Introduction to WHO Prequalification of
Medicines Programme
Essential requirements
Dr Milan Smid and many team colleagues
WHO Prequalification of Medicines Programme
Amman, June 2013
Steps in WHO prequalification
I
Expression
of Interest
Assessment
Product dossier
SMF
Additional information
and data
Inspections
Corrective
actions
Compliance
Compliance
Prequalification
Maintenance and monitoring
Amman, June 2013
Application requirements - Full dossier
Generic Product application
3
•
Covering letter, in English, confirming that the
information submitted in the product dossiers is true
and correct.
•
Product dossier (including full BE report where
applicable), in English, in CTD format and the QOSPD + QIS + BTIF/BW forms ALL completed in word
format
•
A product sample
•
A site master file, for each manufacturing site
Amman, June 2013
How to Submit an application
• Submit electronic copy ONLY of Dossier in CTD
format and Forms on CD/DVD To WHO Geneva
• After dossier has been accepted for assessment
and has been allocated a WHO reference number
you will be notified to proceed to step 2
• Updated or finalised Dossier and Forms (paper
copies + CD/DVDs) incorporating any improvements
or changes requested in step 1 and samples To
UNICEF- Copenhagen
• Submit Site Master File & Contract Research
Organization Master File (CROMF) (hard copies
+CD/DVDs) to Geneva address
Amman, June 2013
WHO/CF workshop, New Delhi,
November 2012
Data requested for prequalification
An application to prequalify an FPP typically has three parts,
relevant Good Practices have to be followed during
manufacture and control:
API
Information on the preparation and control of the API.
+
FPP
Information on the preparation and control of the FPP.
+
S&E
Safety and efficacy data, e.g. commonly replaced
by demonstration of bioequivalence
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Data requested for prequalification
guideline for applicants
• Consists of two parts:
– Preparation of product dossiers (PDs) in Common
Technical Document (CTD) format
• The preparation guideline
– Guideline on submission of documentation on
multisource (Generic) Finished Pharmaceutical
Product (FPP): Quality part
• Main quality guide
• Being implemented since September 2010
Amman, June 2013
Adapting the CTD-NDS (new drug)
to CTD-ANDS (generic)
Regional
Admin
Information
Not Part of
the CTD
Module 1
Nonclinical
Overview
Module 2
Quality
Overall
Summary
Clinical
Overview
Nonclinical
Summary
Quality
Nonclinical
Study Reports
Module 3
Module 4
WHO/UNFPA workshop, Nov 2012
The CTD
Clinical
Summary
Clinical
Study Reports
Module 5
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Main sub-sections of 3.2.S. Drug
Substance (API)
•
•
•
•
•
•
•
3.2.S.1 General information
3.2.S.2 Manufacture
3.2.S.3 Characterization
3.2.S.4 Control of the API
3.2.S.5 Reference standards or materials
3.2.S.6 Container closure system
3.2.S.7 Stability
Amman, June 2013
Main sub-sections of 3.2.P. Drug Product
(FPP)
•
•
•
•
•
•
•
•
3.2.P.1 Description and Composition of the FPP
3.2.P.2 Pharmaceutical development
3.2.P.3 Manufacture
3.2.P.4 Excipients
3.2.P.5 Control of the FPP
3.2.P.6 Reference standards or materials
3.2.P.7 Container closure system
3.2.P.8 Stability
Amman, June 2013
Specific quality documents: quality
summaries (templates - QIS/QOS)
• The instructions for the QOS-PD (quality over all
summary) run throughout the quality guideline
• Instructions for the QIS are in Section 3.2 and
preface the QIS (quality information summary)
template
WHO/UNFPA workshop, Nov 2012
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11
Amman, June 2013
Key aspects of quality assessment
• To ensure that all future batches, throughout their shelf
life, will perform as the clinical/biobatch
– Characteristics of the API batch used in the biobatch, details of
FPP manufacturing process and quality attributes of the the
biobatch are critical reference information
• To ensure that processes are adequately described and
controlled and that they are validated
• To ensure that the level of impurities in the API and FPP
are within safe limits
• To ensure that container closure system will protect the
product from chemical, physical and biological
deterioration and that it's compatible with the product
• To ensure that analytical methods used at different
stages are reliable and reproducible
Amman, June 2013
FPP Prequalification and four options for
submission of API information
API
WHO PQ API
+
FPP
APIMF
Procedure
Amman, June 2013
+
EDQM
CEP
S&E
3.2.S
The APIMF Procedure
• The API manufacturer supplies the FPP manufacturer
with the open part of their APIMF. The FPP
manufacturer use this information to complete the
necessary sections of their submission.
• The API manufacturer supplies the FPP with a letter of
access.
• The FPP manufacturer attaches the open part of the
APIMF and the letter of access to their FPP submission.
• The API manufacturer sends the open and closed
sections of their APIMF directly to WHO. It is held in
confidence.
Amman, June 2013
The APIMF Procedure
APIMF holder
APIMF submission to
APIMF focal point
FPP applicant
Letter of Access
FPP
submission
APIMF assessment
APIMF acceptance
FPP assessment
FPP prequalification
WHO/UNFPA workshop, Nov 2012
15
Advantages of the APIMF Procedure
• It allows the submission of confidential information by the API
manufacturer without disclosure to the FPP applicant.
• One APIMF may be used to support multiple FPP applications
without the need for repeated evaluations.
• It is applicable to both pharmacopoeial and nonpharmacopoeial APIs.
• The APIMF holder prepares and maintains the APIMF
information and answers all queries directly.
• Normally all API-related changes would require the submission of a
variation from associated FPP manufacturers.
Amman, June 2013
Notable Requirements
– Number of batches required to establish the FPP
shelf-life
– Uniformity demonstration for the biolot instead of
process validation report for pilot batches
– process validation/pharmaceutical development
requirements for “established” generics
17
Amman, June 2013
Accelerated procedure for accepting RH
and 2nd Line TB dossiers for assessment
• Stability Data at the time of submission only, may be reduced to
no less than 3 months accelerated, plus 3 months long-term
data, for not less than two primary batches of at least pilot scale.
One of the primary batches should be the batch that was used for
bioequivalence studies.
• In some cases, several years of long-term stability data on batches
under uncontrolled storage conditions may also be accepted from
Zone IV countries.
• NB all prequalification requirements for final acceptability of the
dossier remain in effect, without exception, including but not limited
to the submission of updated stability data during the assessment
period as it becomes available, and a commitment to provide:
– stability data on three production batches, and
– process validation of three consecutive production batches to be
completed prior to marketing.
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Amman, June 2013
Scope of WHO PQ guidance on Variations
to a Pre-qualified medicinal product
• applies to quality part of product dossiers for an API or an
FPP.
• notification requirements for API-related changes differ
depending on the manner in which API information was
submitted with the original FPP application.
• FPPs that rely upon the APIMF or CEP procedure have
reduced reporting requirements.
• Variations for FPPs prequalified on the basis of SRA
approval should be approved by the same SRA and WHO
PQP notified of the approval of the changes.
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Amman, June 2013
Requalification
Procedure for prequalification of pharmaceutical
products requires holders of WHO-prequalified
products to submit a quality review after five
years from the date of prequalification of the
product, or when requested to do so by PQP
(whichever date is earlier)
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Amman, June 2013
Demonstration of bioequivalence
Bioequivalence study
or
PD studies
Clinical
studies
In vitro
methods
ONLY EXCEPTIONAL!
Jakarta, March 2013
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Comparators for the Prequalification
Programme
• Innovator product with established Q,S, and E sourced from
well regulated market (ICH process countries). Guidance on
selection and the to be provided documents should be
followed.
• The comparator should be selected from the comparator list
(http://apps.who.int/prequal/info_applicants/info_for_applica
nts_BE_comparator.htm)
• Other comparators must be justified. Recommended to
consult WHO at: prequalassessment@who.int
• Remember: Comparator is not always identical with a
comparator required by national regulatory authority!
Jakarta, March 2013
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Tested product
 GMP
 batch size
 pilot batch
 commercial batch
 not smaller than 100 000 units or 10 % of industrial batch
size (whichever is higher)
 difference regarding the content of the investigative
products (T and R) should preferably not be more than
5%
 strength with the largest sensitivity to detect differences
in the two products
Amman, June 2013
Analytical methods
• FDA Guidance for Industry
– Bioanalytical method validation, May 2001
• ICH Guidance for industry
– Validation of analytical methods: definitions and
terminology, June 1995
– Validation of analytical procedures: methodology,
November 1996
• EMA guideline
– Bioanalytical method validation, 2011
Amman, June 2013
Quality of Bioequivalence Studies
Good Clinical Practice (GCP) is an
international ethical and scientific quality
standard for designing, conducting,
recording and reporting trials that involve
the participation of human subjects.
Compliance with this standard provides
public assurance that the rights, safety and
well-being of trials subjects are protected,
consistent with the principles that have their
origin in the Declaration of Helsinki, and
that the clinical trial data are credible.
Amman, June 2013
Frequent GCP non-compliances
• No informed consent, complex language
• Ethics committee not independent
• Dosing procedure is inadequately documented, no drug
accountability
• Certificates of analysis are not consistent with study products
or not sufficiently detailed
• No testing on addictive substances performed
• Withdrawals are improperly documented
• Meals not standardized and not documented
• Storage of blood samples is not monitored
• Method of calculation of PK parameters is not specified
• Insufficient explanation of outliers
• Chromatograms not consistent with data
Amman, June 2013
WHO BCS-based biowaiver
Active substances selected for biowaiving
by WHO
HIV/AIDS:
TB:
•
•
•
•
Lamivudine (BCS 3)
Stavudine (BCS 1)
Zidovudine (BCS 1)
Abacavir sulphate
(BCS 3)
• Emtricitabine (BCS 1)
Amman, June 2013
•
•
•
•
•
Levofloxacin (BCS 1)
Ofloxacin (BCS 1)
Ethambutol ((BCS 3)
Isoniazid (BCS 3)
Pyrazinamide (BCS 3)
International norms, standards and guidelines used in
inspection activities to ensure wide applicability
•
HANDBOOK FOR GOOD CLINICAL RESEARCH PRACTICE (GCP) Guidance for
implementation
http://whqlibdoc.who.int/publications/2005/924159392X_eng.pdf
•
Guidelines for good clinical practice (GCP) for trials on pharmaceutical products.
World Health Organization, 1995 (WHO Technical Report Series, No. 850), Annex
3.
http://apps.who.int/prequal/info_general/documents/TRS850/WHO_TRS_850-Annex3.pdf
•
Additional guidance for organizations performing in vivo bioequivalence studies.
WHO Technical Report Series, No. 937, 2006, Annex 9
http://apps.who.int/prequal/info_general/documents/TRS937/WHO_TRS_937__annex9_eng.pdf
•
Guidelines for the preparation of a contract research organization master file. World
Health Organization, WHO Technical Report Series, No. 957, 2010 Annex 7, Page
271. http://www.who.int/medicines/publications/TRS957_2010.pdf
Amman, June 2013
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Generics approved by SRA
• http://apps.who.int/prequal/info_applicants/Guidelin
es/PQProcGenericSRA_July2011.pdf
• 1. Applicants should submit the following documentation:
– A letter of undertaking (template attached) with a clear statement by the responsible
person that the information submitted is true and correct.
– A QA-certified copies of the Marketing and Manufacturing Authorizations issued by the
relevant SRA.
– An original or certified copy of WHO-type Certificate of a Pharmaceutical Product,
issued by one of the SRAs, together with the
– approved Summary of Product Characteristics (SPC), or an equivalent thereof,
including Patient Information Leaflet (PIL) and Labelling.
– Assessment report(s) issued by the relevant SRA (expected to be replaced by
specifications and control methods).
• 2. Evidence of minimum five (5) years of current and continuous
manufacturing experience and a copy of the last Annual Product Report.
(expected to be deleted).
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Generics approved by SRA
• A sample of the FPP(s) in market packaging and certificate of analysis
should be provided.
• Undertaking:
– authorizes WHO PQP to publish "Main characteristics of the prequalified
medicinal product" on its website;
– will inform WHO prequalification programme with a copy of the regulatory
acceptance letter of any change to the main characteristics of the product
immediately after the variation has been approved by the relevant SRA.
– if the change affects the information in SmPC, PIL and/or container labels
(immediate and outer) in electronic format
– c) has nominated a responsible employee for communication with WHO on
any issues, including quality failures
Amman, June 2013
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GMP Inspections by WHO
• Inspections are conducted before prequalification,
on an on-going basis and in special circumstances
• Initial inspection target: <180days from dossier
receipt
• Re-inspection frequency determined on a risk basis
• Inspections are normally announced 1-2 months in
advance
• Inspections conducted by a Stringent Regulatory
Authority are taken into account when planning
inspections
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GMP inspections by WHO
• Inspections are conducted by a team
– A WHO inspector leads the team
– An inspector from another Regulatory Authority
(usually a PIC/S member) assists
– The Regulatory Authority of the country of
manufacture is invited (and encouraged) to
accompany the team
– Inspection report provided within target of 30 days
– Closed out after review of corrective actions
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Origin of Co-Inspectors
• 2011
• 2012
Amman, June 2013
Inspections of FPP manufacturers
• Normally over 4 days
• Covers all aspects of GMP
– Quality management, Quality assurance, Premises, Equipment,
Documentation, Validation, Materials, Personnel
– Utilities (e.g. HVAC, water) . . .
• Also data verification (dossier) including stability data,
validation (process), development batches and bio
batches
• Quality control laboratory – specifications, reference
standards, methods of analysis, validation and
qualification
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All FPP sites: Top 10 observation in 2011 -2012
50
PQR lacking information
47
Inadequate Quality Control
laboratory practice
Inadequate HVAC system
45
41
40
Inadequate purified water
system
Inadequate handling of
deviations
Inadequate premises
35
30
25
24
24
23
20
20
15
20
18
18
18
Inadequate quality risk
management
Cleaning validation
10
5
0
3
Risk of contamination and cross
contamination
Inadequate cleaning validation
API Sites: Top 10 observation categories
50
45
Inadequate quality control
laboratory controls
46
42
Inadequate materials
management
40
35
30
25
27 26
Inadequate buildings and
facilities
24
22 21
20
20
13 12
15
10
Inadequate
documentation/documentati
on control
Inadequate handling of
process equipment
Inadequate Validation
5
0
Amman, June 2013
Classification of observations
Critical Observation An observation that has produced, or may result in a
significant risk of producing, an API that, when used in a finished product, is harmful
to the user.
Major Observation A non-critical observation that has produced or may produce a
product which does not comply with its prequalification application (including
variations); 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 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.
Other Observation An observation that cannot be classified as either critical or
major, but indicates a departure from good manufacturing practice.
Jakarta, March 2013
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37
Analysis of inspection of observations
Total number of Observations
Average number of observations
3000
20.0
18.0
2500
16.0
14.0
2000
12.0
1500
10.0
8.0
1000
6.0
4.0
500
2.0
0
Total Observations
Critical Observations
Major Observations
0.0
All
FPP
API
2885
82
727
1440
15
246
1218
34
304
CR
O
329
23
93
QC
L
198
10
43
Average all
observations
Average critical
Average Major
All
FPP
API
CRO
QCL
15.6
19.2
18.7
10.6
14.1
0.4
3.9
0.2
3.8
0.5
4.7
0.7
3.0
0.7
3.1
Ask if you are not sure, PQP contacts are:
• Dossiers and assessment: prequalassessment@who.int
• Inspections: prequalinspection@who.int
• Quality control: prequallaboratories@who.int
• General: prequal@who.int
• Tele/videoconferences are possible
Thank you for the attention
smidm@who.int
Amman, June 2013
39