technical assistance and regulatory support
possible
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CASE STUDY

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This case study describes a compliance event
where in-house finished product defect inspectors
reported the observation of apparent visible glass
fragments in a sterile liquid product. Initial problem-
solving focus assumed some form of glass container
damage during the vial preparation and/or bottle
filling processes.
The investigation involved interviews of the
relevant personnel, documentation reviews, and
analytical testing.
The observed glass fragments were isolated,
microscopically examined and tested for elemental
composition.
 Elemental results indicated the presence of
calcium and phosphorous. The particulate that was
previously thought to be glass was actually a calcium
Hydroxyphosphate salt with a transparent glassy
appearance.
GLASS FRAGMENTS IN PARENTERAL PRODUCT

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The problem root cause was determined to be an
interaction between the calcium carbonate in the
rubber closures and the sodium phosphate in the
product formulation. Trace amounts of calcium may
have leached from the rubber closure in the product
solution resulting in the calcium precipitate.
The corrective action/preventative action (CAPA)
entailed the replacement of the rubber closure with a
calcium-carbonate- free closure as the ultimate long
term corrective action.
 Ongoing monitoring of product stability confirmed
successful corrective actions.
This case study demonstrated an unlikely cause of
a compliance problem -- chemical properties of
primary packaging commodities.
 Compliance personnel must keep an open mind
without preconceived beliefs when investigating
problem situations.
 Further, they must be sufficiently flexible to allow
for changes in direction as based on new data and
information.

37. FALSE NEGATIVE CLEANING DATA
• This case study describes a compliance event
in which failing cleaning validation for API
residue from a small molecule extended
release tablet dosage form was observed.
The initial two lots in the cleaning were
successful. The third lot failed acceptable
residue limits. Investigation of the failure
comprised cleaning process performance,
residue sampling, sample handling, sample
analysis, and evaluation of the analytical
method. Investigation of this compliance event
initially involved interviews of relevant
personnel and reviews of associated
documentation. Two areas were identified for
further evaluation residue sampling and the
cleaning process. 37

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Regarding sampling, a newly trained
technician, working alone, sampled the
first two acceptable lots, while an
experienced technician working with a
colleague sampled the third failing.
Evaporation of solvent occurred causing
residue to not be adequately recovered
from the equipment surface resulting a
false negative test results. Regarding the
cleaning process, manufacturing
operators commented that the new
extended release formulation was more
difficult to clean than the original
immediate release formulation although
the same cleaning procedure was utilized
for both products.

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Evaluation of the cleaning process indicated that the process
parameters were not optimal to clean the new product. An
improved cleaning process with increased cleaning agent
concentration, increased cleaning time, and higher
temperature was developed, implemented, and ultimately
validated.
Cleaning validation sampling personnel must have good
technical understanding of their work, and must know the
technical reasons for the procedures they perform and
potential problems if procedures are not correctly performed.
Sampling personnel training for cleaning validation should
include a quantitative demonstration of acceptable cleaning by
means of analytical testing. Training exercises must also
include worst-case sampling such as with volatile solvents,
multiple sampling equipment, and other potential variations
used in sampling. SOPs must be carefully written to describe
potential problems and include performance constraints to
minimize variation and risks. Inactive ingredients in a
formulation may have very significant effects on cleaning
processes. Cleaning of residues does not depend solely on the
properties of the API.

40. CONCLUSION
• The availability of quality, safety and efficacy
of medicines is a major concern of WHO.
• To ensure that quality pharmaceuticals are
available, WHO sets norms and standards,
develops guidelines and advises Member
States on issues related to quality assurance
of medicines in national and international
markets.
• WHO assists countries in building national
regulatory capacity through networking,
training and information sharing.
• These activities have been endorsed and
supported by Member States through
numerous World Health Assembly
resolutions. 40

41. REFERENCES
• http://www.allcountries.org/health/the_who_prequalificati
on_project.html
• http://apps.who.int/prequal/info_applicants/API_introducti
on.htm
• http://www.who.int/prequal/info_general/notes.htm
• http://www.who.int/prequal/lists/PQ_QCLabsList.pdf.
• WHO PREQUALIFICATI ON OF MEDICIN ES
PROGRAMME UPDATE FOR 2006
• The WHO Prequalification Programme for Essential
Reproductive Health Medicines:
• A Workshop on Using the Programme in Procurement
Practices
41

42. Cont….
• Training modules can be found on the Prequalification
web site (http://apps.who.int/prequal/).
• http://apps.who.int/prequal/
• http://www.who.int/mediacentre/factsheets/fs278/en/
• World Health Organization Wikipedia, the free
encyclopedia
• http://www.encyclopedia.com/topic/World_Health_Organi
zation.aspx
• Compliance Case Study #11 “Glass” Fragments in a
Parenteral Product Alan M. Mancini, Joanne Wong, and
Paul L. Pluta Journal of GXP Compliance Volume 18
Number 3 on
• Compliance Case Study #12 False Negative Cleaning
Data Paul L. Pluta Journal of GXP Compliance Volume
18 Number 3
42

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